Adrenal Disoders

Question 1

How are adrenal hormones synthesized

Answer 1

All adrenal steroid synthesis begins with cholesterol. Cholesterol in the adrenal tissue may be synthesized in situ from acetate or may come from cholesterol made in the liver and transported to the adrenal gland by LDL

•The rate-limiting step in the synthesis of all steroids is the conversion of cholesterol to pregnenolone. This step is stimulated by ACTH in the zona fasciculata and zona recticularis and by angiotensin III in the zona glomerulosa

•The pathway leading to progesterone is common to both aldosterone and cortisol synthesis. In the zona reticularis and fasciculata, progesterone is hydroxylated at the 17, 21 and 11 positions to form cortisol.

•Under normal circumstances, 10 to 30mg of cortisol is synthesized a day. The zona glomerulosa does not contain 17 hydroxylase activity. Instead, hydroxylation occurs at positions 21, 11 and 18.

Question 2

What are some causes of adrenal insufficiency

Answer 2

Selective destruction of Adrenal Cortex, Tuberculosis, autoimmune disease
•Cx’s : ACTH, adrenal medulla intact
•Total adrenal destruction- Bacterial and fungal infections, amyloidosis, metastatic carcinoma, TB
•Cx’s: ACTH
3. 20 adrenal insufficiency- ACTH deficiency due to hypo. Pituitary disease
•Cx’s medulla and zona glomerulosa intact but atrophy of zona fascilulata an zona reticularis
• ACTH

Question 3

What are some clinical presentations of adrenal disorders

Answer 3

Weight loss
•Abdominal pain
•Pigmentation
•Anorexia
•Lethargy
•In acute crisis- vomiting, postural hypotension, nusea and dehydration

Question 4

What is the biochemical presentation of adrenal disorders

Answer 4

Hyponatraemia- due to lack of aldosterone leading to pathological sodium loss by the kidney
•Absence of cortisol also leads to impairment of water load excretion
•Hyperkalaemia
•Elevated serum urea
•Hypotension
•Pre-renal uraemia
•Raised ACTH (Why?)

Question 5

How are adrenal disorders diagnosed

Answer 5

Ensure adequate sodium intake whilst investigation proceeds
•Serum aldosterone measurement have no clinical significance in initial diagnosis
•A single serum cortisol measurement could be misleading
•The Short Synacten Test: indicates the ability of the adrenal cortex to respond to Synacten (a synthetic analogue of ACTH)
•Measure baseline plasma cortisol (280-720nmol/L). I.V. admn. Of 0.25mg Synacten
•Measure the increase in plasma cortisol after 30mins
•RESULTS:? - In a normal individual the basal value shd be > 225nmol/L and there should be an increment of >200nmol/L and the final conc. Shd be >500nmol/L.
•Failure to meet this criteria confirms adrenal insufficiency
•A normal response to the test excludes primary hypofunction
•An elevated ACTH, confirms primary adrenal failure in a patient with an impaired response to the Synacten test. Why?

Question 6

How are adrenal disorders managed

Answer 6

Life-long treatment with HRT
•30mg of hydrocortisone daily in divided doses supplemented with α-fludrocortisone(mineralocorticoid)

Question 7

How is hyperfunction of the adrenal cortex caused

Answer 7

Prolonged exposure to cortisol or any other glucocorticoids
•Pituitary adenoma
•Ectopic ACTH
•Adrenal adenoma
•Adrenal carcinoma

Question 8

What are the products affected when there is hyperfunction of the adrenal cortex

Answer 8

Cortisol
Adrenal androgens
Aldosterone

Question 9

What are the clinical presentations of hyperfunction of the adrenal cortex

Answer 9

•Baldness and facial hirsutism in females
•Buffalo hump
•Increased abdominal striae
•Hypertension
•Skin thining
•Brusability
•Poor wound healing
•Muscle weakness
•Osteoporosis
•Moon face, Plethoric cheeks

Question 10

How is adrenocortical hyperfunction diagnosed

Answer 10

Iatrogenic Cushing’s should be diagnosed from the patient history and clinical examination
•The steroid may have been taken orally, inhaled or applied topically
•Cortisol secreted in excess by the adrenal cortex, will rapidly exceed the CBG threshold
•Urinary free cortisol in 24-H collection (High), or screening for the urinary cortisol:creatinine ratio (often high)
•Circadian rhythm of cortisol (cf to normal subjects), evening sample often lower than morning but no so in the AdHyp patient
•Failure to suppress serum cortisol ff 1mg overnight intake of Dexamethasone implies Cushing’s
•Failure of the serum cortisol to rise after insulin-induced hypoglycaemia is often a Cx’tic feature of Cushing’s syndrome (Patient’s with cortisol over-production will be resistant and a std. 0.15unis insulin/Kg body weight will not be adequate to achieve hypoglycaemic state, a higher dose may be required)

Question 11

What is the chemical structure of steroids

Answer 11

Steroids contain a cyclopentanoperhydrophenanthrene nucleus as their basic structure (Figure 40-1). The three six-sided rings (A, B, and C) constitute the phenanthrene nucleus, to which is attached the D or cyclopentane ring. The prefix
“perhydro” refers to the saturation of the compound with hydrogen atoms. This class of compounds includes such natural products as sterols (e.g., cholesterol), bile acids (e.g., cholanic acid), sex hormones (e.g., estrogens and androgens), vitamin D, and the corticosteroids. Steroid hormones contain up to 21 carbon atoms (C21 steroids), numbered as shown in Figure 40-1.
Steroids are three-dimensional molecules. Their constituent atoms lie in different planes, which results in the creation of isomers. The direction of the hydrogen atoms, the substituents, and the side chain play a much more important role in the differentiation among various steroid compound isomers than do the relative positions of the carbon atoms in the rings. Thus the isomers resulting from fusion of two rings are identified on the basis of the spatial relationship between the hydrogen atoms or the suhstituents at common carbon atoms. When rings A and B are fused, two isomers are possible depending on whether the hydrogen atom at C-5 and the methyl group at C-10 are on the same or the opposite side of the plane of the rings. If the hydrogen atom points in the same direction as that of the angular methyl group at C-10, the compound is in the cis, or normal, form. However, if they are on opposite sides, the compound is in the trans, or allo, form.
Depending on which side of the molecule the substituents are attached to relative to these two methyl groups, they have either an & or B orientation. For example, when the substitu-ents are on the same side as the two methyl groups, they have a B configuration, which is indicated by a solid line (- )joining the substituents to the appropriatecarbon atoms in the nucleus.
Suhstituents on the opposite side are attached by a broken line (- -_) to denote an & configuration.
Individual steroids containing the cyclopentanoperhydro-phenanthrene nucleus are differentiated by the presence of double bonds between certain pairs of carbon atoms, the introduction of suhstituentsfor the hydrogen atoms, or the addition of a specific type of side chain. On the basis of such structural characteristics, the steroidal compounds are classified as derivatives of certain parent hydrocarbons (e.g., estrane for estro-gens, androstane for androgens, and pregnane for corticosteroids and progestins). Various suffixes and prefixes are used to describe steroids (Table 40-1).

Question 12

How are steroids metabolized

Answer 12

The liver is the major site of steroid metabolism. The kidney and the gastrointestinal tract, however, also both carry out important metabolic transformation of steroids. Important biochemical steps for neutralizing the potent biological activity of hormones and facilitating their rapid elimination from the systemic circulation include (1) the introduction of an additional hydroxyl group (e.g., estradiol to estriol); (2) dehydrogenation (e.g., testosterone to androstenedione); (3) reduction of a double bond (e.g., cortisol to dihydrocortisol); and (4) conjugation of an essential hydroxyl group or groups with a chemical moiety, such as glucuronic acid (e.g., testosterone to testosterone glucuronide). The conjugation of these hormones and their metabolites with sulfuric or glucuronic acid is the most efficient single metabolic process for their excretion in the urine. Almost all steroid metabolites are excreted as water-soluble glucuronides or sulfates.

Question 13

What are glucocorticoids

Answer 13

Cortisol is the major glucocorticoid synthesized from cholesterol in the zona fasciculata and reticularis of the human adrenal cortex (Figure 40-3). It is secreted at the rate of approximately 25 mg/day. When released into the circulation, cortisol is principally bound to corticosteroid-bindingglobulin (CBG) and transported as such. Cortisol is metabolized and conjugated in the liver to several inactive forms. More than 95% of cortisol and its metabolite cortisone is conjugated to glucuronic acid and excreted into the urine as a conjugate. Less than 2% of cortisol is excreted in the urine unmetabolized as urinary free cortisol.
Glucocorticoids have major effects on carbohydrate, protein, and lipid metabolism (Figure 40-4). They also affect fat metabolism with an activation in lipolysis and the release of free fatty acids into the circulation. When present in excess, glucocorticoids cause a central distribution of fat to the face, neck, and trunk. Glucocorticoids also stimulate adipocyte differentiation and promote lipogenesis through the activation of enzymes such as lipoprotein lipase and increased messenger ribonucleic acid (mRNA) expression for leptin.
Circulating glucocorticoids also have antiinflammatory properties and suppress the immune system (see Figure 40-4).
Consequently, glucocorticoids are used therapeutically to treat inflammatory conditions such as rheumatoid arthritis.

Question 14

What are mineralocorticoids

Answer 14

Mineralocorticoids regulate salt homeostasis (sodium conservation and potassium loss) and extracellular fluid volume.
Aldosterone is the most potent naturally occurring mineralo-corticoid and is synthesized exclusively in the zona glomerulosa region of the adrenal cortex. This zone uniquely contains the enzyme aldosterone synthase, an obligatory enzyme in the synthetic pathway to aldosterone (see Figure 40-3). It is secreted at the rate of approximately 200 kg/day. 1,10
Other adrenocortical steroids that have mineralocorticoid properties with varying degrees of potency include deoxycorti-costerone (DOC), 18-hydroxy-DOC, corticosterone, and cor-tisol. A large number of analogues with mineratocorticoidand glucocorticoid activity have been synthesized; some are actually more potent than those that occur naturally.

Question 15

What are adrenal androgens

Answer 15

The adrenal glands also secrete androgens, progesterone, and estrogen, all of which are produced by the gonads as well (see Chapter 42).’ Adrenal androgens are synthesized in the zona fasciculata and/or reticularis from the precursor substrate 17o-hydroxypregnenolone. The adrenal androgens include dehydroepiandrosterone (DHEA), androstenedione, and testosterone (see Figure 40-3). DHEA and its sulfated deriva-tive, DHEA sulfate (DHEA-S),are the most important adrenal androgens found in the circulation and are present in the highest concentration. The adult adrenal secretes approximately 6 to 8 mg/day of DHEA, 8 to 16 mg/day of DHEA-S, 1.5 mg/day of androstenedione, and 0.05 mg/day of testoster-one. The amount of DHEA and/or DHEA-S produced is second only to that of cortisol among the adrenal steroids released daily into the circulation. These amounts account for about 50% of DHEA and more than 90% of DHEA-S that circulates in plasma. The adrenal glands also produce small amounts of the estrogens estradiol and estrone and insignificant amounts of progesterone and other precursor steroids on a daily basis.

Question 16

What are the circulating forms of steroids

Answer 16

Steroid hormones circulate in blood either as free hormones or bound to carrier proteins, such as 02-globulin, CBG, albumin, or sex hormone- bindingglobulin (SHBG). O Some steroids are conjugated to glucuronide or sulfate and thus circulate independent of a protein carrier. The excretion of steroids occurs via the kidneys or gastrointestinal tract, where they are reab-sorbed. CBG, albumin, and SHBG are produced by the liver.
CBG and SHBG concentrations are increased by estrogens and in some patients with hepatitis and reduced by glucocorticoids, testosterone, and in patients with liver and kidney disease. At physiological concentrations, about 90% to 98% of steroid hormones circulate bound to a carrier protein, usually with high affinity for a binding globulin, such as CBG and SHBG.
At higher physiological concentrations, albumin, which has a high capacity but low affinity for steroids, becomes a more important transport medium for steroids. When a steroid has low affinity for a “carrier protein,” 60% to 70% of the steroid circulates bound principally to albumin.” Some steroids, such as aldosterone, have a relatively high affinity for CBG, but CBG is not a major carrier protein because cortisol, corticosterone, and 17-hydroxyprogesterone far exceed the concentration of aldosterone. Similarly, testosterone and dihydrotestosterone circulate primarily bound to SHBG in men, whereas estradiol, despite high binding affinity for SHBG, is bound largely to albumin because its concentration is low relative to that of testosterone. DHEA-S and DHEA circulate primarily bound to albumin, and neither CBG nor SHBG is important in the transport of these adrenal androgens. Pred-nisolone is the only synthetic glucocorticoid with high binding affinity for CBG, whereas dexamethasone, methylpredniso-lone, and triamcinolone acetonide are primarily bound to albumin.

Question 17

How are steroid hormones generally metabolized

Answer 17

The liver is the principal site for the transformation and conjugation of steroid hormones, largely through the enriched presence of the cytochrome P-450 metabolizingenzyme systems (see Chapter 30). The kidneys also play an important role in steroid metabolism. The kidney excretes approximately 90% of conjugated steroids released by the liver and about 50% of secreted cortisol appears in the urine as tetrahydrocortisol (THF) and tetrahydrocortisone (THE). Many tissues contain the necessary enzymes that activate steroids or render them biologically inactive. Cortisol, for example, is metabolized to cortisone through the activity of 11B-hydroxysteroid dehydro-genase; this change renders this steroid incapable of binding to the glucocorticoid receptor. The liver, however, is capable of converting cortisone back to cortisol, which is biologically active. Androgens such as DHEA and androstenedione are Iznown to be converted to testosterone in fat tissue and then to dihydrotestosterone in tissues containing the 5o-reductase enzyme. The aromatase enzyme converts testosterone and androstenedione to estradiol and estrone, respectively, in tissues such as fat and the liver. Even sulfated and glucuroni-dated steroids are activated by the action of the enzymes sul-fatase and a-glucuronidase. Macrophages, for example, convert DHEA-S to DHEA, which alters cytokine production by associated T lymphocytes. Testosterone is a potent androgen in muscle, a tissue that has little 5-reductase activity. In skin and prostate tissue, with high A*-5o-reductase activity, testosterone is a prohormone for dihydrotestosterone, the active androgen in these tissues. Thus considerable metabolism of steroids takes place outside of their original site of synthesis.
Liver, kidney, and thyroid disease affect the secretion and metabolism of the adrenal steroids. Other factors affecting these processes include (1) stress, (2) age, (3) estrogen therapy,
(4) nutrition, and (5) drugs.

Question 18

How is cortisol metabolized

Answer 18

An understanding of the metabolism of cortisol is important in interpreting tests designed to evaluate alterations in cortisol production rates and disorders of adrenal function.” Less than 2% of cortisol is excreted unchanged in the urine. As a result of its tight binding to CBG, cortisol is metabolized slowly. In the liver, metabolism of cortisol involves enzymatic reduction of the double bond between C-4 and C-5 to form dihydrocor-tisol or dihydrocortisone. Further metabolism of cortisol and cortisone produces THF and THE, respectively, which are in turn metabolized to cortol and cortolone. More than 95% of the metabolites of cortisol and cortisone are conjugated by the liver. Glucuronidation at the 3@-hydroxyl position is favored over the other hydroxyl groups, and the 21-hydroxyl group is favored for sulfations; glucuronide metabolites are more abundant than sulfated steroids.

Question 19

How are androgens metabolized

Answer 19

Adrenal androgens also have a complex metabolic fate. For example, DHEA-S is formed in the adrenal cortex or by sulfo-kinases in the liver and kidney from DHEA and excreted by the kidney. DHEA and DHEA-S is metabolized by 7u- and 16ß-hydroxylases. Reduction (17-B) of both compounds forms A-5-androstenediol and its sulfate. Androstenedione also is metabolized to androsterone after 30- and 5o-reduction. 5B-Reduction results in the formation of etiocholanolone. These metabolites are conjugated to glucuronides and sulfates, which are then excreted in the urine.

Question 20

Describe the hypothalamic pituitary adrenal cortical axis

Answer 20

Secretion of adrenal glucocorticoids and androgens is regulated by ACTH (see Chapter 39), which in turn is under the control of corticotropin-releasing hormone (CH) a hypothalamic peptide.” The pituitary gland also has been found to secrete a separate hormonal factor that specifically regulates adrenal androgen production.’ This substance, called cortical androgen-stimulating hormone, has been identified as a gly-copeptide in human pituitary extracts and shows sequence homology to an 18-amino acid N-terminal component of pro-opiomelanocorticotropin, the precursor peptide of ACTH and of melanocyte-stimulating hormone. The hypothalamic-pituitary-adrenal (HPA) relationships in health and in various adrenal disorders are depicted in Figure 40-5.
CRH/ACTH
Biorhythms and other physiological events in the brain result in episodic and circadian secretion of CRH from the hypo-thalamus. This in turn elicits similar circadian variation in ACTH release? Secreted ACTH then stimulates cortisol pro-duction, which provides negative feedback inhibition to the CRH-ACTH axis. The secretion of CRH, a 40-amino acid peptide, is modulated by neuroendocrine, physical, and emotional factors. Besides CRH, other circulating factors have an influence on the secretory dynamics of ACTH release. For example, arginine vasopressin (antidiuretic hormone) from the posterior pituitary and other peptides (angiotensin lI, activin, cytokines, opiates, and somatostatin) and catecholamines influence the secretion of ACTH from the adenohypophy-sis. 10

The circadian rhythm of ACTH secretion under normal wake and sleep cycles produces higher cortisol concentrations in the morning between 0400 and noon and lower concentrations in late evening and early morning. The magnitude of the morning cortisol concentration is affected by familial and genetic factors. 1,10
Physical stresses that elevate plasma cortisol concentrations and alter the circadian rhythm include (1) trauma, (2) fever,
(3) surgery, (4) hypoglycemia, (5) alcohol ingestion, (6) uncontrolled diabetes, and (7) nutritional deprivation, including that associated with anorexia nervosa. Major depression and severe anxiety are psychological stresses that also elevate plasma cortisol concentrations. ACTH secretion in response to minor stresses is inhibited by the administration of exogenous glucocorticoids.
Prolonged suppression of ACTH by administration of glucocorticoids causes atrophy of the adrenal cortex.’ The degree of atrophy is related to the duration and magnitude of suppression of ACTH secretion. With prolonged intense suppression, recovery of the HPA takes several days to a few months.

Question 21

How is cortisol secreted

Answer 21

ACTH has both trophic and steroidogenic effects on the adrenal cortex and is under negative feedback control from nonprotein-bound cortisol.’ Cortisol is secreted within a few minutes after a rise in serum ACTH. Deficiency of ACTH results in atrophy of the zona fasciculata and zona reticularis.
Atrophy of the adrenal cortex from various causes and reduced cortisol synthesis and release causes plasma ACTH concentrations to increase. Other modifying factors such as (1) age, (2) various diseases, (3) estrogen therapy, (4) nutrition, (5) general illness, and (6) drugs also affect cortisol secretion. Both hyper-trophy and hyperplasia of the adrenal cortex occur in response to chronic exposure to ACTH. The trophic response to ACTH is reproduced by cyclic adenosine monophosphate (cAMP) stimulation of insulin-like growth factor-I1 rather than CAMP directly.
The proinflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (INFo) also increase cortisol secretion through an increase in pituitary ACTH secretion as part of the important immune-endocrine interaction that occurs with disease and infection.

Question 22

How is aldosterone secreted

Answer 22

The primary control mechanism for the secretion of aldosterone involves the renin-angiotensin system. Renin is a proteo-lytic enzyme synthesized and stored in the juxtaglomerular epithelial cells, located along the terminal part of the afferent arterioles of the renal glomeruli.’ These specialized cells constitute part of the juxtaglomerular apparatus (see Chapter 34).
Upon stimulation of the juxtaglometular apparatus, renin is released into the circulation, where it hydrolyzes its substrate, angiotensinogen, to produce a decapeptide known as angiotensin I. Angiotensin I is then rapidly converted to an octapep-tide, angiotensin II, by a circulating angiotensin-converting enzyme (ACE), which is found in abundance in the lung. Angiotensin II is a potent vasoconstrictor and stimulates the cells of the zona glomerulosa to produce aldosterone. Angiotensin II stimulates aldosterone secretion by increasing the transcription of cytochrome 450 CYP11B2, the gene responsible for aldosterone synthase through common intracellular signaling path-ways. Potassium stimulates aldosterone synthesis and release through a membrane depolarization effect that opens up calcium channels in adrenal cells. This activates cell signaling mechanisms such as phospholipase C, leading to an increase in aldosterone synthase synthesis and release. The primary stimuli for renin release are (1) a decrease in renal arteriolar pressure, (2) oncotic pressure, (3) an increase in sympathetic drive to the macula densa of the juxtaglomerular apparatus, and (4) a negative sodium balance. ACTH also increases aldosterone secretion. However, the size and function of the zona glomerulosa are affected primarily by the renin-angiotensin system and potassium. Hyperplasia results when concentrations of angiotensin I or K+.
, or both, are elevated,
and atrophy occurs with a deficiency of angiotensin II or with defects in its actions.

Question 23

What are the hypofunction disorders of the adrenal cortex

Answer 23

Adrenal insufficiency
Hypoaldosteronism

Question 24

What is adrenal insufficiency

Answer 24

Adrenal insufficiency is classified as primary, secondary, or tertiary (Table 40-3).
Primary adrenal insufficiency, also known as Addison disease, results from progressive destruction or dysfunction of the adrenal glands caused by a local disease process or systemic disorder (Box 40-1).’ Because the entire cortex is affected in primary adrenal insufficiency, all classes of adrenal steroids are deficient. The onset of clinical manifestationsis usually gradual, and the degree and severity of symptoms depend on the extent of adrenal failure. Early or mild expressions of primary adrenal insufficiency may not be evident unless the patient is under stress. Complete glucocorticoid deficiency will manifest in a variety of ways, including (1) fatigue, (2) weak-ness, (3) weight loss, (4) gastrointestinal disturbances, and (5) postprandial hypoglycemia. Mineralocorticoid deficiency leads to dehydration with hypotension, hyponatremia, and hyperkalemia. Excessive pituitary release of ACTH and related precursor peptides, unchecked by the negative feedback system, may cause hyperpigmentation of the skin and mucous membranes through the action of melanocyte-stimulating hormone on melanocytes.
Measurement of basal ACTH and cortisol concentrations along with the ACTH stimulation test is recommended if primary adrenal insufficiency is suspected from the patient’s clinical history and symptoms. Basal plasma ACTH concentrations >150 pg/mL with serum cortisol concentrations <10 kg/ dI are diagnostic of adrenal insufficiency. A subnormal cortisol response in the ACTH stimulation test supports the diagnosis of primary adrenal insufficiency. A normal cortisol response to ACTH stimulation establishes that the adrenal cortex is capable of releasing cortisol in a normal fashion. A subnormal response to ACTH stimulation suggests the diagnosis of secondary or tertiary adrenal failure (Table 40-3).
In secondary and tertiary adrenal insufficiencyinadequate cor tisol production may be due to destructive processes in the hypothalamic-pituitary that result in a decreased ability to secrete ACTH (secondary)or CRH (tertiary). 3,0 However, the most common cause of tertiary insufficiency is chronic pharmacological administration of glucocorticoids that suppress CRH synthesis. This leads to a decrease in both ACTH release and cortisol secretion. The clinical features of secondary and tertiary adrenal insufficiency are similar to those of primary insufficiency, except that hyperpigmentation is not present and hypotension is less severe; mineralocorticoid deficiency and ACTH excess are not seen in secondary or tertiary adrenal insufficiency. The ACTH stimulation test is also used to determine adrenal insufficiency in patients with secondary and tertiary adrenal insufficiency.
The CRH stimulation test is used to differentiate tertiary from secondary adrenal insufficiency.? Those with tertiary disease show an elevation in ACTH with intravenous CRH administration. Those with secondary disease show only minimal changes in ACTH concentrations.
Measurement of adrenal autoantibodies -antibodies against the 21-hydroxylase enzyme has been shown to be useful in evaluating patients suspected of adrenal insufficiency.

Question 25

What is hypoaldosteronism

Answer 25

Deficient aldosterone production occurs in individuals with Addison disease (Table 40-4).’ It also occurs in patients with
(1) inadequate production of renin by the kidney, which leads to secondary aldosterone deficiency (hyporeninemic hypoal-dosteronism); (2) inherited enzyme defects in aldosterone bio-synthesis; and (3) acquired forms of primary aldosterone deficiency (heparin therapy and postsurgery). The resulting metabolic changes are hyperkalemia and hyponatremia, often with a hypochloremic acidosis. Mild or moderate volume depletion, often with postural or unprovoked hypotension, may also occur. Hyporeninemic hypoaldosteronism also has been established by demonstrating failure of both plasma renin and aldosterone to increase in response to furosemide stimulation or upright posture. This disorder is more common in older patients and in individuals with diabetes mellitus. A high-renin form has been observed less frequently than the hyporenin form.
Patients with primary adrenal insufficiency usually also have aldosterone deficiency. Most endocrinologists, however, do not conduct tests to confirm aldosterone deficiency in these patients.

Question 26

What is Cushing syndrome

Answer 26

Cushing syndrome is the result of autonomous, excessive production of cortisol leading to classic symptoms characteristic of this disorder. !,0 The clinical picture includes (1) truncalobesity,
(2) moon face, (3) hypertension, (4) hirsutism, (5) hypokale-mic metabolic alkalosis, (6) carbohydrate intolerance, (7) disturbance of reproductive function, and (8) neuropsychiatric symptoms. The incidence of the clinical manifestations in Cushing syndrome are shown in Table 40-5. Frequently the cause is iatrogenic, caused by excessive exogenous steroid therapy. Endogenous disorders that cause hypersecretion of cortisol and Cushing syndrome are classified either as ACTH dependent or ACT H independent (Table 40-6). Cushing disease is the pituitary-dependent form of Cushing’s syndrome that accounts for 70% of the cases seen in clinical practice. In Cushing disease, hypersecretion of ACTH by a pituitary micro-adenoma is the primary defect that leads to bilateral adrenal hyperplasia and cortisol overproduction. In the ectopic ACTH syndrome, nonendocrine tumors (e.g., lung, gut, ovarian, and carcinoid tumors) develop the ability to secrete ACTH, resulting in (1) adrenal hyperplasia, (2) unregulated cortisol secre-tion, and (3) suppression of pituitary ACTH activity. In the form of Cushing syndrome associated with primary adrenal disease, such as adrenocortical adenoma or carcinoma (see Table 40-7), secretion of increased concentrations of cortisol suppresses both CRI synthesis and ACTH secretion. This results in atrophy of nontumorous adrenal tissue. Multiple endocrine neoplasia type 1 (MEN 1) and type 2 (MEN 2) also are causes of Cushing syndrome. MEN 1 results in Cushing syndrome through ACTH hypersecretion from a pituitary microadenoma or from an ectopic ACTH-secreting tumor of the pancreas or medullary thyroid carcinoma.

Question 27

What are some conditions that could mimic Cushing’s syndrome

Answer 27

Alcohol abuse has been known to induce a “pseudo-Cushing syndrome” that mimics the clinical and biochemical features of the actual disease. The abnormalities are all reversible once alcohol abuse by the patient is eliminated. The clinician must therefore use considerable judgment in detecting the cause of Cushing syndrome before therapy. Human immunodeficiency virus (HIV), anorexia nervosa, and depression are associated with elevated serum cortisol concentrations, and patients with these disorders may have positive low-dose overnight dexamethasone suppression tests. However, the clinical features of patients with HIV and anorexia nervosa are not typical of those with Cushing syndrome. Measurement of urinary free cortisol and plasma cortisol with the dexametha-sone suppression test improves the predictive value in the diagnosis of both Cushing syndrome and depression. 1
Obese patients also have presented with clinical features that mimic true Cushing syndrome. Features of Cushing syndrome that occur in normal, obese subjects include (1) truncal obesity, (2) striae, and (3) the excretion of elevated concentrations of 17-hydroxysteroids. Urinary Gee cortisol, sexual development are observed in girls, whereas male pseu-dohermaphroditism is seen in boys. The diagnosis is usually made at the time of puberty when patients present with hypo-gonadism in association with hypertension and hypokalemia.
The effectivenessof a treatment program for CAH is judged on the basis of the presence or absence of normal linear growth, normal sexual development, and suppression of abnormal blood and urine steroid concentrations into the reference interval.

Question 28

What is congenital adrenal hyperplasia (Adrenogenital Syndrome)

Answer 28

The biosynthesis of cortisol and aldosterone from cholesterol requires the action of specific enzymes in the adrenal cortex for the chemical modification and introduction of the different functional groups. CAH’ is characterized by the congenital absence or deficiency of one or more of the biosynthetic enzymes that lead to cortisol biosynthesis. As noted in Figure 40-3, a defect or deficiency in any one or all of the four key enzymes of adrenocorticoid biosynthesis can occur. As a result, cortisol biosynthesis is impaired, leading to a compensatory increase in ACTH release. ACTH then stimulates steroid biosynthesis to the point of the enzyme block.
The term CAH is used to denote the congenital presentation of this disorder (usually at birth) and the adrenocortical hyperplasia that results from the compensatory ACTH response to cortisol deficiency. “Adrenogenital syndrome” is also used to describe this disorder in that it affects the genitalia and secondary sex characteristics of the newborn. In girls, particu-larly, the diagnosis of CA H in the neonatal period is commonly suggested first by the observed presence of ambiguous genitalia.
In boys the abnormality may not be suspected until signs of precocious puberty or accelerated growth are present. Because aldosterone production has been observed to be compromised with accumulation and diversion of intermediate steroids to other pathways, hypertension and salt wasting may also be present. The adrenogenital syndrome is recognized with increased frequency in adults, with affected people presenting with subtle abnormalities at the time of puberty that go unrec-ognized. In adult women, the clinical presentation may be indistinguishable from the polycystic ovary syndrome (POS) or idiopathic hirsutism.

Deficiency of the 21-hydroxylase enzyme is the most common form of CAH, with more than 90% of cases caused by 21-hydroxylase deficiency. A deficiency of 11B-hydroxylase is the second most common form of CAH, with an incidence of 1 per 100,000 births, and is associated with (1) manifestations of virilization, (2) elevated concentrations of plasma androstenedione and DHEA-S, and (3) hypertension. A deficiency of 3ß-hydroxysteroid dehydrogenase-isomerase has been observed to lead to an elevation in the ratio of 170-hydroxypregnenolone to 17-hydroxyprogesterone and to an increased ratio of DHEA to androstenedione. In severe forms of this rare disorder, female infants have pseudoher-maphroditism, and male infants present with incomplete masculinization.
A reduction in the conversion of 17-hydroxypregnenolone to DHEA and of 17-hydroxyprogesterone to androstenedione results from a deficiency of C-17,20-lyase/17o-hydroxylase. A defect of this enzyme complex in the gonads of genetic females results in pubertal failure, and a defect in genetic males causes pseudohermaphroditism. The synthesis of cortisol, androgens, and estrogens is decreased, and the production of progesterone, corticosterone, and DOC is increased. In the complete form, hypertension and hyperkalemia with a lack of sexual development are observed in girls, whereas male pseu-dohermaphroditism is seen in boys. The diagnosis is usually made at the time of puberty when patients present with hypo-gonadism in association with hypertension and hypokalemia.
The effectivenessof a treatment program for CAH is judged on the basis of the presence or absence of normal linear growth, normal sexual development, and suppression of abnormal blood and urine steroid concentrations into the reference interval.

Question 29

What is Conn’s syndrome

Answer 29

Hyperaldosteronism, commonly referred to as Conn syndrome, is a syndrome associated with hypersecretion of the major mineralocorticoid, aldosterone (Table 40-8). Primary and secondary are the two types of hyperaldosteronism.
Primary Aldosteronism
In primary aldosteronism, excessive aldosterone production originates from within the adrenal gland; it was first described by Conn in 1955 and is characterized by an elevated plasma concentration of aldosterone along with hypertension and hypokalemia. Overproduction of aldosterone may be due to (1) an autonomous and inappropriate secretion of aldosterone by an adenoma of one adrenal gland (aldosterone-producing adrenal adenoma [APA] or Conn syndrome), (2) hyperplasia of aldosterone-producing cells in both glands (idiopathic adrenal hyperplasia [AHI), (3) an aldosterone-producing adrenal car-cinoma, or (4) a rare familial condition known as glucocorticoid-suppressible aldosteronism. The clinical features of primary aldosteronism are generally related to the consequences of aldosterone overproduction. They include (1) increased retention of sodium through the effects of aldosterone on the renal tubular handling of sodium, (2) expansion of extracellular fluid volume, and (3) increased tubular secretion of potassium and hydrogen ions. Hypokalemia and metabolic alkalosis result as a consequence of a progressive renal depletion of body potassium. As a consequence of sodium retention, there is a modest expansion of extracellular fluid volume and an increase in arterial blood pressure.

Secondary Aldosteronism
In secondary aldosteronism, a stimulus outside the adrenal gland activates the renin-angiotensin system.
The interaction of renin, angiotensin, and aldosterone is important in the regulation of extracellular fluid volume, blood pressure, and the balance of sodium and potassium ions. A change in one of these variables leads to changes in the others.
Secondary hyperaldosteronism is suspected in patients with volume depletion, edema, and hypokalemic alkalosis. Measurements of renin activities and aldosterone concentrations are seldom needed in these cases. Their measurements are invalu-able, however, in the investigation of primary disturbances in the renin-angiotensin-aldosteronesystem, in the assessment of renal artery stenosis, and in the genesis and maintenance of arterial hypertension.

Question 30

How is Conn’s diagnosed in the laboratory

Answer 30

Hypokalemia is the key clinical finding that primary aldos-teronism may be present in a patient with diastolic hyperten-sion? To confirm the diagnosis, it is necessary to demonstrate
(1) hyposecretion of renin that is not appropriately corrected during volume depletion, and (2) hypersecretion of aldosterone that fails to suppress appropriately during volume expansion. Figure 40-6 shows a suggested scheme for evaluating patients with suspected mineralocorticoid excess.

Most patients with autonomous aldosterone overproduction are hypokalemic. However, most patients with hypokalemia do nothave primary aldosteronism. In hyperaldosteronism, urinary potassium excretion is inappropriately high, and a random urine potassium of < 30 mmol/L is usually indicative of primary aldosteronism or some type of mineralocorticoid excess condi-tion. If hypokalemia is shown to be due to nonrenal potassium loss, the diagnosis of aldosteronism does not need to be considered further.! “
In primary aldosteronism, low renin activity and high aldosterone concentration are expected. Many other factors, however, influence the secretion of renin and aldosterone, and these factors must be recognized and understood before testing.
Because drugs such as ACE inhibitors, beta blockers, and spironolactone alter renin release, patients should be withdrawn from these medications for several weeks before determining the plasma aldosterone/plasma renin activity ratio. The use of an ACE inhibitor such as captopril has also been employed for the diagnosis of primary aldosteronism. In individuals who are normotensive or have essential hypertension, acute inhibition of ACE decreases angiotensin-mediated aldosterone production, and the autonomous aldosterone production from a aldosterone-producing adenoma is unaffected by the ACE inhibitor.
The determination of plasma renin responsiveness, however, is not sufficient to diagnose primary aldosteronism because suppressed plasma renin activity (PRA) also occurs in about 25% of patients with essential hypertension. It is possible to differentiate primary aldosteronism from other hypermineralo-corticoid states on the basis of inappropriate secretion of aldo-sterone. The demonstration of an elevated concentration of aldosterone in blood or urine in a patient with an unequivocally suppressed plasma renin concentration (a plasma aldosterone/plasma renin ratio > 50) is presumptive evidence of primary aldosteronism. Because hypokalemia has a suppressive effect on aldosterone secretion, the potassium deficit should be replaced before aldosterone measurements are done.
To establish aldosterone autonomy, the clinician may attempt to suppress aldosterone production with rapid volume expansion using either a potent mineralocorticoid or captopril.
Failure of aldosterone to be suppressed using these maneuvers confirms a diagnosis of primary aldosteronism.
Once the diagnosis of primary aldosteronism is established, it is necessary to distinguish between APA and bilateral IAH.
This differentiation is vital because most patients with adrenal adenomas respond positively to surgical removal of the tumor.
Patients with adrenal hyperplasia do not respond and are managed medically. Localization using imaging techniques has been helpful. A number of biochemical clues also help with the differential diagnosis. Aldosterone hypersecretionand plasma renin suppression are usually greater with adrenal ade-nomas. After sodium depletion or after 2 to 4 hours of upright posture, patients with APA usually show no change or a paradoxical fall in plasma aldosterone. Patients with IAH typically show an increase in plasma aldosterone. Elevated plasma concentrations of aldosterone precursor substrates, such as
18-hydroxycorticosteroid (> 85 ng/dL), are observed in most patients with APA but not in those with IAH.

Question 31

What are some other causes of adrenal mineralocorticoid excess

Answer 31

Adrenocortical carcinomas have been found to produce excess mineralocorticoid and cause hypertension with hypokalemia.
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Either aldosterone or DOC, or both, may be produced in excess. Mineralocorticoid concentrations do not respond to glucocorticoid therapy or alterations in salt status. CT scans are helpful. Adrenal carcinomas are usually large tumors that weigh more than 30 g; aldosterone-secreting adenomas are usually much smaller. Finding low plasma renin activity and aldosterone concentration under circumstances that should cause an elevation (furosemide stimulation or upright posture) would support the diagnosis.
Other unusual conditions that suggest aldosterone excess or deficiency but are not connected to the renin-angiotensin-aldosterone system include Liddle and Barter syndromes. Liddle syndrome also is known as pseudohyperaldosteronism and resembles primary aldosteronism clinically, but aldosterone production is low and hypertension is absent. In Barter syn-drome, which involves a prostaglandin-mediated renal potassium wasting and renal chloride handling defect, both aldosterone concentrations and renin activities are elevated.
In renal tubular acidosis and pseudohypoaldosteronism, the clinical picture of hypoaldosteronism is seen concurrent with greater-than-normal concentrations of aldosterone.