Pituitary Tumors

As many as 85% of the space-occupying lesions in the hypothalamic–pituitary axis may be associated with elevation of the serum prolactin. Twenty percent of women with secondary amenorrhea may have hyperprolactinemia. Prolactin is so important that reproductive disorders can be classified into normal and hyperprolactinemic states, as shown in Table 144.1. The serum prolactin value determined at the time of the initial evaluation will often predict whether the etiology of the prolactin abnormality is functional or tumorous. Serum prolactin values greater than 200 ng/ml are almost always associated with a prolactin-secreting pituitary tumor. In general, the higher the serum prolactin, the greater the size of the tumor. The major diagnostic problem is the patient with a serum prolactin between 30 and 200 ng/ml. This may be caused by functional factors or a microadenoma. At present there are no biochemical provocative or suppressive tests that will consistently differentiate functional from tumorous hyperprolactinemia. Imaging the hypothalamus and pituitary by coronal CT after injection of a contrast agent is the most commonly used way of differentiating between these diagnostic possibilities. Recently, radiologists have noted a high prevalence of false positive diagnosis of microadenoma by CT, especially if the suspected tumor is smaller than 6 mm. Magnetic resonance imaging (MRI) is a superior imaging technique for the diagnosis of pituitary microadenoma.

Table 144.1

Abbreviated Tests of Pituitary Reproductive Function.

Bromocriptine

The decline in serum prolactin in response to treatment with the dopaminergic agonist bromocriptine is usually dramatic in both functional or tumorous hyperprolactinemia. Restoration of ovulation indicated by a return of cyclic menses in women, or normalization of sexual function in men, occurs concomitantly with the drop in prolactin. If sexual symptoms do not improve, serial serum prolactin determinations and repeat imaging procedures are necessary to check for tumor growth.

Hypopituitarism

Prolactin deficiency may occur with destructive lesions of the pituitary such as vascular insults, inflammatory diseases, or nonprolactin-secreting macroadenomas. These conditions also compromise the release of other pituitary hormones, causing symptoms and signs of panhypopituitarism such as loss of sexual function and secondary sexual characteristics, fatigue, pallor, and disordered water metabolism. Pituitary injury occurring in the postpartum period often presents as a failure of lactation due to prolactin deficiency. The presence and severity of the pituitary injury can be assessed by measuring the serum prolactin and TSH response to TRH. Failure to stimulate both hormones is consistent with panhypopituitarism (Table 144.2). The details and limitation of the TRH test for the diagnosis of hypopituitarism are discussed with TSH.

Table 144.2

Abbreviated Tests of Pituitary or Target Gland Dysfunction.

Primary Ovarian Failure

Elevated FSH and LH levels are diagnostic of primary ovarian failure. Clinical signs include amenorrhea, vasomotor phenomena such as hot flashes and cold sweats, and loss of breast mass. The causes of primary ovarian failure are chromosomal defects such as Turner's syndrome, ovarian dysgenesis, or autoimmune ovaritis, which is often associated with other endocrine deficiencies. Anovulatory menses or breakthrough bleeding in women, associated with elevated FSH and LH, is usually a perimenopausal phenomenon, but if the clinical setting is not appropriate, estradiol levels should be obtained. In these instances a low estradiol will confirm ovarian failure or impending menopause.

Steady-State Syndrome

Infertility with amenorrhea or anovulatory menses with hirsutism and other signs of virilization is consistent with steady-state syndrome. The name is derived from the FSH and LH secretory patterns. Classically FSH is low normal and LH is released in a noncyclic or tonic pattern characteristic of its secretion in men. This results in excessive androgen production by ovarian interstitial cells. Serum testosterone is often mildly elevated, varying from 100 to 200 ng/dl. Progressive virilization with elevated testosterone and suppressed LH values is against the diagnosis of steady-state syndrome and indicates the need to search for an autonomous ovarian or adrenal source of androgens.

Functional Disorders

The most common clinical problem of the reproductive axis in women involves the differentiation of amenorrhea caused by functional suppression of FSH and LH versus a destructive process in the pituitary. Measuring FSH and LH as an abbreviated test following GnRH injection does not reliably make this differential diagnosis in all cases. Thus the distinction is made on clinical grounds by correlating changes in serum FSH and LH to serum prolactin (Table 144.1). Functional suppression of FSH and LH in postmenopausal women is unusual, so low values in such patients would be strongly suggestive of pituitary pathology. In contrast, low values in young women without an increase in prolactin usually result from a functional disorder, often suggested by the clinical setting. For example, this is seen in women who are under stress, who induce vomiting, or who place a high priority on body weight (e.g., models, professional dancers, actresses). Women athletes may also experience functional suppression of gonadotropins.

Testicular Failure

Hypogonadism in men is suggested clinically by loss of libido, difficulties with sexual performance, and attenuation of male sexual characteristics. The cause of primary hypogonadism may be chromosomal defects in the testes (such as Klinefelter's syndrome) or acquired causes (such as vascular injury from testicular torsion) or thermal injury (such as undescended testes). A common clinical problem is the evaluation of the male with infertility secondary to hypospermia. Most often, serum FSH/LH are in the normal range with normal testosterone and thus no defect in the hormonal axis is detectable. The most common structural abnormality causing secondary testicular failure is the prolactin-producing tumor discussed above.

Sex Binding Protein Abnormalities

When symptoms of sexual dysfunction in men are associated with low testosterone and a normal FSH and LH, one should consider incidental depression of the sex steroid binding protein before proceeding with a pituitary evaluation for secondary hypogonadism. Testosterone is transported in the serum bound to this protein. Reductions in the binding protein caused by genetic factors, obesity, or thyroid or liver dysfunction will depress the total serum testosterone value. Thus the free or unbound serum testosterone test is necessary to determine if the sex hormone is adequate. The finding of a low total serum testosterone with normal free testosterone would confirm the binding protein abnormality and suggest that sexual symptoms may have a psychogenic cause.

Congenital Defects

Kallman's syndrome is a functional depression of FSH and LH release secondary to hypothalamic defects in GnRH synthesis and release. This syndrome occurs in both sexes and is recognized at puberty because of failure of sexual development associated with midline anomalies causing anosmia or hyposmia, color blindness, or cleft palate. FSH and LH release can be stimulated by GnRH given therapeutically—but formal endocrine testing, rather than an abbreviated test with GnRH, is necessary to confirm this type of hypothalamic hypogonadism. Selected defects may occur at any site in the axis. Isolated impairment of LH secretion may result in failure of Leydig cell function with a consequent failure of sperm maturation. Treatment with the LH-like gonadotropin HCG will restore testosterone production and reverse infertility.

Differential Diagnosis

The assays for HCG and its beta subunit are performed to diagnose pregnancy and the presence of abnormal trophoblastic tissue such as hydatidiform mole and choriocarcinonia in women, as well as various testicular carcinomas in men. Secretion of HCG can cause isosexual precocious puberty in children and gynecomastia in men. In both syndromes, the effect is mediated by sex steroids released by gonadal interstitial cells under HCG stimulation.

The sources of excess HCG in men may be a tumor in testicular tissue. Ultrasound is useful for diagnosis. HCG may be produced ectopically by anaplastic lung cancer, hepatoma, islet cell tumors, and other neoplasms. The presence of HCG in serum in the absence of pregnancy is a tumor marker that may be used to determine the effectiveness of treatment and recurrence during follow-up.

Deficiency

GH and SmC levels are helpful in testing pituitary function and evaluating children with short stature. GH release, like that of pituitary gonadotropins, is readily impaired by disease processes in the sella turcica. This is best demonstrated by provocative endocrine testing with insulin-induced hypoglycemia. The finding of a low fasting serum GH with a reduced SmC also suggests a defect in GH regulation. Children with short stature without apparent systemic or congenital diseases may have hypopituitarism or isolated defects involving GH. As a screening test, these children may be exercised in the fasting state until they become diaphoretic. An acute increase in GH to greater than 10 ng/nl following exercise rules out both disorders and eliminates the necessity for further pituitary testing.

Hypersecretion

The diagnosis of acromegaly is usually obvious by clinical inspection and pituitary imaging. In such cases elevation of GH above 30 ng/ml with increased SmC is diagnostic (Table 144.2). Acromegaly may be associated with marginal elevations of GH that overlap the range for physiologic stress. In these cases the diagnosis of active disease must be confirmed by demonstrating failure of GH to suppress following glucose. This is done by measuring GH during a 2-hour standard glucose tolerance test. When the signs of acromegaly are subtle and the serum GH, SmC, and postglucose GH values are all equivocal, an increase of greater than 5 ng/ml in GH following 500 mcg of TRF is indicative of defective hypothalamic GH regulation consistent with acromegaly.

Elevated Values

In hypothyroidism, serum TSH ranges from 10 to 200 μU/ml depending on the clinical situation. Some of the most severely myxedematous patients will demonstrate a relatively mild elevation, probably because of myxedema of the pituitary. Some patients with subtle symptoms and indolent onset of hypothyroidism such as after radioactive iodide therapy of Graves" disease will have TSH levels greater than 150 μU/ml.

Sick Euthyroid Syndrome

In severely ill but euthyroid patients, thyroxin may be depressed and TSH is normal. This profile is also consistent with secondary hypothyroidism caused by hypopituitarism. Differentiation of the sick euthyroid patient from the one with secondary hypothyroidism is often difficult by thyroid tests. In secondary hypothyroidism, other abnormalities in FSH, LH, prolactin, and ACTH are also present. A TRH test may demonstrate hypopituitarism if serum TSH and prolactin are both determined.

TRH Test for Diagnosis of Hypopituitarism

After blood for TSH and prolactin is drawn, 500 μg of TRH is given intravenously (IV) to the patient maintained in the supine position. Repeat samples are obtained in 30 minutes. In normal persons, prolactin and TSH levels increase twofold or more. A marked elevation of prolactin at baseline would suggest significant pituitary pathology—most likely a macroadenoma, which might compress TSH-producing cells. However, the response of prolactin to TRH does not differentiate functional from tumorous causes of hyperprolactinemia. Low prolactin and TSH at baseline with failure of both hormones to rise indicate panhypopituitarism—often secondary to a vascular etiology. A normal prolactin response without change in TSH is either an equivocal result (indicating the need for more extensive pituitary studies) or is due to hyperthyroidism (see below). TRH testing does not differentiate secondary from tertiary causes of hypothyroidism associated with hypothalamic defects. Injection of TRH is occasionally associated with acute increases in blood pressure. Caution is required in patients in the older age groups or those with cardiovascular disease.

Diagnosis of Hyperthyroidism

Most patients with hyperthyroidism will have unequivocal elevation of thyroxin or triiodothyronine. These studies confirm the diagnosis, and no further studies are necessary. When thyroid hormones are borderline or marginally elevated and the clinical picture is suggestive but nondiagnostic, the HS–TSH assay should be done. The TRH test should be reserved for rare clinical circumstances when all other data are ambiguous.

The test is performed as described above. Only serum TSH need be measured. A baseline sample is taken and another sample 20 to 30 minutes after TRH injection. A doubling of the baseline or an increase of 4 μU/ml rules out autonomous thyroid function. No change in TSH levels is consistent with hyperthyroidism. False positive results may occur in nonhyperthyroid older patients who often fail to have a TSH response. In older patients the diagnosis of hyperthyroidism may require measurement of thyroidal radioiodide uptake, free thyroxine, and thyroid stimulating hormone.

Addison's Disease

This diagnosis is suspected clinically in a patient with fatigue, nonspecific abdominal complaints, hyperpigmentation, and orthostatic hypotension. A markedly elevated plasma ACTH associated with a profoundly low serum cortisol confirms the diagnosis of Addison's disease. If symptoms and signs are subtle, plasma ACTH values may not be high enough to confirm the diagnosis. Thus, when the diagnosis is not clinically obvious, a cortrosyn test of adrenal function is the appropriate screening study for Addison's disease.

Ectopic Production of ACTH

The patient with this diagnosis presents with generalized weakness associated with weight loss, nocturia, hypertension, myopathy, peripheral edema, and evidence of neoplasia. Profound hypokalemia with metabolic alkalosis is indicative of the highest cortisol values seen clinically. Plasma ACTH values in the nanogram range confirm the diagnosis and may serve as a marker of the neoplasm. The syndrome is most often caused by undifferentiated carcinomas of the lung, both large (anaplastic) cell and small (oat) cell, which are synthesizing large ACTH precursor molecules of variable biological activity. ACTH-secreting tumors have also been found in the pancreas as islet cell tumors and in the thymus. Carcinoid tumors both malignant and benign may secrete ACTH, but these tumors have a long indolent course that cause the classical stigmata of Cushing's syndrome (obesity, stria, osteopenia). Thus carcinoid tumors mimic Cushing's disease clinically; ACTH levels in both conditions may be at the nonspecific high normal range of 150 to 200 pg/ml. The differential diagnosis of carcinoid-causing Cushing's syndrome requires more extensive dexamethasone testing and imaging studies.

Differential Diagnosis of Cushing's Syndrome

When the diagnosis of Cushing's syndrome is considered after demonstrating lack of cortisol suppression by physiologic dexamethasone (overnight dexamethasone test, see below), the plasma ACTH level will differentiate a pituitary or ectopic tumor source of ACTH from autonomous cortisol-producing adrenal tumor. In the latter, ACTH should be suppressed to less than 20 pg/ml. The presence of an adrenal adenoma or carcinoma should be readily confirmed by cross-sectional imaging.

A common clinical problem is the exclusion of Cushing's syndrome in a woman with obesity, hypertension, hirsutism, diabetes, and menstrual abnormalities. Though these are all characteristics of excess glucocorticoids, these signs are nonspecific and are typically a manifestation of exogenous obesity. In this situation ACTH and cortisol profiles are not helpful, since high values associated with circadian rhythm and stress overlap the values of Cushing's disease. The overnight dexamethasone suppression test may readily make the differentiation. However, 15% of patients without Cushing's syndrome will fail to suppress. The 24-hour urine free cortisol determination is not confounded by obesity, making it a useful second screening study.

Suppressed Pituitary–Adrenal Axis

Another common question of pituitary–adrenal function is the status of the axis after exposure to pharmacologic dosage of glucocorticoids or following surgical removal of an adrenal tumor. Usually the axis requires 6 to 9 months after withdrawal of long-term steroids to recover ACTH and cortisol responsiveness to stress. Some patients continue to have constitutional complaints suggestive of adrenal insufficiency for 1 to 2 years. ACTH levels are of no value in assessing adrenal recovery, since the pituitary recovers before the adrenal. Finding a cortisol level above 18 μg/dl would essentially exclude a prolonged adrenal suppression syndrome. If the value is lower, cosyntropin or metyrapone tests would be necessary to determine the responsiveness of the axis to stress.

Overnight Dexamethasone Suppression Test

This test measures the suppressibility of ACTH produced by the hypothalamic–pituitary axis following a physiologic dosage of dexamethasone. A normal suppression indicated by a reduced cortisol rules out Cushing's syndrome. A failure of cortisol to suppress after dexamethasone requires measuring the 24-hour urinary free cortisol and/or a 48-hour dexamethasone suppression test to rule out a false positive result.

In normal individuals 1 mg of dexamethasone taken at 11:00 p.m. suppresses early morning elevation of ACTH and results in an 8:00 a.m. serum cortisol value of less than 5 μg/dl. Patients with Cushing's syndrome show no response to dexamethasone and maintain their serum cortisol level greater than 20 μg/dl throughout the day. This loss of suppressibility and the loss of normal diurnal circadian rhythm of ACTH and cortisol secretion are pathognomonic of Cushing's syndrome.

Cortrosyn^® (Cosyntropin) Stimulation Test

This test measures the increment in serum cortisol following an injection of Cortrosyn (cosyntropin). The test is extremely useful in screening for Addison's disease and secondary (pituitary dependent) adrenal insufficiency. A normal response definitely rules out Addison's disease—but an abnormal response requires further testing before the diagnosis of adrenal insufficiency can be made with certainty. Cortrosyn, 250 μg given IV or IM, normally increases baseline cortisol by at least 7 μg/dl to a value greater than 18 μg/dl. This response is observed in 30 minutes after IV or in 60 to 90 minutes after IM injection.

If both the 7 μg/dl increment in cortisol and the stimulated value of 18 μg/dl are attained, the adrenal gland is presumed to be under adequate stimulation by endogenous ACTH. Therefore these values not only rule out Addison's disease but nearly always exclude the possibility of secondary adrenal insufficiency.

The Cortrosyn test may be used under emergency conditions when the diagnosis of acute adrenal insufficiency or adrenal crisis is suspected on clinical grounds. In this setting (usually associated with the marked stress of a life-threatening infection or a bleeding diathesis) treatment could be instituted before cortisol values are known. Cortrosyn can be given IV concomitantly with dexamethasone, glucose, and saline, after a baseline blood for serum cortisol is drawn. Dexamethasone will not inhibit the cortrosyn effect. Blood for serum cortisol is again taken in 30 minutes, after which time the steroid infusion may be changed to high dosage hydrocortisone to provide an additional mineralocorticoid effect. The same criteria are used to interpret results. With normal adrenal function, however, the serum cortisol is directly proportional to the severity of the stress. A baseline value less than 18 μg/dl that fails to stimulate confirms the diagnosis of adrenal crisis.

The Cortrosyn test may also be used as an aid in the differential diagnosis of Cushing's syndrome. If Cortrosyn is given to a patient with Cushing's disease, the baseline cortisol will be high and an exaggerated stimulatory response will occur indicative of adrenal hyperplasia (e.g., 25 μg/dl baseline to 75 μg/dl). In adrenal adenoma, the baseline will be elevated, but often no response will occur because of autonomous tumor function. Remarkable elevations of serum cortisol, such as baseline values of 60 to 80 μg/dl, are suggestive of adrenal carcinoma or ectopic production of ACTH. In neither case does cortrosyn produce a further stimulation. The adrenal carcinoma, even more than the adenoma, is likely to be autonomous. In the paraneoplastic syndrome, the adrenal gland is already under maximal stimulation by extraordinarily high concentrations of ectopic ACTH.

Overnight Metyrapone Challenge Test

This test measures the hypothalamic–pituitary feedback response to an acute inhibition of cortisol synthesis. The increase in 11-deoxycortisol following metyrapone also indicates normal adrenal gland function. Thus the metyrapone test assesses all levels of adrenal gland regulation. A normal response definitively rules out both Addison's disease and secondary adrenal insufficiency. A subnormal response requires that each level of the axis be tested, starting with the adrenal response to cortrosyn.

In the normal individual 30 mg/kg of metyrapone given at bedtime is associated with an acute increase in ACTH that elevates the 0800 h 11-deoxycortisol to greater than 10 μg/dl. This value is tenfold higher than the normal baseline of less than I μg/dl (30 nmol/L) (which need not be measured). The metyrapone test should be used cautiously, if at all, in patients suspected of having Addison's disease. A metyrapone-induced reduction in cortisol synthesis in an Addisonian may produce acute adrenal insufficiency. Metyrapone is also contraindicated if a patient is in acute distress, under which circumstances the cortrosyn test with dexamethasone is indicated. The metyrapone test, like the Cortrosyn test, may be done in patients with Cushing's syndrome. The 11-deoxycortisol response for the various causes of Cushing's disease is compared to the cortrosyn responses in Table 144.3.