Pituitary disorders-Diabetes Insipidus and Cushing's Syndrome
Diabetes insipidus is a clinical disorder characterized by the excretion of large quantities of diluted urine and caused either by failure of ADH release (hypothalamic diabetes insipidus) or by lack of response of the tubules to normal quantities of circulating ADH (nephrogenic diabetes insipidus).
Criteria for the diagnosis of hypothalamic diabetes insipidus include:
(1) insufficient ADH release despite serum hyperosmolality and
(2) an increase in urine osmolality in response to exogenous ADH.
Causes of hypothalamic diabetes insipidus:
1. Surgery: section of the supraopticohypophyseal tract above the median em inence. Disruption of the tract at the level of the pituitary stalk leads 10 transient diabetes insipidus which disappears in 1 to 2 weeks.
2. Trauma to the hypothalamus or the median eminence. Most commonly, dia betes insipidus resulting from trauma is transient, but it may be permanent.
3. Tumors that destroy the site of production and release of ADH are either primary, such as craniopharyngioma or metastatic, the most common being carcinoma of the breast.
4. Infiltration of the hypothalamus by leukemic cells, granuloma (sarcoidosis, tuberculosis), histiocytes (Hand-Schuller-Christian disease), or infections. All these are rare causes of diabetes insipidus.
Diabetes insipidus can be masked by a concomitant deficiency of the anterior pituitary hormones. In the absence of cortisol, there may be enhanced release of ADH as well as increased sensitivity of the tubules to ADH, both of which lead to an impairment in water excretion. In addition, growth hormone, cortisol, and thyroxin increase the glomerular filtration rate. In patients with panhypopituitarisrn, diabetes insipidus becomes clinically manifest when cortisol and thyroxin replacement begin.
Causes of nephrogenic diabetes insipidus:
1. Hereditary factors: X-linked transmission with predominance in males.
2. Acquired factors:
Dietary factors: With marked restrictions of protein intake, there is decreased availability of urea, which normally accounts for 50 percent of medullary interstitial hypertonicity during antidiuresis. Dietary sodium deficiency causes a concentrating defect by enhancing proximal salt reabsorption, thereby limiting sodium delivery to the loop of Henle.
Electrolyte disorders. Patients with chronic hypokalemia or chronic hypercalcemia may develop both polyuria and the inability to concentrate the urine. In both conditions, medullary tonicity is diminished but the identity of the primary pathophysiologic mechanism is unclear. The urine of patients with hypokalemia and polyuria is usually isotonic (osmolalily 300), in contrast to the hypotonic urine found in patients with diabetes insipidus.
Drugs: Lithium carbonate, demeclocycline. methoxyflurane. and amphotericin B interfere with the action of ADH on the tubules. Patients on these drugs can develop marked hypotonic polyuria. The presence of mas sive polyuria a few days after anesthesia with methoxyflurane may lead to severe dehydration if it is not recognized and treated promptly. Massive polyuria is usually reversible.
Renal disease Chronic renal disease of different types may produce isotonic mild polyuria, which is resistant to the action of ADH
The hallmark of diabetes insipidus is the excretion of large quantities of urine (usually 5 to 10 L/day, but the amount can be more). In mild forms of diabetes insipidus, polyuria may be minimal with urine volumes of 2 to 4 L/day.
Polydipsia (ingesting of large amounts of mostly cold water).
Insomnia, decreasing of appetite, dryness of skin and mucous membranes, pharyngitis, gastritis, constipation are common in patients.
In situations in which the patient has no access to water, is unconscious, or has an abnormality of the thirst mechanism, severe dehydration may ensue.
A careful study of the patient's history, a physical examination, and an awareness of previous laboratory abnormalities are required in evaluating patients with polyuria.
Typically, in severe diabetes insipidus the urine has a specific gravity of less than 1,005 and an osmolality of less than 100 mosmol/kg; serum osmolality is increased. Patients with partial diabetes insipidus can concentrate the urine to isotonic or mod erately hypertonic levels. Some patients with diabetes insipidus are able to compensate for the urine loss by ingesting large amounts of fluids so that serum osmolalily, which is usually elevated, may be normal or only slightly increased.
First it is necessary to determine whether one is dealing with diabetes insipidus or other types of polyurea, such as diabetes mellitus, or increased fluid intake. Then a distinction between hypothalamic and nephrogenic diabetes insipidus must be made. The so-called psychogenic polydipsia, a condition which occurs in patients who ingest large quantities of water and other fluids, is the most important these responses to keep in mind.
History: Insidious onset
Physical examination: Normal hydration
- serum osmolality: 270 – 290 (↓ to N)
urine osmolality: < 200 (↓)
Pituitrin administration: Patient feels ill; no change in serum osmolality; increase in urine osmolality
Hypothalamic diabetes insipidus
History: Abrupt onset, brain surgery, tumor present, steroid therapy
Physical examination: Dehydration may be present
serum osmolality: 285 – 320 (N to ↑)
urine osmolality: < 200 (↓)
Pituitrin administration: Patient feels better; decrease in serum osmolality; increase in urine osmolality
Nephrogenic diabetes insipidus
History: Family history, chronic hypokalemia, chronic hypercalcemia, postanesthesia
Physical examination: Dehydration may be present
serum osmolality: 285 – 320 (N to ↑)
urine osmolality: < 200 (↓)
Pituitrin administration: No change in serum or urine osmolality
In an acute situation when a rapid effect is desirable, Pituitrin (aqueous Pitressin) should be given intravenously at a rate of 5 mU/min or subcutaneously in doses of 5 to 20 U every 4 to 6 h. The preparation is available in vials containing 20 U/ml.
In the chronic management of hypothalamic diabetes insipidus, the following drugs have been used:
Adiurecrin powder nasal spray0,03 g 1 – 3 times a day was formerly used (nasal irritation and bronchopulmonary allergic reactions, however, are considerable problems).
Adiuretin in drops 1 – 3 times a day.
Synthetic lysine vasopressin is available as a nasal spray in 5-ml vials containing 50 U/ml of the drug. The usual dose is 1 to 2 sprays three or four times a day.
Pituitrin 0,5 – 1 ml subcutaneous 2 – 3 times a day. The patient's body weight, urine, and serum osmolality should be monitored at weekly or monthly intervals depending upon the clinical response.
The oral hypoglycemic agent chlorpropamide has been effective in control ling polyuria in as many as 80 percent of patients with hypothalamic diabetes insipidus. The major action of the drug is potentiation of the effect of ADH on the tubules. An additional effect on stimulation of ADH release is controversial. It is given in doses similar to those employed in patients with diabetes mellitus—that is, doses of 100 to 500 mg/day. The hypolipidemic agent clofibrate can also stimulate release of ADH and is useful in treatment of some patients with hypothalamic diabetes insipidus. The dose is similar to that used for hyperlipidemia, namely 500 mg four times daily. Chlorpropamide and clofibrate are synergistic. This allows usage of lower doses of each drug in combination.
Because of lack of response of the tubules to ADH, none of the agents listed above is effective in the treatment of nephrogenic diabetes insipidus. This entity is treated by means of dietary protein and sodium restriction in order to minimize the osmotic load that must be excreted and, hence, minimize the urine flow. A thiazide diuretic (50 to 100 mg/day of hydrochlorothiazide) is added to enhance the sodium depletion and impair the ability of the tubules to generate a dilute urine. Inhibitors of prostaglandin synthesis, particularly indomethacin, have effected a decrease in urine flow in a few patients with nephrogenic diabetes insipidus. The E prostaglandins (PGEs) have been shown to inhibit ADH action on the renal tubules by decreasing cAMP formation.
Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids.
The source of cortisol excess can be:
- the adrenal gland (endogenous Cushing's syndrome)
- administration of supraphysiologic doses of a glucocorticoid (exogenous Cushing's syndrome).
Endogenous Cushing's syndrome can be:
1) ACTH – dependent, caused by:
- increased pituitary ACTH secretion (it has frequently been referred to as Cushing’s disease, implying a partucular physiologic abnormality. Patients with Cushing’s disease may have a basophilic adenoma of the pituitary, or a chromophobe adenoma. In some cases, no histologic abnormality is found in the pituitary despite clear evidence of ACTH overproduction. Microadenomas, which are difficult to visualize radiographically, are often the cause);
- nonpituitary ACTH secretion by nonendocrine tumors;
2) Non – ACTH – dependent:
- caused by cortisol secretion by benign or malignant adrenal tumors;
- micronodular or macronodular dysplasia of the adrenal (the condition occurs most commonly in children and young adults).
In pituitary-dependent Cushing's syndrome, increased secretion of endogenous ACTH leads to bilateral adrenal hyperplasia and cortisol overproduction. ACTH secretion continues despite high circulating cortisol, indicating an ab normality in the feedback mechanism. A good number of these patients harbor a pituitary microadenoma which secretes ACTH. Despite normal x-rays of the sella, including tomograms, the neurosurgeon often finds and removes the microadcnoma through the transsphenoidal route. Pituitaty – dependent adrenal hyperplasia accounts for about 60 to 70 percent of endogenous Cushing’s syndrome cases.
A polypeptide that resembles pituitary ACTH in its biologic and immunologic action can be secreted by a great variety of nonendocrine tumors, particularly oat cell carcinoma of the lung, but also by carcinoid bronchial adenomas, and by carcinomas of the prostate, ovaries, and pancreas, as well as others. Nonpituitary ACTH stimulates the adrenals to hypertrophy and to overproduce cortisol. Because the feedback mechanism is intact, pituitary ACTH secretion is suppressed by cortisol.
In patients with adrenal tumors, the excessive production of cortisol suppresses endogenous secretion of ACTH by the pituitary gland. An adrenal tumors is foud in 20 percent of the patients.
Exogenous, or iatrogenic, Cushing’s syndrome is caused by administration of supraphysiologic doses of glucocorticoids. Besides cortisol, other synthetic steroids with glucocorticoid activity have the ability to suppress ACTH secretion by the anterior pituitary. Adrenal atrophy and a decrease in cortisol secretion then result. Although the patients exibits the clinical manifestations of Cushing’s syndrome, adrenal insufficiency may actually occur if the steroid is discontinued abruptly. Because of the widespread use of glucocorticoids, iatrogenic Cushing’s syndrome is the most common type.
· Patients with Cushing syndrome may complain of weight gain, especially in the face, supraclavicular region, upper back, and torso.
· Frequently, patients notice changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning.
· Women may complain of irregular menses and hirsutism.
· Because of progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms.
· Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop.
· New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur.
· Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, polyuria and nocturia, visual problems, or galactorrhea.
· If sufficient mass effect from the tumor is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, and hypogonadism may develop.
· In addition, look for the following:
o Irregular menses or amenorrhea in women and decreased libido, infertility, and impotence in men
o Polyuria or polydipsia from diabetes mellitus or diabetes insipidus
o Impaired wound healing or predisposition to infections from immunosuppression
· When rapid onset of glucocorticoid excess occurs, virilization in women or feminization in men may be seen. This scenario suggests an adrenal carcinoma as the underlying cause of the Cushing syndrome.
o Patients may have increased adipose tissue in the face (moon facies), upper back at the base of the neck (buffalo hump), and above the clavicles (supraclavicular fat pads).
o Central obesity with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.
o Facial plethora may be present, especially over the cheeks.
o Violaceous striae, usually more than 1 cm in width, is observed most commonly over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts .
o Ecchymoses may be present.
o Patients may have telangiectasias and purpura.
o Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident.
o Hirsutism and male pattern balding may be present in women.
o Patients may have increased lanugo facial hair.
o Steroid acne, consisting of papular or pustular lesions over the face, chest, and back, may be present.
o Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over the elbows, around the neck, and under the breasts.
Cardiovascular and renal
o Hypertension may be present.
o Volume expansion may occur, with edema from sodium and water retention.
o Diabetes mellitus may be present.
o Peptic ulceration may occur with or without symptoms.
o Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).
o Hypothyroidism may occur from anterior pituitary tumors, which can interfere with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function.
o Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.
o Other pituitary function may be interrupted. Possibilities include polyuria and nocturia from diabetes insipidus.
o Menstrual irregularities, amenorrhea, and infertility may occur due to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing hormone-releasing hormone (LHRH) pulse generation.
o Low testosterone levels in men may lead to decreased testicular volume from inhibition of LHRH and LH/FSH function.
o Low estrogen levels in women may result from inhibition of LHRH and LH/FSH function.
o Increased synthesis of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides may occur.
o With severe hypercortisolism, hypokalemic metabolic alkalosis may occur.
o Proximal muscle weakness may be evident.
o Osteoporosis may lead to incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip also is possible from glucocorticoid excess.
o Patients may experience emotional liability, fatigue, and depression.
o Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasm.
o Patients with cushingoid features may present to the emergency department in adrenal crisis. Adrenal crisis may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. It also may occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor.
o Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium level or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.
There are two phases of investigation:
- confirmation of the presence or absence of Cushing’s syndrome;
- differential diagnosis of its case.
1. Exogenous Cushing's syndrome should offer no problems in diagnosis since a history of chronic ingestion of suprapliysiologic doses of glucocorlicoids is usually present. However, occasionally patients deny, either deliberately or because of ignorance, that they have been taking the glucocorticoid. In this case, the diagnosis can easily be made by obtaining a blood sample at 8 a.m. for corlisol and ACTH, both of which are characteristically low. Glucocorlicoids suppress ACTH secretion, causing adrenal atrophy and decreased cortisol syn thesis. Current radioimmunoassay techniques for measuring cortisol in plasma are very specific and do not detect appreciable quantities of any of the synthetic glucocorticoids (prednisone, prednisolone, dexamethasone, etc.) that the patient may be taking. Cortisol is unlikely to yield a significant plasma level as well since the steroid has a short half-life; it disappears from blood 4 to 8 h after oral administration. If a plasma ACTH assay is not available, a plasma cortisol determination is sufficient.
2. Single-dose dexamethasone suppression test. This is the pre ferred procedure for screening patients for Cushing's syndrome. The patient ingests 1.0 mg of dexamethasone at bedtime (10 to 12 p.m.), and a blood sam ple for plasma cortisol is obtained the following morning at 8 a.m. In normal patients, the steroid suppresses plasma cortisol below 5 mkg/dl. whereas patients with Cushing's syndrome do not respond and cortisol values of greater than 20 mkg/dl are not unusual. This procedure is simple, convenient, and inexpensive since it does not require hospitalization. It is also very reliable, being accurate in about 95 percent of the patients. A few patients with Cushing's syndrome will respond to 1.0 mg of dexamethasone by suppression of plasma cortisol. If the clinical suspicion is strong, 0.5 mg of dcxamethasone should be given and cortisol determination should again be made. This procedure takes advantage of the fact that while normal subjects suppress equally well with 0.5 and 1.0 mg of dexathasone, the few patients with Cushing's syndrome who suppress with 1.0 mg will not suppress with the lower dosage.
(There are a few clnical situations in which failure of dexamethasone suppression occurs in the absence of Cushing's syndrome. Patients who are under acute stress, particularly those with fever and infections, and depressed individuals may not respond to dexamelhasone. Therapy with estrogen, and occasionally phenobarbital or phenothiazines may alter the response to dexamethasone. To some extent, all these drugs induce the hepatic microsomal enzymes that metabolize dexamethasone, and acceleration of the hepatic metabolism of the steroid results in insufficient plasma levels to yield Anormal response. In these conditions, and in any others in which an abnormality in the metabolism of dexamethasone is suspected, simultaneous quantitation of the plasma dexamethasone concentration offers extremely useful information. Compared with individuals who exhibit no abnormalities in the metabolism of the steroid, individuals with altered hepatic metabolism have a much lower plasma concentration. Estrogens also increase the synthesis of corticusteroid-binding globulin (CBG) by the liver. Since plasma cortisol assays measure both bound and free cortisol, values are high in people on estrogen medication.)
3. 48 – hour low dose dexamethasone test. The results obtained with the single-dose dexamethasone suppression test are comparable to those of the first suppression test developed by Liddle. In this procedure, eight 0.5-mg doses of dexamethasone at 6-h intervals are given orally; 24-h urine samples for 17-hydroxycorticosteroids (17-OHCS) excretion are collected before and during dexamethasone administration. In normal subjects, 17-OHCS values are below 3 mg per 24 h on the second dexamethasone day. Patients with Cushing's syndrome fail to suppress. Not only is this test less convenient and more expensive but it may not be accurate if incomplete urine collections have been obtained.
4. High-dose dexamethasone suppression test. After the oral administration of a single dose of 4.0 mg of dexamethasone between 10 p.m. and midnight, the measured 8 a.m. cortisole the following morning is less than 2 mkg/dl in normal individuals. Patients with pituitary-dependent Cushing’s syndrome demonstrate a plasma cortisol suppression of more than 50 % compared with the baseline values. Those wiyh adrenal tumors or nonpituitary ACTH-secreting tumors do not respond. (This procedure is comparable to the high-dose dexamethasone suppression test developed by Liddle(2.0 mg dexamethasone every 6 h for eight doses with three 24-h urine sample collections for 17-OHCS, one collection before and two during dexamethasone administration). The single-dose 4.0 mg dexamethasone suppression test is simpler, less expensive, and more convinient.
5. RADIOLOGIC DIAGNOSIS Includes X-ray examination for a pituitary tumor, and computed tomography which is the most popular procedure for visualizing the adrenals in patients with Cushing's syndrome.
SURGERY. If clinical manifestations are severe and definitive correction is immediately required, surgery will be the procedure of choice for most patients with Cushing's syndrome. Pituitary surgery is the preferred therapeutic modality for pituilary-dependent Cushing's syndrome. The transsphenoidal route is most commonly utilized, but transfruntal exploration may be required for large tumors or areas where there is extrasellar extension. There is general agreement that once the diagnosis of pituitary-dependent Cushing's syndrome has been established the pituitary should be explored with or without radiologic evidence of a pituitary tumor. Operative morbidity of pituitary surgery is 2 to 5 %. Transphenoidal hypophysectomia is usually successfulwhen carried out by an experienced neurosurgeon. While the majority of patients may be cured by this operation and normal pituitary function will remain intact, recurrences occur and may appear months or years after the operation.
Because a pituitary adenoma is not found in all cases, complete tumor removal is difficult, and recurrences arise following adenomectomy, partial or even total hypophysectomy has been recommended by some clinicians. With partial hypophyseclomy best results are obtained by removing the central mucoid zone which contains most of the ACTH-secreting cells. With total hypophysectomy, the problem of recurrences is resolved but hypopituitarism develops, necessitating permanent hormone-replacement therapy. Therefore, indiscriminate use of total hypophysectomy is not justified. Adrenalectomy is the treatment of choice in patients with adrenal tumors. Since the lesion is unilateral in most cases, only one adrenal is removed. Therapy with glucocorticoids, is required for as long as a year because of chronic suppression of ACTH secretion and atrophy of the contralaleral adrenal.
Bilateral adrenalectomy is utilized to treat patients with primary adrenocortical nodular dysplasia. although a few patients with this condition have responded to hypophyseclomy. Bilateral adrenalectomy is a difficult procedure, with an operative mortality of 4 to 10 percent of patients. There is a recurrence of the disease as the result of hyperplastic remnant in 10 percent of patients, and development of hyperpigmentation with rapid growth of pituitary tumors in 10 to 20 percent.
In patients with nonpituitary tumors that are secreting ACTH, surgery or chemotherapy my be helpful. In patients with severe hypercortisolism that is not controlled by surgery or drugs, bilateral adrenalectomy may be necessary . The changes produced by Cushing's disease are partially reversible (after several months).
PITUITARY IRRADIATION. If clinical manifestations are not severe, pituitary irradiation may be tried initially. Pituitary irradiation is delivered by means of conventional cobalt radiotherapy (4500 rads), by proton-beam irradiation, or by pituitary implantation of radioactive material. Conventional cobalt radiotherapy has a cure rate in 46 to 83 percent of patients. Two-thirds of these patients experience a complete resolution of the signs and symptoms, and the others man ifest some degree of improvement. The response is better in younger individuals. Improvement, however, is slow and may take 6 to 18 months. Radiation effects continue for many years, and the incidence of hypopituitarism is 80 percent at 20 years. If there is no response to pituitary irradiation after 6 month, adrenalectomy is indicated.
DRUGS. Several drugs have been used to treat patients with Cushing's syn drome. Improvement of the clinical manifestations is the result of a decrease in ACTH secretion by the pituitary gland or cortisol secretion by the adrenals.
Cyproheptadine (Periactin) and peritol have been helpful in some patients with pituitary-dependent Cushing's syndrome. Cyproheptadine has peripheral and central antiserotonergic, antihistaminergic, anticholinergic, and antidopaminergic actions, but the inhibition on ACTH secretion is the result off its antiserotonin effect on the hypothalamus. The drug is administered orally at an initial dose of 4 mg three times a day, which is increased to a maximum dose of 4 mg every 4 h over 2 to 4 weeks. Clinical and biochemical responses occur within 2 to 3 months after initiation of therapy, and the return of dexamethasone suppressibility and ACTH and cortisol periodicity are observed by 6 to 12 months. Remission of the disease occurs in 30 to 50 percent of the patients and the longest duration of remission has been 5 years. Although a few cases of permanent remission after discontinuation of the drug have been reported, relapse is the rule. Cyproheptadine can be used in combination with pituitary irradiation. The drug is given for 4 to 6 months to control symptoms before the effects of irradiation are manifested. The two major side effects are hyperphagia (with weight gain) and somnolence. The dopamine agonist bromocrip tine is very useful. The usual dose is 2.5 mg three times a day. But the therapy has to be began from the ¼ of a tablet (2.5 mg) at a bedtime for 3 to 4 days (because of its side effect such as somnelence), then it has to be increased on ¼ of a tablet each 3 days to 7.5 mg.
Several adrenal cortisol inhibitors are available to treat patients with Cushing's syndrome, particularly those with adrenal carcinomas or nonpi-tuitary ACTH-secreting tumors. Mitotane, Lysodren inhibit adrenal growth and interferes with cortisol synthesis by blocking the conversion of cholesterol into pregnenolone. The dose is 1 to 10 g/day. Side effects in clude gastrointestinal complaints, sedation, depression, and adrenal insufficiency. Because of its inhibitory effect on adrenal growth, the drug is preferred for the treatment of adrenal cancer. Aminoglutethimide (Cytadren, Elipten) inhibits the conversion of cholesterol into pregnenolone as well, but it does not have any effect on adrenal growth. The usual dose is 250 to 500 mg four times a day. Side effects are gastrointestinal complaints, drowsiness, skin rash, goiter, and adrenal insufficiency. Metyrapone (Metopirone) inhibits the last step in cortisol synthe sis - the conversion of 11-deoxycortisol into cortisol. Effective doses range from1 to 4 g/day. Better results are obtained when metyrapone is administered every 2 h rather than every 4 h. Hirsutism is the most frequent problem with prolonged metyrapone usage. Trilostane, at a dosage of 0.25 to 1.0 g/day, can reduce corti sol synthesis effectively. A combination of two drugs, such as aminoglutethimide and metyrapone, usually is more effective than any drug alone. Problems shared by all of these drugs are (1) the fact that their effects cease as the result of both a compensatory increase in ACTH secretion and of stimulation of partially suppressed adrenals and (2) the development of adrenal insufficiency. These prob lems can be minimized by administering physiologic amounts of a glucocorticoid, such as 0.5 mg/day of dexamethasone. If hypotension and electrolyte problems develop, 0.1 mg/day of the mineralocorticoid 9-alfa-fluorohydrocortisone (Florinef) should be given.
1. The Merck Manual of Diagnosis and Therapy (fourteenth Edition)/ Robert Berkow and others. – published by Merck Sharp & Dohme Research Laboratories, 1982. – P. 987 – 992, 916 – 921. 990 – 997. 1032 – 1037, 1680 – 1681.
2. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 21 – 33. 34 – 38,52 – 63. 416 - 497.
3. Manual of Endocrinology and Metabolism (Second Edition)/ Norman Lavin. – Little, Brown and Company.- Boston-New York-Toronto-London, 1994. - P. 55 – 56. 179 - 274.
HYPOTHALAMIC SYNDROME OF PUBERTAL PERIOD
1. Obesity is not cushingoid (not central).
2. Striae (pink and not very large).
3. Hypertension (constant or permanent).
4. Glucose intolerance.
1. Diet 8.
2. Parlodel (2.5 – 5 mg for 3 – 6 month).
3. Peritol (4 mg 2 times a day for 1 month).
4. Dehydration therapy (hypothiasid 50 – 100 mg/day MgSO4 25 % solution intramuscular 10 – 15 times).
5. Nonsteroid antiinflammatory drugs (indometacine).
6. Biogenic stimulators (aloe, plasmol).
7. Increasing of microcirculation of the blood in the brain (cavinton, piracetam).
9. Symptomatic therapy (hypotensive therapy).
THE SYNDROME OF INAPPROPRIATE SECRETION OF ADH.
Normally, serum hyperosmolality stimulates and hypoosmolality suppresses ADH release. Increased ADH promotes renal water reabsorption, thereby increasing urine concentration, and decreased ADH results in increased renal water excretion and the production of a dilute urine. Thus. in normal subjects, changes in urine osmolality parallel those in serum osmolality.
The syndrome of inappropriate ADH secretion is characterized by persistent ADH secretion and the excretion of a concentrated urine despite serum hypoosmolality.
The syndrome of inappropriate ADH secretion may develop under a wide variety of clinical settings. It should be understood that inappropriate ADH secretion is associated with numerous conditions: the syndrome occurs following surgery and trauma, with many drugs, in patients with pulmonary and central-nervous-system diseases, and in association with cancer and tuberculosis. (ADH activity has been found in tuberculous lesions, and it is believed that the tuberculomas secrete ADH or an ADH-like substance). Abnormalities which are similar to those observed in the syndrome of inappropriate ADH secretion are seen in certain other endocrine disorders, notably hypothyroidism and pituitary insufficiency, and in patients with congestive heart failure and cirrhosis of the liver.
Hyponatremia and serum hypoosmolality result from excessive water retention, Suppression of aldosterone and inhibition of proximal tubular sodium reabsorption, by volume expansion, lead to increased urinary sodium excretion. However, caution should be exercised in interpreting urinary sodium excretion in patients with [he syndrome of inappropriate ADH secretion. Urine sodium excretion is a reflection of the amount ingested or the amount given parenterally. For this reason, a high urinary sodium excretion is not always seen, and a low urinary sodium does not exclude the diagnosis of the syndrome. The quantities of water retained in patients with the syndrome rarely exceeds 5 L, an amount not sufficient to produce edema. This is compounded by the increased urinary sodium losses. Plasma ADH levels are inappropriately high for the degree of hypoosmolality. Hypouricemia and hypercalciuria also have been reported in patients with this syndrome.
The characteristic features of the syndrome include:
2. Serum hypoosmolality.
3. Continuous urinary sodium excretion despite hyponatremia.
4. Urine osmolalily usually greater than the serum osmolality.
5. Absence of clinical edema.
6. Reversal of the abnormalities following water restriction.
7. Symptoms are usually not present unless the serum sodium concentration falls below 120 meq/L. When this occurs, headaches, anorexia, nausea, and vomiting may ensue. With marked hyponatremia (100 to 110 meq/L), symptoms related to the central nervous system, such as confusion, disorientation, hostility, convulsions, and coma, may predominate. Arrhythmia may also occur.
It is recommended that cardiac, hepatic, adrenal, and renal disease be ruled out before making the diagnosis of inappropriate ADH secretion.
The differential diagnosis of the syndrome of inappropriate ADH secretion is that
of dilutional hyponatremia. The most important diagnosis to be considered because of its therapeu tic implications is that of adrenal insufficiency.
Identification of the underlying cause and measures to correct it are important therapeutic goals.
The mainstay of therapy for the syndrome of inappropriate ADH secretion is water restriction to less than 1 L/day. Weight loss and an increase in serum sodium concentration will occur 3 to 7 days after therapy has been started.
In patients who present with marked hyponatremia (less than 110 meq/L) and neurologic symptoms, particularly seizures, infusion of 250 ml of hypertonic saline (3 % NaCI) over 2 to 4 h is indicated.
Furosemide in combination with intravenous or oral sodium chloride sometimes is effective. The therapeutic goal is to increase free water clearance and at the same time to replace the sodium urinary losses .