Articles on Medical Diseases and Conditions

Tag: Adrenal

  • Female Delayed Puberty and Primary Amenorrhea

    Onset of normal puberty in girls is somewhat variable, with disagreement in the literature concerning at what age to diagnose precocious puberty and at what age to suspect delayed puberty. The most generally agreed-on range of onset for female puberty is between 9 and 16 years. Signs of puberty include breast development, growth of pubic and axillary hair, and estrogen effect as seen in vaginal smears using the Papanicolaou stain. Menstruation also begins; if it does not, the possibility of primary amenorrhea arises. Primary amenorrhea may or may not be accompanied by evidence that suggests onset of puberty, depending on the etiology of the amenorrhea. Some of the causes of primary amenorrhea are listed in the box.

    Some Etiologies of Female Delayed Puberty and Primary Amenorrhea
    Mullerian dysgenesis (Mayer-Rokitansky syndrome): congenital absence of portions of the female genital tract, with absent or hypoplastic vagina. Ovarian function is usually normal. Female genotype and phenotype.
    Male pseudohermaphroditism: genetic male (XY karotype) with female appearance due to deficiency of testosterone effect.
    1. Testicular feminization syndrome: lack of testosterone effect due to defect in tissue testosterone receptors.
    2. Congenital adrenal hyperplasia: defect in testosterone production pathway.
    3. Male gonadal dysgenesis syndromes: defect in testis function.
    a. Swyer syndrome (male pure gonadal dysgenesis): female organs present except for ovaries. Bilateral undifferentiated streak gonads. Presumably testes never functioned and did not prevent mьllerian duct development.
    b. Vanishing testes syndrome (XY gonadal agenesis): phenotype varies from male pseudohermaphrodite to ambiguous genitalia. No testes present. Presumably testes functioned in very early embryologic life, sufficient to prevent mьllerian duct development, and then disappeared.
    c. Congenital anorchia: male phenotype, but no testes. Presumably, testes functioned until male differentiation took place, then disappeared.
    Female sex chromosome abnormalities (Turner’s syndrome—female gonadal dysgenesis— and Turner variants): XO karyotype in 75%-80% of patients, mosaic in others. Female phenotype. Short stature in most, web neck in 40%. Bilateral streak gonads.
    Polycystic (Stein-Leventhal) or nonpolycystic ovaries, not responsive to gonadotropins.
    Deficient gonadotropins due to hypothalamic or pituitary dysfunction.
    Hyperprolactinemia: pituitary overproduction of prolactin alone.
    Effects of severe chronic systemic disease: chronic renal disease, severe chronic GI disease, anorexia nervosa, etc.
    Constitutional (idiopathic) delayed puberty: puberty eventually takes place, so this is a retrospective diagnosis.
    Other: Cushing’s syndrome, hypothyroidism, and isolated GH deficiency can result in delayed puberty.

    Physical examination is very important to detect inguinal hernia or masses that might suggest the testicular feminization type of male pseudohermaphroditism, to document the appearance of the genitalia, to see the pattern of secondary sex characteristics, and to note what evidence of puberty exists and to what extent. Pelvic examination is needed to ascertain if there are anatomical defects preventing menstruation, such as a nonpatent vagina, and to detect ovarian masses.

    Laboratory tests

    Basic laboratory tests begin with chromosome analysis, since a substantial minority of cases have a genetic component. Male genetic sex indicates male pseudohermaphroditism and leads to tests that differentiate the various etiologies. Turner’s syndrome and other sex chromosome disorders are also excluded or confirmed. If there is a normal female karyotype and no chromosome abnormalities are found, there is some divergence of opinion on how to evaluate the other important organs of puberty—the ovaries, pituitary, and hypothalamus. Some prefer to perform serum hormone assays as a group, including pituitary gonadotropins (FSH and LH), estrogen (estradiol), testosterone, prolactin, and thyroxine. Others perform these assays in a step-by-step fashion or algorithm, depending on the result of each test, which could be less expensive but could take much more time. Others begin with tests of organ function. In the algorithm approach, the first step is usually to determine if estrogen is present in adequate amount. Vaginal smears, serum estradiol level, endometrial stimulation with progesterone (for withdrawal bleeding), and possibly endometrial biopsy (for active proliferative or secretory endometrium, although biopsy is considered more often in secondary than in primary amenorrhea)—all are methods to detect ovarian estrogen production. If estrogen is present in adequate amount, this could mean intact hypothalamic-pituitary-ovarian feedback or could raise the question of excess androgen (congenital adrenal hyperplasia, Cushing’s syndrome, PCO disease, androgen-producing tumor) or excess estrogens (obesity, estrogen-producing tumor, iatrogenic, self-medication). If estrogen effect is absent or very low, some gynecologists then test the uterus with estrogen, followed by progesterone, to see if the uterus is capable of function. If no withdrawal bleeding occurs, this suggests testicular feminization, congenital absence or abnormality of the uterus, or the syndrome of intrauterine adhesions (Asherman’s syndrome). If uterine withdrawal bleeding takes place, the uterus can function, and when this finding is coupled with evidence of low estrogen levels, the tentative diagnosis is ovarian failure.

    The next step is to differentiate primary ovarian failure from secondary failure caused by pituitary or hypothalamic disease. Hypothalamic dysfunction may be due to space-occupying lesions (tumor or granulomatous disease), infection, or (through uncertain mechanism) effects of severe systemic illness, severe malnutrition, and severe psychogenic disorder. X-ray films of the pituitary are often ordered to detect enlargement of the sella turcica from pituitary tumor or suprasellar calcifications due to craniopharyngioma. Polytomography is more sensitive for sellar abnormality than ordinary plain films. CT also has its advocates. Serum prolactin, thyroxine, FSH, and LH assays are done. It is necessary to wait 4-6 weeks after a progesterone or estrogen-progesterone test before the hormone assays are obtained to allow patient hormone secretion patterns to resume their pretest status. An elevated serum prolactin value raises the question of pituitary tumor (especially if the sella is enlarged) or idiopathic isolated hyperprolactinemia. However, patients with the empty sella syndrome and some patients with hypothyroidism may have an enlarged sella and elevated serum prolactin levels, and the other causes of elevated prolactin levels (see the box) must be considered. A decreased serum FSH or LH level confirms pituitary insufficiency or hypothalamic dysfunction. A pituitary stimulation test can be performed. If the pituitary can produce adequate amounts of LH, this suggests hypothalamic disease (either destructive lesion, effect of severe systemic illness, or malnutrition). However, failure of the pituitary to respond does not necessarily indicate primary pituitary disease, since severe long-term hypothalamic deficiency may result in temporary pituitary nonresponsiveness to a single episode of test stimulation. Hormone therapy within the preceding 4-6 weeks can also adversely affect test results.

    The box lists some conditions associated with primary amenorrhea or delayed puberty and the differential diagnosis associated with various patterns of pituitary gonadotropin values. However, several cautionary statements must be made about these patterns. Clearly elevated FSH or LH values are much more significant than normal or mildly to moderately decreased levels. Current gonadotropin immunoassays are technically more reproducible and dependable at the upper end of usual values than at the lower end. Thus, two determinations on the same specimen could produce both a mildly decreased value and a value within the lower half of the reference range. In addition, blood levels of gonadotropins, especially LH, frequently vary throughout the day. The values must be compared with age- and sexmatched reference ranges. In girls, the levels also are influenced by the menstrual cycle, if menarche has begun. Second, the conditions listed—even the genetic ones, although to a lesser extent—are not homogeneous in regard to severity, clinical manifestations, or laboratory findings. Instead, each represents a spectrum of patients. The more classic and severe the clinical manifestations, the more likely that the patient will have “expected” laboratory findings, but even this rule is not invariable. Therefore, some patients having a condition typically associated with an abnormal laboratory test result may not show the expected abnormality. Laboratory error is another consideration. Also, the spectrum of patients represented by each condition makes it difficult to evaluate reports of laboratory findings due to differences in patient population, severity of illness, differences in applying diagnostic criteria to the patients, variance in specimen collection protocols, and technical differences in the assays used in different laboratories. In many cases, adequate data concerning frequency that some laboratory tests are abnormal are not available.

    Gonadotropin Levels in Certain Conditions Associated With Primary Amenorrhea or Delayed Puberty
    FSH and LH decreased*
    Hypopituitarism
    Hypothalamic dysfunction
    Constitutional delayed puberty
    Some cases of primary hypothyroidism
    Some cases of Cushing’s syndrome
    Some cases of severe chronic illness
    FSH and LH increased†
    Some cases of congenital adrenal hyperplasia
    Female gonadal dysgenesis
    Male gonadal dysgenesis
    Ovarian failure due to nonovarian agents
    LH increased, FSH not increased‡
    Testicular feminization
    Some cases of PCO disease

    Elevated FSH and LH levels or an elevated LH level alone suggests primary ovarian failure, whether from congenital absence of the ovaries or congenital inability to respond to gonadotropins, acquired abnormality such as damage to the ovaries after birth, or PCO disease.

    An elevated estrogen or androgen level raises the question of hormone-secreting tumor, for which the ovary is the most common (but not the only) location. Nontumor androgen production may occur in PCO disease and Cushing’s syndrome (especially adrenal carcinoma).

    As noted previously, there is no universally accepted single standard method to investigate female reproductive disorders. Tests or test sequences vary among medical centers and also according to findings in the individual patients.

    When specimens for pituitary hormone assays are collected, the potential problems noted earlier in the chapter should be considered.

  • Adrenal and Nonadrenal Causes of Hypertension

    Cushing’s syndrome, primary aldosteronism, unilateral renal disease (rarely, bilateral renal artery stenosis), and pheochromocytoma often produce hypertension. Hypertension due to these diseases is classified as secondary hypertension, in contrast to primary idiopathic (essential) hypertension. Although patients with these particular diseases that cause secondary hypertension are a relatively small minority of hypertension patients, the diseases are important because they are surgically curable. The patient usually is protected against the bad effects of hypertension by early diagnosis and cure. Patients who must be especially investigated are those who are young (less than age 50 years), those whose symptoms develop over a short time, or those who have a sudden worsening of their hypertension after a previous mild stable blood pressure elevation.

  • Adrenal Medulla Dysfunction

    The only syndrome in this category is produced by pheochromocytomas. Pheochromocytoma is a tumor of the adrenal medulla that frequently secretes epinephrine or norepinephrine. This causes hypertension, which may be continuous (about 30% of patients) or in short episodes (paroxysmal). Although rare, pheochromocytoma is one of the few curable causes of hypertension and so should be considered as a possible etiology in any patient with hypertension of either sudden or recent onset. This is especially true for young or middle-aged persons.

    Approximately 90% of pheochromocytomas in adults arise in the adrenal (more often in the right adrenal). Of the 10% that are extraadrenal, the great majority are located in the abdomen, with 1%-2% in the thorax and neck. Extraadrenal abdominal tumors are usually found in the paraaortic sympathetic nerve chain (below the level of the renal artery), but perhaps one third are located in the remnants of the organ of Zuckerkandl (which is situated in the paraaortic region between the origin of the inferior mesenteric artery and the bifurcation of the aorta). About 20% of pheochromocytomas are multiple and about 10% are bilateral. Approximately 5%-10% (range, 3%-14%) of all pheochromocytomas are malignant, but the malignancy rate for extraadrenal abdominal tumors is reported to be about 25%-30%. Although hypertension is the most common significant clinical finding, 10%-20% of pheochromocytomas do not produce hypertension (Table 30-3). Hyperglycemia is reported in about 50% of patients. In one autopsy series of 54 cases, only 25% were diagnosed during life.

    Common signs and symptoms of pheochromocytoma

    Table 30-3 Common signs and symptoms of pheochromocytoma

    About 5% of pheochromocytoma patients have neurofibromatosis, and in 5%-10% the pheochromocytoma is associated with the multiple endocrine neoplasia (MEN) syndrome type II (also known as “IIA,” with medullary carcinoma of the thyroid) or III (also known as “IIB,” with mucosal neuromas). The MEN syndrome pheochromocytomas are bilateral in 50%-95% of cases and multiple in about 70% of cases, whereas nonfamilial (sporadic) pheochromocytomas are usually unilateral and are multiple in about 20% of cases. About 5% of the familial cases are said to be malignant.

    In children, extraadrenal pheochromocytomas are more common (30% of cases), more often bilateral (25%-70% of cases), and more often multiple (about 30% of cases) than in adults. About 10%-20% of adrenal or extraadrenal childhood pheochromocytomas are reported to be malignant.

    Tests for pheochromocytoma

    Regitine test. The first tests for pheochromocytomas were pharmacologic, based on neutralization of epinephrine effects by adrenergic-blocking drugs such as Regitine. After basal blood pressure has been established, 5 mg of Regitine is given intravenously, and the blood pressure is checked every 30 seconds. The result is positive if systolic blood pressure decreases more than 35 mm Hg or diastolic pressure decreases 25 mm Hg or more and remains decreased 3-4 minutes. Laboratory tests have proved much more reliable than the pharmacologic procedures, which yield an appreciable percentage of false positives and negatives.

    Clonidine suppression test. Clonidine is a centrally acting alpha-adrenergic agonist that inhibits sympathetic nervous system catecholamine release from postganglionic neurons. The patients should not be on hypertensive medication (if possible) for at least 12 hours before the test. After a baseline blood specimen is obtained, a single 0.3-mg oral dose of clonidine is administered and a second blood specimen is drawn 3 hours later. Most patients without pheochromocytoma had postdose plasma norepinephrine values more than 50% below baseline and plasma catacholamine values less than 500 pg/ml. Most patients with pheochromocytoma showed little change in plasma norepinephrine values between the predose and postdose specimens and had a plasma catacholamine postdose level greater than 500 pg/ml. Apparently, better results are obtained when baseline urine norepinephrine values are greater than 2000 pg/ml (86%-99% sensitivity) than when the baseline value is less than 2000 pg/ml (73%-97% sensitivity). Medication such as tricyclic antidepressants, thiazide diuretics, and beta blockers may interfere with the test.

    Catecholamine/vanillylmandelic acid/metanephrine assay. The catecholamines epinephrine and norepinephrine are excreted by the kidney, about 3%-6% free (unchanged), and the remainder as various metabolites. Of these metabolic products, the major portion is vanillylmandelic (vanilmandelic) acid (VMA), and the remainder (about 20%-40%) is compounds known as metanephrines. Therefore, one can measure urinary catecholamines, metanephrines, or VMA. Of these, urine metanephrine assay is considered by many to be the most sensitive and reliable single test. There are also fewer drugs that interfere.

    Most investigators report that urine metanephrine assay detects about 95% (range, 77%-100%) of patients with pheochromocytoma. Sensitivity of urine catecholamines is approximately 90%-95% (range, 67%-100%) and that of urine VMA assay is also about 90%-95% (range, 50%-100%). One report indicates that metanephrine excretion is relatively uniform and that a random specimen reported in terms of creatinine excretion can be substituted for the usual 24-hour collection in screening for pheochromocytoma. Methylglucamine x-ray contrast medium is said to produce falsely normal urine metanephrine values for up to 72 hours. One report found that 10%-15% of mildly elevated urine metanephrine values were falsely positive due to medications (such as methyldopa) or other reasons.

    Although the metanephrine excretion test is slowly gaining preference, VMA and catecholamine assay are still widely used. All three methods have detection rates within 5%-10% of one another. A small but significant percentage of pheochromocytomas are missed by any of the three tests (fewer by metanephrine excretion), especially if the tumor secretes intermittently. The VMA test has one definite advantage in that certain screening methods are technically more simple than catecholamine or metanephrine assay and therefore are more readily available in smaller laboratories. The VMA screening methods are apt to produce more false positive results, however, so that abnormal values (or normal results in patients with strong suspicion for pheochromocytoma) should be confirmed by some other procedure.

    Catecholamine production and plasma catecholamine levels may be increased after severe exercise (although mild exercise has no appreciable effect), by emotional stress, and by smoking. Uremia interferes with assay methods based on fluorescence. Other diseases or conditions that may increase plasma or urine catecholamines or urine catecholamine metabolites are hypothyroidism, diuretic therapy, heavy alcohol intake, hypoglycemia, hypoxia, severe acidosis, Cushing’s syndrome, myocardial infarction, hemolytic anemia, and occasionally lymphoma or severe renal disease. In addition, bananas, coffee, and various other foods as well as certain medications may produce falsely elevated results. These foods or medications produce appreciable numbers of false-positive results in some of the standard screening techniques for VMA. An abnormal result with the “screening” VMA techniques should be confirmed by some other VMA method. Although other VMA methods or methods for metanephrine and catecholamine assay are more reliable, they too may be affected by certain foods or medications, so it is best to check with individual laboratories for details on substances that affect their particular test method. Reports differ on whether some patients with essential hypertension may have elevated serum or urine catecholamine or catecholamine metabolite results; and if so, how often it occurs and what percentage are due to conditions known to elevate catecholamines, or to medications, or to unknown causes.

    Some investigators use urine fractionated catecholamines (epinephrine and norepinephrine, sometimes also dopamine) by high-pressure liquid chromatography as a confirmatory test for pheochromocytoma. It is said that about 50%-70% of pheochromocytomas produce epinephrine, about 75%-85% produce norepinephrine, and about 95% produce one or the other.

    Plasma catecholamine assay. Several investigators report better sensitivity in pheochromocytoma with plasma catecholamine assay than with the particular urine metabolite assays they were using. Another advantage is the simplicity of a single blood specimen versus 24-hour collection. However, upright posture and stress can greatly affect plasma catecholamine levels, even the stress of venipuncture, so it is best to draw the specimen in the early morning before the patient rises. Even then, some advocate placement of an indwelling venous catheter or heparinized scalp vein apparatus with an interval of 30 minutes between insertion of the catheter and withdrawal of the blood specimen. One investigator reported that plasma catecholamine values decreased rapidly if the red blood cells (RBCs) were not removed within 5 minutes after obtaining the specimen. Placing the specimen on ice was helpful but only partially retarded RBC catecholamine uptake. Plasma catecholamine assay detection rate in pheochromocytomas is about 90% (literature range, 53%-100%). Failure to detect the tumor in some instances is due to intermittent tumor secretion. Urine collection has the advantage of averaging the 24-hour excretion.

    Tumor localization methods. Once pheochromocytoma is strongly suspected by results of biochemical testing, certain procedures have been useful in localizing the tumor. Intravenous pyelography with nephrotomography is reported to have an accuracy of about 70% in detecting adrenal pheochromocytoma. CT has been reported to detect 85%-95% (range, 84%-over 95%) of pheochromocytomas, including some in extraadrenal locations. Consensus now is that CT (or magnetic resonance imaging [MRI]) is the best single localization test (better than ultrasound). Radioactive mIBG has been used to locate pheochromocytomas and other neural tumors with sensitivity of about 85%. However, this procedure is only available in a very few nuclear medicine centers. Angiographic procedures are reported to detect 60%-84% of pheochromocytomas; but angiography is somewhat controversial because it is invasive, because it yields about 10% false negative results in adrenal tumors, and because some investigators believe that the incidence of tumor bilaterality warrants exploration of both sides of the abdomen regardless of angiographic findings.

    Miscellaneous procedures. Serum chromogranin A (CgA), a substance produced in the adrenal medulla and some other endocrine and neuroendocrine tissues and tumors, has been used in diagnosis of pheochromocytoma. CgA is not affected by posture, venipuncture, and many medications that interfere with catecholamine assay; in one series CGA detected 86% of pheochromocytomas.

    Deoxyribonucleic acid (DNA) analysis by flow cytometry in small numbers of patients suggest that pheochromocytomas with diploid ploidy are most often (but not always) benign, whereas those that are aneuploid are most often (but not always) malignant.

    Serum neuron-specific enolase (NSE) in small numbers of patients suggest that pheochromocytomas with normal NSE levels are usually benign, but those with elevated values are often malignant.

  • Secondary Adrenal Insufficiency

    Secondary adrenal insufficiency is due to deficient production of ACTH by the pituitary. This usually results from pituitary disease but is occasionally due to hypothalamic disorders. In general, primary adrenocortical insufficiency (Addison’s disease) is associated with inability of the adrenal to produce either cortisol or aldosterone. In addition, there may be cutaneous hyperpigmentation due to pituitary hypersecretion of melanocytic-stimulating hormone (MSH). In secondary adrenal insufficiency, aldosterone secretion is usually sufficient to prevent hyperkalemia, and hyponatremia tends to be less severe. Cutaneous pigmentation does not occur because the pituitary does not produce excess MSH. The major abnormality is lack of cortisol due to deficiency of ACTH. The laboratory picture may simulate inappropriate ADH syndrome.

    Differentiation of primary from secondary adrenal insufficiency includes plasma ACTH assay (typically increased levels in primary Addison’s disease and normal or low in pituitary or hypothalamic etiology disease) and in some cases, the prolonged ACTH test. Other tests for pituitary function (metapirone test or CRH test) may be useful in some patients.

  • Congenital Adrenal Hyperplasia

    Congenital adrenal hyperplasia (CAH), also known as the “adrenogenital syndrome,” is an uncommon condition caused by a congenital defect in one of several enzymes that take part in the chain of reactions whereby cortisol is manufactured from its precursors. There are at least six fairly well-defined variants of CAH that result from the various enzyme defects. The most common of these are types I and II, which are due to C21-hydroxylase enzyme deficiency. All CAH variants are inherited as autosomal recessive traits. The clinical and laboratory findings depend on which metabolic pathway—and which precursor in the metabolic pathway— is affected. All variants affect the glucocorticoid (cortisol) pathway in some manner. In CAH due to 21-hydroxylase defect (types I and II) and in CAH type III, although formation of cortisone and cortisol is blocked, the precursors of these glucocorticoids are still being manufactured. Most of the early precursors of cortisone are estrogenic compounds, which also are intermediates in the production of androgens by the adrenal cortex. Normally, the quantitative production of adrenal androgen is small; however, if the steroid precursors pile up (due to block in normal formation of cortisone), some of this excess may be used to form more androgens.

    Three things result from these metabolic pathway abnormalities. First, due to abnormally high production of androgen, secondary sexual characteristics are affected. If the condition is manifest in utero, pseudohermaphroditism (masculinization of external genitalia) or ambiguous genitalia occur in girls and macrogenitosomia praecox (accentuation of male genitalia) occurs in boys. If the condition does not become clinically manifest until after birth, virilism (masculinization) develops in girls and precocious puberty in boys. In CAH variants IV, V, and VI there is some degree of interruption of the adrenal androgen pathway, so that the external appearance of the female genitalia is not significantly affected and subsequent virilization is minimal or absent. External genitalia in genotypic boys appear to be female or ambiguous.

    Second, the adrenal glands themselves increase in size due to hyperplasia of the steroid-producing adrenal cortex. This results because normal pituitary production of ACTH is controlled by the amount of cortisone and hydrocortisone produced by the adrenal. In all variants of congenital adrenal hyperplasia, cortisone production is partially or completely blocked, the pituitary produces more and more ACTH in attempts to increase cortisone production, and the adrenal cortex tissue becomes hyperplastic under continually increased ACTH stimulation.

    Third, when the mineralocorticoid pathway leading to aldosterone is blocked, there are salt-losing crises similar to those of Addison’s disease. This occurs in CAH types II, IV, and VI. On the other hand, hypertension may develop if there is accumulation of a salt-retaining precursor (CAH type III) in the mineralocorticoid pathway or a mineralocorticoid production increase due to block in the other adrenal pathways (CAH type V).

    Since 21-hydroxylase deficiency is responsible for more than 90% of the CAH variants and the others are rare, only laboratory data referable to this enzyme defect (CAH types I and II) will be discussed.

    The CAH 21-hydroxylase deficiency is brought to the attention of the physician by either abnormalities in newborn external genitalia (CAH types I and II, the most common cause of female pseudohermaphroditism) or salt-losing crises (type II, constituting one third to two thirds of 21-hydroxylase deficiency cases). In later childhood, virilization is the most likely clinical problem. In patients with ambiguous genitalia, a buccal smear and chromosome karyotype establish the correct (genotypic) sex of the infant. In salt-losing crises, the infant is severely dehydrated and may develop shock. The serum sodium level is low and the serum potassium level is high-normal or elevated. For a number of years, the diagnosis was made through elevated urine 17-KS levels (metabolites of androgens) and increased urinary pregnanetriol levels (metabolite of 17-OH-progesterone). However, 17-KS values may normally be 4-5 times as high in the first 2 weeks of life as they are after 4 weeks, and pregnanetriol values may be normal in some neonates with CAH in the first 24-48 hours of life. At present, plasma 17-OH-progesterone is considered the best screening test for neonatal 21-hydroxylase deficiency. After the first 24 hours of life, plasma 17-OH-progesterone is markedly elevated in most patients with CAH type I or II. Also, plasma specimens are easier to obtain in neonates or infants than 24-hour urine collections. However, plasma 17-OH-progesterone may be elevated to some extent by pulmonary and other severe illnesses. Also, because there is diurnal variation, the blood specimen should be drawn in the morning.

  • Adrenal Cortex Hormones

    This chapter will begin with adrenal cortex hormones and conclude with adrenal medulla hormones. The adrenal medulla produces epinephrine and norepinephrine. The relationships of the principal adrenal cortex hormones, their actions, and their metabolites are shown in Fig. 30-1. The adrenal cortex is divided into three areas. A narrow outer (subcapsular) region is known as the “zona glomerulosa”. It is thought to produce aldosterone. The cortex middle zone, called the “zona fasciculata”, mainly secretes 17-hydroxycortisone, also known as “hydrocortisone” or “cortisol”. This is the principal agent of the cortisone group. A thin inner zone, called the “zona reticularis”, manufactures compounds with androgenic or estrogenic effects. Pathways of synthesis for adrenal cortex hormones are outlined in Fig. 30-2. Production of cortisol is controlled by pituitary secretion of adrenal cortex-stimulating hormone, or adrenocorticotropic hormone (corticotropin; ACTH). The pituitary, in turn, is regulated by a feedback mechanism involving blood levels of cortisol. If the plasma cortisol level is too high, pituitary action is inhibited and ACTH production is decreased. If more cortisol is needed, the pituitary increases ACTH production.

    30-1

    Fig. 30-1 Derivation of principal urinary steroids.

    30-2

    Fig. 30-2 Adrenal cortex steroid synthesis. Important classic alternate pathways are depicted in parentheses, and certain alternate pathways are omitted. Dotted lines indicate pathway that normally continues in another organ, although adrenal capability exists.

    Excess or deficiency of any one of adrenal cortex hormones leads to several well-recognized diseases which are diagnosed by assay of the hormone or its metabolites. In diseases of cortisol production, three assay techniques form the backbone of laboratory diagnosis: 17-hydroxycorti-costeroids (17-OHCS), 17-ketosteroids (17-KS), and direct measurement of cortisol. Before the use of these steroid tests in various syndromes is discussed, it is helpful to consider what actually is being measured.

    17-Hydroxycorticosteroids

    These are C21 compounds that possess a dihydroxyacetone group on carbon number 17 of the steroid nucleus (Fig. 30-3). In the blood, the principal 17-OHCS is hydrocortisone. In urine, the predominating 17-OHCS are tetrahydro metabolites (breakdown products) of hydrocortisone and cortisone. Therefore, measurement of 17-OHCS levels can be used to estimate the level of cortisone and hydrocortisone production. Estrogen therapy (including oral contraceptives) will elevate plasma 17-OHCS values, although degradation of these compounds is delayed and urine 17-OHCS levels are decreased.

    Adrenal cortex steroid nomenclature.

    Fig. 30-3 Adrenal cortex steroid nomenclature. A, basic 17-OHCS nucleus with standard numerical nomenclature of the carbon atoms. B, configuration of hydrocortisone at the C-17 carbon atom. C, configuration of the 17-KS at the C-17 carbon atom.

    17-Ketosteroids

    These are C19 compounds with a ketone group on carbon number 17 of the steroid nucleus (see Fig. 30-3). They are measured in urine only. In males, about 25% of 17-KS are composed of metabolites of testosterone. The remainder of 17-KS in males and nearly all 17-KS in females is derived from androgens other than testosterone, although lesser amounts come from early steroid precursors and a small percentage from hydrocortisone breakdown products. Testosterone itself is not a 17-KS. The principal urinary 17-KS is a compound known as dehydroisoandrosterone (dehydroepiandrosterone; DHEA). This compound is formed in the adrenal gland and has a weak androgenic effect. It is not a metabolite of cortisone or hydrocortisone, and therefore 17-KS cannot be expected to mirror or predict levels of hydrocortisone production.

    In adrenogenital or virilization syndromes, high levels of 17-KS usually mean congenital adrenal hyperplasia in infants and adrenal tumor in older children and adults. In both conditions, steroid synthesis is abnormally shifted away from cortisone formation toward androgen production. High 17-KS levels are occasionally found in testicular tumors if the tumor produces androgens greatly in excess of normal testicular output. In Cushing’s syndrome, 17-KS production is variable, but adrenal hyperplasia is often associated with mild to moderate elevation, whereas adrenal carcinoma frequently produces moderate or marked elevation in urinary values. In adrenal tumor, most of the increase is due to DHEA.

    Low levels of 17-KS are not very important because of normal fluctuation and the degree of inaccuracy in assay. Low levels are usually due to a decrease in DHEA. This may be caused by many factors, but the most important is stress of any type (e.g., trauma, burns, or chronic disease). Therefore, normal 17-KS levels are indirectly a sign of health.

    Plasma cortisol

    Plasma cortisol, like thyroxine, exists in two forms, bound and unbound. About 75% is bound to an alpha-1 globulin called “transcortin,” about 15% is bound to albumin, and about 10% is unbound (“free”). The bound cortisol is not physiologically active. Increased estrogens (pregnancy or estrogenic oral contraceptives) or hyperthyroidism elevates transcortin (raising total serum cortisol values without affecting free cortisol), whereas increased androgens or hypothyroidism decreases transcortin. In addition, pregnancy increases free cortisol. A marked decrease in serum albumin level can also lower total serum cortisol levels. There is a diurnal variation in cortisol secretion, with values in the evening being about one half those in the morning. Lowest values are found about 11 P.M.

    Cortisol test methods. All current widely used assays for serum cortisol measure total cortisol (bound plus free). There are three basic assay techniques: Porter-Silber colorimetric, Mattingly fluorescent, and immunoassay. The Porter-Silber was the most widely used of the older chemical methods. It measures cortisol, cortisone, and compound S (see Fig. 30-2), plus their metabolites. Ketosis and various drugs may interfere. The Mattingly fluorescent procedure is based on fluorescence of certain compounds in acid media at ultraviolet wavelengths. It is more sensitive than the Porter-Silber technique, faster, requires less blood, and measures cortisol and compound B but not compound S. Certain drugs that fluoresce may interfere. Immunoassay has two subgroups, competitive protein binding (CPB) and radioimmunoassay (RIA) or enzyme immunoassay (EIA). The CPB technique is the older of the two. It is based on competition of patient cortisol-like compounds with isotope-labeled cortisol for space on cortisol-binding protein. CPB measures cortisol, cortisone, compound S, and compound B. Advantages are small specimen requirement and less interference by drugs. RIA or EIA is based on competition of patient cortisol with labeled cortisol for anticortisol antibody. The method is nearly specific for cortisol, with less than 20% cross-reaction with compound S. In certain clinical situations, such as congenital adrenal hyperplasia or the metyrapone test, it is important to know what “cortisol” procedure is being performed to interpret the results correctly.

    All techniques measure total blood cortisol, so that all will give falsely increased values if increases in cortisol-binding protein levels occur due to estrogens in pregnancy or from birth control pills. Stress, obesity, and severe hepatic or renal disease may falsely increase plasma levels. Androgens and phenytoin (Dilantin) may decrease cortisol-binding protein levels. In situations where cortisol-binding protein levels are increased, urine 17-OHCS or, better, urine free cortisol assay may be helpful, since urine reflects blood levels of active rather than total hormone.