Articles on Medical Diseases and Conditions

Tag: TRH

  • Laboratory Tests in Psychiatry

    Until recently, the laboratory had relatively little to offer in psychiatry. Laboratory tests were used mainly to diagnose or exclude organic illness. For example, in one study about 5% of patients with dementia had organic diseases such as hyponatremia, hypothyroidism, hypoglycemia, and hypercalcemia; about 4% were caused by alcohol; and about 10% were due to toxic effects of drugs. A few psychiatric drug blood level assays were available, of which lithium was the most important. In the 1970s, important work was done suggesting that the neuroendocrine system is involved in some way with certain major psychiatric illnesses. Thus far, melancholia (endogenous psychiatric depression or primary depression) is the illness in which neuroendocrine abnormality has been most extensively documented. It was found that many such patients had abnormal cortisol blood levels that were very similar to those seen in Cushing’s syndrome (as described in the chapter on adrenal function) without having the typical signs and symptoms of Cushing’s syndrome. There often was blunting or abolition of normal cortisol circadian rhythm, elevated urine free cortisol excretion levels, and resistance to normally expected suppression of cortisol blood levels after a low dose of dexamethasone.

    Because of these observations, the low-dose overnight dexamethasone test, used to screen for Cushing’s syndrome, has been modified to screen for melancholia. One milligram of oral dexamethasone is given at 11 P.M., and blood is drawn for cortisol assay on the following day at 4 P.M. and 11 P.M. Normally, serum cortisol levels should be suppressed to less than 5 µg/100 ml (138 nmol/L) in both specimens. An abnormal result consists of failure to suppress in at least one of the two specimens (about 20% of melancholia patients demonstrate normal suppression in the 4 P.M. specimen but no suppression in the 11 P.M. specimen, and about the same number of patients fail to suppress in the 4 P.M. specimen but have normal suppression in the 11 P.M. sample). The psychiatric dexamethasone test is different from the dexamethasone test for Cushing’s syndrome, because in the Cushing protocol a single specimen is drawn at 8 A.M. in the morning after dexamethasone administration.

    The Cushing’s disease protocol is reported to detect only about 25% of patients with melancholia, in contrast to the modified two-specimen psychiatric protocol, which is reported to detect up to 58%. Various investigators using various doses of dexamethasone and collection times have reported a detection rate of about 45% (literature range, 24%-100%). False positive rates using the two-specimen protocol are reported to be less than 5%. Since some patients with Cushing’s syndrome may exhibit symptoms of psychiatric depression, differentiation of melancholia from Cushing’s syndrome becomes necessary if test results show nonsuppression of serum cortisol. The patient is given appropriate antidepressant therapy and the test is repeated. If the test result becomes normal, Cushing’s syndrome is virtually excluded.

    Various conditions not associated with either Cushing’s syndrome or melancholia can affect cortisol secretion patterns. Conditions that must be excluded to obtain a reliable result include severe major organic illness of any type, recent electroshock therapy, trauma, severe weight loss, malnutrition, alcoholic withdrawal, pregnancy, Addison’s disease, and pituitary deficiency. Certain medications such as phenobarbital, phenytoin (Dilantin), steroid therapy, or estrogens may produce falsely abnormal results.

    At present, there is considerable controversy regarding the usefulness of the modified low-dose dexamethasone test for melancholia, since the test has a sensitivity no greater than 50% and significant potential for false positive results.

    Besides the overnight modified low-dose dexamethasone test, the thyrotropin-releasing hormone (TRH) test has been reported to be abnormal in about 60% of patients with primary (unipolar) depression. Abnormality consists of a blunted (decreased) thyrotropin-stimulating hormone response to administration of TRH, similar to the result obtained in hyperthyroidism or hypopituitarism. However, occasionally patients with melancholia have hypothyroidism, which produces an exaggerated response in the TRH test rather than a blunted (decreased) response.

    One investigator found that about 30% of patients with melancholia had abnormal results on both the TRH and the modified dexamethasone tests. About 30% of the patients had abnormal TRH results but normal dexamethasone responses, and about 20% had abnormal dexamethasone responses but normal TRH responses. The TRH test has not been investigated as extensively as the modified dexamethasone test.

    A more controversial area is measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with depression. One theory links depression to a functional deficiency of norepinephrine in the central nervous system (CNS). 3-Methoxy-4-hydroxyphenylglycol is a major metabolite of norepinephrine. It is thought that a significant part of urinary MHPG is derived from CNS sources (20%-63% in different studies). Some studies indicated that depressed patients had lower urinary (24-hour) excretion of MHPG than other patients, and that patients in the manic-phase of bipolar (manic-depressive) illness had increased MHPG levels. There was also some evidence that depressed patients with subnormal urinary MHPG levels responded better to tricyclic antidepressants such as imipramine than did patients with normal urine MHPG levels. However, these findings have been somewhat controversial and have not been universally accepted.

  • Prolactin Secretion Abnormalities

    Prolactin is another peptide pituitary hormone. It stimulates lactation (galactorrhea) in females, but its function in males is less certain. The major regulatory mechanism for prolactin secretion is an inhibitory effect exerted by the hypothalamus, with one known pathway being under control of dopamine. There is also a hypothalamic stimulating effect, although a specific prolactin-stimulating hormone has not yet been isolated. TRH stimulates release of prolactin from the pituitary as well as release of TSH. Dopamine antagonists such as chlorpromazine or reserpine block the hypothalamic inhibition pathway, leading to increased prolactin secretion. Serum prolactin is measured by immunoassay. Prolactin secretion in adults has a diurnal pattern much like that of GH, with highest levels during sleep.

    Some Conditions Associated With Generalized Retardation or Acceleration of Bone Maturation Compared to Chronologic Age (as Seen on Hand-Wrist X-ray Films
    Bone age retarded
    Hypopituitarism with GH deficiency
    Constitutional growth delay
    Gonadal dysgenesis (Turner’s syndrome)
    Primary Hypothyroidism (20%-30% of patients)
    Cushing’s syndrome
    Severe chronic disease (renal, inflammatory gastrointestinal [GI] disease, malnutrition, chronic
    anemia, cyanotic congenital heart disease)
    Poorly controlled severe type I diabetes mellitus
    Bone age accelerated
    Excess androgens (adrenogenital syndrome; tumor; iatrogenic)
    Excess estrogens (tumor; iatrogenic)
    Albright’s syndrome (polyostotic fibrous dysplasia)
    Hyperthyroidism

    Prolactin assay

    Prolactin-secreting pituitary tumors. Prolactin assay has aroused interest for two reasons. First, about 65% of symptomatic pituitary ad enomas (literature range, 25%-95%), including both microadenomas (<1 cm) and adenomas, produce elevated serum levels of prolactin. The pituitary cell type most often associated with hyperprolactinemia is the acidophil cell adenoma, but chromophobe adenomas (which are by far the most frequent adenoma type) are also involved. In addition, about 20%-30% of women with postpubertal (secondary) amenorrhea (literature range, 15%-50%) have been found to have elevated serum prolactin levels. The incidence of pituitary tumors in such persons is 35%-45%. Many patients have been cured when pituitary adenomas were destroyed or when drug therapy directed against prolactin secretion was given. Hyperprolactinemia has also been reported to be an occasional cause of male infertility.

    Some reports indicate that extension of a pituitary adenoma outside the confines of the sella turcica can be detected by assay of cerebrospinal fluid (CSF) prolactin. Prolactin in CSF rises in proportion to blood prolactin levels but is disproportionately elevated when tumor extension from the sella takes place. A CSF/plasma prolactin ratio of 0.2 or more suggests suprasellar extension of a pituitary tumor. Simultaneously obtained CSF and venous blood specimens are required.

    Not all pituitary tumors secrete prolactin. Autopsy studies have demonstrated nonsymptomatic pituitary adenomas in 2.7%-27% of patients. Theoretically, nonfunctional tumors should have normal serum prolactin levels. Reports indicate, however, that some tumors that do not secrete prolactin may be associated with elevated serum prolactin levels, although the values are usually not as high as levels found with prolactin-secreting tumors.

    Prolactin assay drawbacks. Elevated serum prolactin levels may be associated with conditions other than pituitary tumors, idiopathic pituitary hyperprolactinemia, or hypothalamic dysfunction. Some of these conditions are listed in the box. Especially noteworthy are the empty sella syndrome, stress, and medication. The empty sella syndrome is associated with an enlarged sella turcica on x-ray film. Serum prolactin is elevated in some of these patients, although the elevation is most often not great; and the combination of an enlarged sella plus elevated serum prolactin level could easily lead to a false diagnosis of pituitary tumor. Stress is important since many conditions place the patient under stress. In particular, the stress of venipuncture may itself induce some elevation in serum prolactin levels, so some investigators place an indwelling heparin lock venous catheter and wait as long as 2 hours with the patient resting before the sample is drawn. Estrogens and other medications may contribute to diagnostic problems. In general, very high prolactin levels are more likely to be due to pituitary adenoma than to other causes, but there is a great deal of overlap in the low- and medium-range elevations, and only a minority of pituitary adenomas display marked prolactin elevation. Statistics depend on the diagnostic cutoff level being used. The level of 100 ng/ml (100 µg/L) is most frequently quoted; the majority (45%-81%) of pituitary adenomas are above this level, but only 25%-57% of patients with prolactin levels above 100 ng/ml are reported to have a pituitary adenoma. A value of 300 ng/ml gives clear-cut separation but includes only about one third of the adenomas (literature range, 12%-38%).

    Conditions Associated With Increased Serum Prolactin (% With Elevation Varies)
    Sleep
    Stress (including exercise, trauma, illness)
    Nursing infant
    Pregnancy and estrogens
    Pituitary adenoma
    Hypothalamic space-occupying, granulomatous, or destructive diseases
    Hypothyroidism
    Chronic renal failure
    Hypoglycemia
    Certain medications
    Postpartum amenorrhea syndrome
    Postpill amenorrhea-galactorrhea syndrome
    Empty sella syndrome
    Addison’s disease (Nelson’s syndrome)
    Polycystic ovary (PCO) disease
    Ectopic prolactin secretion (nonpituitary neo-plasms)

    Prolactin stimulation and suppression tests Several stimulation and suppression tests have been used in attempts to differentiate pituitary adenoma from other causes of hyperprolactinemia. For example, several investigators have reported that pituitary adenomas display a normal response to levodopa but a blunted response to chlorpromazine. Normally there is a considerable elevation of prolactin level (at least twofold) after TRH or chlorpromazine administration and a decrease of the prolactin level after levodopa administration. In pituitary insufficiency there typically is failure to respond to TRH, chlorpromazine, or levodopa. In hypothalamic dysfunction there typically is normal response to TRH (which directly stimulates the pituitary), little, if any, response to chlorpromazine, and blunted response to levodopa. Pituitary adenomas are supposed to give a blunted response to TRH and chlorpromazine but a normal decrease with levodopa. Unfortunately, there are sufficient inconsistent results or overlap in adenoma and nonadenoma response that most investigators believe none of these tests is sufficiently reliable. There have also been some conflicting results in differentiating hypothalamic from pituitary disease. Diseases such as hypothyroidism and other factors that affect pituitary function or prolactin secretion may affect the results of these tests.

  • Thyroid Function Tests: Thyrotropin-releasing hormone (TRH) test

    Synthetic TRH (Thypinone) is now available. Intravenous bolus administration of TRH normally results in a marked rise in serum TSH levels by 30 minutes after the dose. Serum prolactin levels also increase. There is some disagreement as to how much TRH to administer, with doses reported in the literature ranging from 100-500 µg. Early studies reported that at least 400 µg was needed to obtain full TRH effect. Interpretation depends on whether the patient has evidence of hyperthyroidism or hypothyroidism. One problem, however, is disagreement in the literature concerning how much TSH increase over baseline is considered “exaggerated.” The normal limit of increase over baseline varies in the literature from 20-40 µU/ml, so that 25 µU/ml seems to be a reasonable compromise. Reactions to the TRH injection are uncommon, but can occur, and the patients should be closely monitored during the procedure. In general, the smaller the dose, the lower the incidence of reactions. Therefore, many laboratories and investigators use a 200-µg dose; and a few, even a 100-µg dose. However, I have not seen any reports that compared sensitivity of these doses to the gold standard of the 400- or 500-µg dose. Even if such a report appears, it would take several studies including a very substantial number of patients with hypothyroidism and hyperthyroidism to verify satisfactory performance.

    Drawbacks. (1) There is conflicting evidence in the literature regarding the effects of severe non thyroid illness on TRH test results. At least one report indicates that a blunted response may occur in some apparently euthyroid patients with depressed T4 levels associated with severe non thyroid illness and also in some patients with hypothyroidism who also had severe non thyroid illness. This would complicate the diagnosis of hypothyroidism in some cases as well as the differential diagnosis of primary versus secondary etiology. (2) Several reports suggest that TSH response to TRH may be less in elderly persons. (3) In addition, certain conditions such as psychiatric unipolar depression, fasting more than 48 hours duration, and therapy with aspirin, levodopa, or adrenocorticosteroids depress TSH response to TRH. (4) Patients should discontinue desiccated thyroid or T4 therapy for 3-4 weeks (literature range, 2-5 weeks) before a TRH test. (5) Another (although not major) drawback is the $30-$40 cost for TRH and the need for two or three TSH assay specimens.

    Thyrotropin-releasing hormone results in hyperthyroidism. In hyperthyroidism, pituitary TSH production is suppressed by direct effect of excess circulating T4/T3 on the pituitary, and TSH assay after TRH fails to demonstrate a significant degree of TSH increase from pretest baseline values (positive test result). Unfortunately, about 5% false positive results (failure to elevate serum TSH levels after TRH) have been reported in persons without demonstrable hyperthyroidism. A flat or blunted TSH response to TRH has also been reported in patients with autonomous thyroid nodules but no clinical evidence of hyperthyroidism, in a considerable number of patients after adequate treatment of Graves’ disease, and in some patients with multinodular goiter. Certain other conditions (discussed later) may also affect results. A flat TRH test result is therefore considered very suggestive but not conclusive evidence of thyrotoxicosis. A normal result (normal degree of TSH elevation after TRH) is considered very reliable in excluding thyrotoxicosis. For this reason the TRH test is currently considered the most reliable confirmatory procedure for hyperthyroidism and is the standard against which all other tests are compared for accuracy.

    Thyrotropin-releasing hormone results in hypothyroidism. In primary hypothyroidism the TRH test usually demonstrates an exaggerated TSH response. This may render the test useful in the occasional patient with both equivocal symptoms and equivocal serum TSH values. Theoretically, the TRH test should be able to differentiate between hypothyroidism from inability of the pituitary to secrete TSH due to pituitary disease (secondary hypothyroidism) and inability of the hypothalamus to secrete TRH (tertiary hypothyroidism). In pituitary disease, the serum TSH level should not rise significantly after TRH administration, whereas in hypothalamic disease there characteristically is a TSH response that is normal in degree but that is delayed for approximately 30 minutes. Unfortunately, a substantial number of patients with pituitary lesions demonstrate relatively normal or delayed TRH test response. Therefore, absent or markedly blunted response is strongly suggestive of primary pituitary disease, but response to TRH is not diagnostic of hypothalamic disease.

    Thyrotropin-releasing hormone results in psychiatric patients. There have been reports that the TRH test is useful in differentiating unipolar (primary depression only) from bipolar (manic-depressive) psychiatric illness and from secondary types of depression. In unipolar depression, TRH-induced TSH response is said to be blunted in up to two thirds of patients, whereas most patients with other categories of depression have normal TSH response. Occasional patients with symptoms of depression may actually have thyrotoxicosis (“apathetic hyperthyroidism”) and some may have hypothyroidism.