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CHAPTER 386 — DISORDERS OF THE ADRENAL CORTEX

COMPLETE EXTRACTION (PDF Only, No Outside Information)

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OVERVIEW

• The adrenal cortex produces three classes of corticosteroid hormones:
  1. Glucocorticoids (e.g., cortisol)
  2. Mineralocorticoids (e.g., aldosterone)
  3. Adrenal androgen precursors (e.g., dehydroepiandrosterone [DHEA])
• Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis.
• Adrenal androgen precursors are converted in the gonads and peripheral target cells to sex steroids that act via nuclear androgen and estrogen receptors.
• Disorders are characterized by deficiency or excess of one or several of the three major corticosteroid classes.
• Hormone deficiency caused by: inherited glandular or enzymatic disorders OR destruction of pituitary or adrenal gland by autoimmune disorders, infection, infarction, or iatrogenic events (surgery or hormonal suppression).
• Hormone excess is usually the result of neoplasia, leading to increased production of ACTH by the pituitary or neuroendocrine ectopic ACTH-producing cells, or increased production of glucocorticoids, mineralocorticoids, or adrenal androgen precursors by adrenal nodules.
• Adrenal nodules are increasingly identified incidentally during cross-sectional imaging of chest or abdomen performed for other reasons.

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ADRENAL ANATOMY AND DEVELOPMENT

• Normal adrenal gland weight: 6-11 g each
• Located above the kidneys; have their own blood supply.
• Arterial blood flows initially to the subcapsular region and then meanders from the outer cortical zona glomerulosa through the intermediate zona fasciculata to the inner zona reticularis and eventually to the adrenal medulla.
• The right suprarenal vein drains directly into the vena cava.
• The left suprarenal vein drains into the left renal vein.
• During early embryonic development, adrenals originate from the urogenital ridge, then separate from gonads and kidneys at about the sixth week of gestation.
• Concordant with the time of sexual differentiation (seventh to ninth week of gestation), the adrenal cortex starts to produce cortisol and the adrenal sex steroid precursor DHEA.
• Orphan nuclear receptors SF1 (steroidogenic factor 1; encoded by gene NR5A1) and DAX1 (dosage-sensitive sex reversal gene 1; encoded by gene NR0B1) play a crucial role during this period of development, regulating a multitude of adrenal genes involved in steroidogenesis.
• Three zones of the adrenal cortex:
  • Outer: Zona glomerulosa - mineralocorticoid synthesis
  • Middle: Zona fasciculata - glucocorticoid synthesis
  • Inner: Zona reticularis - adrenal androgen biosynthesis (precursors for classic and 11-oxygenated androgens)

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REGULATORY CONTROL OF STEROIDOGENESIS

HPA Axis (Glucocorticoids and Adrenal Androgens)

• Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis.
• Mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system.
• Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary.
• Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress.
• CRH stimulates the cleavage of the 241-amino acid polypeptide proopiomelanocortin (POMC) by pituitary-specific prohormone convertase 1 (PC1), yielding the 39-amino acid peptide ACTH.
• ACTH is released by the corticotrope cells of the anterior pituitary and acts as the pivotal regulator of adrenal cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis.
• The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm under the control of the hypothalamus, specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes.
• Adrenal cortisol secretion exhibits a distinct circadian rhythm: starts to rise in the early morning hours prior to awakening, with peak levels in the morning and low levels in the evening (Fig. 386-3).
• Acrophase: 0830 h (peak)
• Nadir: 0015 h (lowest)
• MESOR: 5.25 µg/dL (145 nmol/L) (rhythm-adjusted mean)

Dexamethasone Suppression Test

• Diagnostic tests assessing HPA axis make use of negative feedback.
• Glucocorticoid excess is diagnosed by employing a dexamethasone suppression test.
• Dexamethasone, a potent synthetic glucocorticoid, suppresses CRH/ACTH by binding hypothalamic-pituitary glucocorticoid receptors (GRs), results in downregulation of endogenous cortisol synthesis.
• If cortisol production is autonomous (e.g., adrenal nodule): ACTH is already suppressed, dexamethasone has little additional effect.
• If driven by ACTH-producing pituitary adenoma: dexamethasone suppression ineffective at low doses but usually induces suppression at high doses.
• If driven by ectopic ACTH: tumors are usually resistant to dexamethasone suppression.

ACTH Stimulation Test (Cosyntropin Test)

• The ACTH peptide contains 39 amino acids, but the first 24 are sufficient to elicit a physiologic response.
• Standard ACTH stimulation test: cosyntropin (ACTH 1-24), 0.25 mg IM or IV, blood samples at 0, 30, and 60 min for cortisol.
• Normal response: cortisol level >15-20 µg/dL (>400-550 nmol/L) at 30-60 min after cosyntropin stimulation (precise cutoff dependent on assay used).
• Low-dose (1 µg cosyntropin IV) version: advocated, however it has no superior diagnostic value and is more cumbersome to carry out.

Insulin Tolerance Test (ITT)

• Can be used to assess adrenal function. Involves injection of insulin to induce hypoglycemia (strong stress signal).
• Involves administration of regular insulin 0.1 U/kg IV (dose should be lower if hypopituitarism is likely); blood samples at 0, 30, 60, and 120 min for glucose, cortisol, and GH.
• Oral or IV glucose is administered after patient has achieved symptomatic hypoglycemia (usually plasma glucose <40 mg/dL).
• Normal response: cortisol >20 µg/dL and GH >5.1 µg/L (assay-specific cutoff variability).
• Requires careful clinical monitoring and sequential measurements of glucose.
• Contraindicated in patients with coronary disease, cerebrovascular disease, or seizure disorders, which has made the short cosyntropin test the commonly accepted first-line test.

RAA System (Mineralocorticoids)

• Mineralocorticoid production controlled by the RAA regulatory cycle.
• Initiated by release of renin from juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver.
• ACE cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor [AT1R]), resulting in increased adrenal aldosterone production and vasoconstriction.
• Aldosterone enhances sodium retention and potassium excretion, and increases arterial perfusion pressure, which in turn regulates renin release.
• Because mineralocorticoid synthesis is primarily under the control of the RAA system, hypothalamic-pituitary damage does NOT significantly impact the capacity of the adrenal to synthesize aldosterone.
• If mineralocorticoid excess is present: counter-regulatory downregulation of plasma renin.
• In mineralocorticoid deficiency: plasma renin is markedly increased.
• Physiologically, oral or IV sodium loading results in suppression of aldosterone, a response that is attenuated or absent in patients with autonomous mineralocorticoid excess.

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STEROID HORMONE SYNTHESIS, METABOLISM, AND ACTION

ACTH Receptor Signaling

• ACTH receptor: MC2R (melanocortin 2 receptor) interacts with MC2R-accessory protein MRAP, and the complex is transported to the adrenocortical cell membrane.
• ACTH stimulation generates cyclic AMP (cAMP), which upregulates the protein kinase A (PKA) signaling pathway.
• Inactive PKA is a tetramer of two regulatory and two catalytic subunits dissociated by cAMP into a dimer of two regulatory subunits bound to cAMP and two free and active catalytic subunits.
• PKA activation impacts steroidogenesis in three distinct ways:
  1. Increases the import of cholesterol esters
  2. Increases the activity of hormone-sensitive lipase, which cleaves cholesterol esters to cholesterol for import into the mitochondrion
  3. Increases the availability and phosphorylation of CREB (cAMP response element binding), a transcription factor that enhances transcription of CYP11A1 and other enzymes required for glucocorticoid synthesis

Adrenal Steroidogenesis (Zone-Specific)

• Mineralocorticoid synthesis: outer zona glomerulosa
• Glucocorticoid synthesis: zona fasciculata
• Adrenal androgen biosynthesis: inner zona reticularis (precursors for both classic and 11-oxygenated androgens)
• All steroidogenic pathways require cholesterol import into the mitochondrion, initiated by the action of StAR (steroidogenic acute regulatory) protein, which shuttles cholesterol from the outer to the inner mitochondrial membrane.
• The majority of steroidogenic enzymes are cytochrome P450 (CYP) enzymes, either located in the mitochondrion or endoplasmic reticulum membrane.

• CYP11A1 (side chain cleavage enzyme)
• CYP11B1 (11β-hydroxylase)
• CYP11B2 (aldosterone synthase)

• CYP17A1 (17α-hydroxylase)
• CYP21A2 (21-hydroxylase)
• CYP19A1 (aromatase)
• These enzymes require electron donation via specific redox cofactor enzymes:
  • POR (P450 oxidoreductase) for microsomal CYP enzymes
  • ADX/ADR (adrenodoxin/adrenodoxin reductase) for mitochondrial CYP enzymes
• 3β-HSD2 (3β-hydroxysteroid dehydrogenase type 2), also termed Δ4, Δ5 isomerase, plays a major role in adrenal steroidogenesis.

Glucocorticoid Synthesis Pathway

• CYP11A1 generates pregnenolone from cholesterol.
• Pregnenolone → progesterone by 3β-HSD2
• Progesterone → 17-hydroxyprogesterone (17OHP) by CYP17A1
• 17OHP → hydroxylation at carbon 21 by CYP21A2
• Final step: 11β-hydroxylation by CYP11B1 to generate active cortisol

Mineralocorticoid Synthesis Pathway

• Progesterone → deoxycorticosterone (DOC) by CYP21A2
• DOC → corticosterone → 18-hydroxycorticosterone → aldosterone in three steps catalyzed by CYP11B2

Adrenal Androgen Synthesis Pathway

• Pregnenolone → 17-hydroxypregnenolone (via CYP17A1 17α-hydroxylase activity)
• 17-hydroxypregnenolone → DHEA via CYP17A1 17,20 lyase activity
• The majority of DHEA is secreted by the adrenal in the form of its sulfate ester, DHEAS, generated by DHEA sulfotransferase (SULT2A1).
• DHEA is converted to androstenedione, which can be activated to testosterone or channeled into the 11-oxygenated androgen pathway by 11β-hydroxylation (CYP11B1).
• CYP17A1 uniquely catalyzes two enzymatic reactions: 17α-hydroxylase activity AND 17,20 lyase activity.

Cortisol Circulation and Metabolism

• Following release from adrenal, cortisol circulates mainly bound to cortisol-binding globulin (CBG) and, to a lesser extent, to albumin; only a minor fraction circulates as free, unbound hormone.
• Free cortisol is thought to enter cells directly, not requiring active transport.
• In peripheral target tissues (adipose, liver, muscle, brain), cortisol is generated from inactive cortisone within the cell by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) (Fig. 386-6).
• 11β-HSD1 functions as a tissue-specific prereceptor regulator of glucocorticoid action.
• For the conversion of inactive cortisone to active cortisol, 11β-HSD1 requires NADPH, which is provided by the enzyme hexose-6-phosphate dehydrogenase (H6PDH).
• H6PDH is located in the lumen of the endoplasmic reticulum and converts glucose-6-phosphate (G6P) to 6-phosphogluconate (6PGL), thereby regenerating NADP+ to NADPH.
• Cortisol is inactivated to cortisone by the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (Fig. 386-7), mainly in the kidney, but also in the colon, salivary glands, and other target tissues.
• Cortisol and aldosterone bind the mineralocorticoid receptor (MR) with equal affinity; however, cortisol circulates in the bloodstream at about a 1000-fold higher concentration.
• Only rapid inactivation of cortisol to cortisone by 11β-HSD2 prevents MR activation by excess cortisol - thereby acting as a tissue-specific modulator of the MR pathway.
• In addition to cortisol and aldosterone, DOC also exerts mineralocorticoid activity. DOC accumulation due to 11β-hydroxylase deficiency or tumor-related excess production can result in mineralocorticoid excess.
• Corticosterone also exerts glucocorticoid activity, albeit much weaker than cortisol itself. However, in rodents, corticosterone is the major glucocorticoid.
• In patients with 17-hydroxylase deficiency, lack of cortisol can be compensated for by higher concentrations of corticosterone that accumulates as a consequence of the enzymatic block.

Glucocorticoid Receptor (GR) Action

• In the cytosol of target cells, cortisol binds and activates the GR, which results in dissociation of heat shock proteins (HSPs) from the receptor and subsequent dimerization (Fig. 386-6).
• Cortisol-bound GR dimers translocate to the nucleus and activate glucocorticoid response elements (GREs) in the DNA sequence, thereby enhancing transcription of glucocorticoid-regulated genes (GR transactivation).
• Cortisol-bound GR can also form heterodimers with transcription factors such as AP-1 or NF-κB, resulting in transrepression of proinflammatory genes — mechanism of major importance for the anti-inflammatory action of glucocorticoids.

Mineralocorticoid Receptor (MR) Action and Aldosterone

• Aldosterone synthesis in adrenal zona glomerulosa cells is driven by the enzyme aldosterone synthase (CYP11B2).
• Binding of angiotensin II to the AT1 receptor causes glomerulosa cell membrane depolarization by increasing intracellular sodium through inhibition of Na+/K+ ATPase enzymes as well as potassium channels.
• This drives an increase in intracellular calcium by opening of voltage-dependent calcium channels or inhibition of Ca2+ ATPase enzymes.
• Consequently, calcium signaling pathway is triggered, resulting in upregulation of CYP11B2 transcription (Fig. 386-8).
• Aldosterone (or cortisol) binding to the MR in the kidney tubule cell dissociates the HSP-receptor complex, allowing homodimerization of the MR and translocation of the hormone-bound MR dimer to the nucleus (Fig. 386-7).
• The activated MR enhances transcription of:
  • ENaC (epithelial sodium channel)
  • SGK-1 (serum glucocorticoid-inducible kinase 1)
• In the cytosol, interaction of ENaC with Nedd4 prevents cell surface expression of ENaC.
• SGK-1 phosphorylates serine residues within the Nedd4 protein, reduces the interaction between Nedd4 and ENaC, and consequently enhances the trafficking of ENaC to the cell surface, where it mediates sodium retention.

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CUSHING'S SYNDROME

• Cushing's syndrome reflects a constellation of clinical features that result from chronic exposure to excess glucocorticoids of any etiology.
• ACTH-dependent (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary tumor) OR ACTH-independent (e.g., adrenocortical adenoma, ACC, nodular adrenal hyperplasia), as well as iatrogenic (e.g., administration of exogenous glucocorticoids).
• "Cushing's disease" refers specifically to Cushing's syndrome caused by a pituitary corticotrope adenoma.

TABLE 386-1: Causes of Cushing's Syndrome

Etiology Details

• In at least 90% of patients with Cushing's disease, ACTH excess is caused by a corticotrope pituitary microadenoma, often only a few millimeters in diameter.
• Pituitary macroadenomas (tumors >1 cm in size) are found in only 5-10% of patients.
• Pituitary corticotrope adenomas usually occur sporadically but very rarely can be found in the context of MEN 1 (Chap. 388).
• USP8 mutations: Pituitary adenomas causative of Cushing's disease frequently harbor mutations in the deubiquitinase USP8, which leads to constitutive activation of EGF signaling and consequent upregulated expression of the ACTH precursor POMC.
• USP8 mutations are found more frequently in adults (41 vs 17% in children) and in women (43 vs 17% in men) with Cushing's disease.
• Cushing's disease more frequently affects women, with the exception of prepubertal cases, where it is more common in boys.

• Predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in thymus or pancreas.
• Because of their small size, these tumors are often difficult to locate.
• Advanced small-cell lung cancer can cause ectopic ACTH production.
• In rare cases, ectopic CRH and/or ACTH production has been found to originate from medullary thyroid carcinoma or pheochromocytoma, the latter co-secreting catecholamines and ACTH.
• Ectopic ACTH syndrome is more frequently identified in men.

• Only 10% of patients with Cushing's syndrome have a primary, adrenal cause; most of these patients are women.
• Majority harbor a cortisol-producing adrenal adenoma; somatic mutations in the PKA catalytic subunit PRKACA have been identified as cause of disease in 40% of these tumors.
• ACCs may also cause ACTH-independent disease and are often large, with excess production of several corticosteroid classes.

• Low circulating ACTH but with evidence for autocrine stimulation of cortisol production via intraadrenal ACTH production.
• Often characterized by ectopic expression of G protein-coupled receptors not usually found in the adrenal, including receptors for luteinizing hormone, vasopressin, serotonin, interleukin 1, catecholamines, or gastric inhibitory peptide (GIP), the cause of food-dependent Cushing's.
• Activation of these receptors results in upregulation of PKA signaling, as physiologically occurs with ACTH.
• Combination of germline and somatic mutations in the tumor-suppressor gene ARMC5 have been identified as a prevalent cause of Cushing's due to bilateral macronodular adrenal hyperplasia.
• Constitutively activating mutations in the PKA catalytic subunit PRKACA are found as somatic mutations in one-third of cortisol-producing adrenocortical adenomas and, as germline mutations, can also represent a rare cause of macronodular adrenal hyperplasia associated with cortisol excess.

• Germline mutations in PRKAR1A (one of the regulatory subunits of PKA) are found in patients with PPNAD as part of Carney's complex.
• Carney's complex: autosomal dominant multiple neoplasia condition associated with cardiac myxomas, hyperlentiginosis, Sertoli cell tumors, and PPNAD.
• PPNAD can present as micronodular or macronodular hyperplasia, or both.
• PDE11A and PDE8B mutations have been identified in patients with bilateral adrenal hyperplasia and Cushing's, with and without evidence of PPNAD.

• Caused by activating mutations in GNAS-1 (guanine nucleotide-binding protein alpha stimulating activity polypeptide 1).
• Also associated with polyostotic fibrous dysplasia, unilateral café-au-lait spots, and precocious puberty.
• Such mutations have also been found in bilateral macronodular hyperplasia without other McCune-Albright features, and in rare instances also in isolated cortisol-producing adrenal adenomas.
• The most common cause of Cushing's syndrome overall is the medical use of glucocorticoids for immunosuppression or for treatment of inflammatory disorders (iatrogenic Cushing's).

Clinical Manifestations

• Suppression of gonadotropins → hypogonadism and amenorrhea
• Suppression of hypothalamic-pituitary-thyroid axis → decreased TSH secretion

TABLE 386-2: Signs and Symptoms of Cushing's Syndrome

• Fragility of the skin, with easy bruising and broad (>1 cm), purplish striae (Fig. 386-9).
• Signs of proximal myopathy: most obvious when trying to stand up from a chair without the use of hands or when climbing stairs.
• Clinical manifestations of Cushing's do not differ substantially among the different causes of Cushing's.
• In ectopic ACTH syndrome: hyperpigmentation of the knuckles, scars, or skin areas exposed to increased friction (due to stimulatory effects of excess ACTH and other POMC cleavage products on melanocyte pigment production).
• Patients with ectopic ACTH syndrome, and some with ACC, may have a more brisk onset and rapid progression of clinical signs, namely edema, hypokalemia, and hypertension.
• Patients with Cushing's can be acutely endangered by deep vein thrombosis with subsequent pulmonary embolism (hypercoagulable state).
• Majority also experience psychiatric symptoms, mostly anxiety or depression; acute paranoid or depressive psychosis may occur.
• Even after cure, long-term health may be affected by persistently impaired health-related quality of life and increased risk of cardiovascular disease and osteoporosis.

Diagnosis of Cushing's Syndrome

• Most important first step: establish the correct diagnosis.
• Most mistakes in clinical management are made because the diagnostic protocol is not followed.
• Protocol requires establishing the diagnosis of Cushing's beyond doubt prior to employing any tests for differential diagnosis.
• After excluding exogenous glucocorticoid use, suspected cases should be tested if there are multiple and progressive features, particularly those with potentially higher discriminatory value.
• Exclusion of Cushing's is also indicated in patients with incidentally discovered adrenal masses.

1. Increased 24-h urinary free cortisol excretion in three separate collections (≥2x normal)
2. Failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone (Plasma cortisol >50 nmol/L at 8-9 am after 1 mg dexamethasone at 11 pm)
3. Evidence of loss of diurnal cortisol secretion with high levels at midnight - Midnight salivary cortisol >5 nmol/L (≥2x)

• Low dose DEX test: Plasma cortisol >50 nmol/L after 0.5 mg DEX q6h for 2 days OR a single dose of 8 mg overnight.

• Incomplete 24-h urine collection
• Rapid inactivation of dexamethasone due to concurrent intake of CYP3A4-inducing drugs (e.g., antiepileptics, rifampicin)
• Concurrent intake of oral contraceptives that raise CBG and thus total cortisol can cause failure to suppress after dexamethasone. If in doubt, testing should be repeated after 4-6 weeks off estrogens.
• Patients with pseudo-Cushing states (i.e., alcohol-related) and those with cyclic Cushing's may require further testing.
• Specificity is a common problem with antibody-based assays for urinary free cortisol, greatly improved by introduction of tandem mass spectrometry.

Differential Diagnosis

• Plasma ACTH levels are suppressed (<5 pg/mL) in autonomous adrenal cortisol excess (ACTH-independent).
• Patients with ACTH-dependent Cushing's have normal or increased ACTH (>15 pg/mL), with very high levels in some patients with ectopic ACTH syndrome.
• Imaging should only be used AFTER it is established whether cortisol excess is ACTH-dependent or ACTH-independent because nodules in the pituitary or adrenal are a common finding in the general population.
• In confirmed ACTH-independent excess: adrenal imaging is indicated, preferably using an unenhanced CT scan.

• MRI of the pituitary is the investigation of choice, but may not show an abnormality in up to 40% of cases because of small tumors below the sensitivity of detection.
• Pituitary corticotrope adenomas fail to enhance following gadolinium administration on T1-weighted MRI images.
• CRH test: ACTH increase >40% at 15-30 min + cortisol increase >20% at 45-60 min after CRH 100 µg IV
• High dose DEX test: Cortisol suppression >50% after q6h 2 mg DEX for 2 days
• Most pituitary corticotrope adenomas still display regulatory features: residual ACTH suppression by high-dose glucocorticoids and CRH responsiveness.
• Ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH.
• A small minority of ectopic ACTH-producing tumors exhibit dynamic responses similar to pituitary corticotrope tumors.

• If two tests show discordant results, differential diagnosis can be further clarified by bilateral IPSS with concurrent blood sampling for ACTH in right and left inferior petrosal sinus and a peripheral vein.
• Increased central/peripheral plasma ACTH ratio >2 at baseline and >3 at 2-5 min after CRH injection is indicative of Cushing's disease (with very high sensitivity and specificity).
• Results of the IPSS cannot be reliably used for lateralization because there is broad interindividual variability in the venous drainage of the pituitary region.
• Importantly, no cortisol-lowering agents should be used prior to IPSS.

• High-resolution, fine-cut CT scanning of chest and abdomen for lung, thymus, and pancreas.
• If no lesions identified, an MRI of the chest can be considered because carcinoid tumors usually show high signal intensity on T2-weighted images.
• Octreotide scintigraphy can be helpful because ectopic ACTH-producing tumors often express somatostatin receptors.
• Blood sampling for fasting gut hormones, chromogranin A, calcitonin, and biochemical exclusion of pheochromocytoma.

Treatment of Cushing's Syndrome

• Overt Cushing's is associated with a poor prognosis if left untreated.

• Smaller tumors: minimally invasive approach
• Larger tumors / suspected malignancy: open approach preferred

• Treatment of choice: selective removal of the pituitary corticotrope tumor, usually via an endoscopic transsphenoidal approach.
• Initial cure rate of 70-80% when performed by a highly experienced surgeon.
• Even after initial remission, long-term follow-up is important because late relapse occurs in a significant number of patients.
• If pituitary disease recurs: second surgery, radiotherapy, stereotactic radiosurgery, and bilateral adrenalectomy.

• In some patients with very severe, overt Cushing's (e.g., difficult to control hypokalemic hypertension or acute psychosis), medical therapy may be necessary to rapidly control cortisol excess during the period leading up to surgery; also helps to alleviate hypercoagulability and operative risk.
• Patients with metastasized, glucocorticoid-producing carcinomas may require long-term antiglucocorticoid drug treatment.
• In ectopic ACTH syndrome where tumor cannot be located, carefully weigh whether drug treatment or bilateral adrenalectomy is most appropriate; the latter facilitates immediate cure but requires life-long corticosteroid replacement.
• Regular imaging follow-up for identification of the ectopic ACTH source is paramount.

1. Metyrapone: inhibits cortisol synthesis at the level of 11β-hydroxylase. Typical starting dose: 500 mg tid (maximum dose: 6 g).
2. Ketoconazole (antimycotic drug): inhibits the early steps of steroidogenesis. Typical starting dose: 200 mg tid (maximum dose: 1200 mg).
3. Osilodrostat: potent 11β-hydroxylase inhibitor, recently introduced; also exerts strong inhibition of aldosterone synthase (CYP11B2).
4. Mitotane (derivative of insecticide o,p'DDD): adrenolytic agent, effective for reducing cortisol. Because of its side effect profile, most commonly used in the context of ACC, but low-dose treatment (500-1000 mg/d) has also been used in benign Cushing's.
5. Etomidate: potently blocks 11β-hydroxylase and aldosterone synthase; administered by continuous IV infusion in low, nonanesthetic doses in severe cases.
6. Pasireotide (somatostatin receptor agonist): subcutaneous administration for Cushing's disease, if surgical cure cannot be achieved.

• After successful removal of an ACTH- or cortisol-producing tumor, the HPA axis will remain suppressed.
• Hydrocortisone replacement needs to be initiated at the time of surgery and slowly tapered following recovery, to allow physiologic adaptation to normal cortisol levels.
• Depending on degree and duration of cortisol excess, the HPA axis may require many months or even years to resume normal function and sometimes does not recover.
• Recovery rates: Ectopic ACTH syndrome: best recovery rate (80%); Cushing's disease: intermediate (60%); Adrenal Cushing's: lowest (40%).

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MINERALOCORTICOID EXCESS

Etiology

• Most common cause: primary aldosteronism (excess production of aldosterone by adrenal zona glomerulosa).
• Bilateral micronodular hyperplasia is somewhat more common than unilateral adrenal adenomas (Table 386-3).

• Potassium channel GIRK4 (encoded by KCNJ5): identified as cause in 40% of aldosterone-producing adenomas; rare germline mutations can cause bilateral macronodular adrenal hyperplasia.
• α-subunit of Na+/K+-ATPase (encoded by ATP1A1)
• Plasma membrane calcium-transporting ATPase 3 (encoded by ATP2B3)
• Somatic mutations in CACNA1D or CACNA1H encoding voltage-gated calcium channels CaV1.3 and CaV3.2 respectively.
• All mutations result in upregulation of CYP11B2 and hence aldosterone synthesis.

• Caused by a chimeric gene resulting from crossover of CYP11B1 and CYP11B2 promoter sequences.
• This rearrangement brings CYP11B2 transcription under the control of ACTH receptor signaling; consequently, aldosterone production is regulated by ACTH rather than by renin.
• Family history can be helpful; evidence for dominant transmission of hypertension.
• Recognition is important because it can be associated with early-onset hypertension and strokes.
• Glucocorticoid suppression can reduce aldosterone production.
• Treatment: dexamethasone (using lowest dose possible to control blood pressure); some patients also require additional MR antagonist treatment.

TABLE 386-3: Causes of Mineralocorticoid Excess (Key entries)

• Caused by inactivating mutations in the HSD11B2 gene → lack of renal inactivation of cortisol to cortisone → excess activation of MR by cortisol.
• Characteristically manifests with severe hypokalemic hypertension in childhood.
• Milder mutations may cause normokalemic hypertension manifesting in adulthood (type II SAME).
• Inhibition of 11β-HSD2 by excess licorice ingestion also results in hypokalemic hypertension.
• Overwhelming of 11β-HSD2 conversion capacity by cortisol excess in Cushing's syndrome also results in hypokalemic hypertension.

• Caused by mutations in the β or γ subunits of ENaC, disrupting its interaction with Nedd4 → decreasing receptor internalization and degradation.
• The constitutively active ENaC drives hypokalemic hypertension.
• Autosomal dominant disorder.
• Very sensitive to amiloride treatment but will NOT respond to MR antagonist treatment because the defect is due to a constitutively active ENaC.

• Rare individuals who harbor a MR mutation that enhances binding and activation by progesterone.
• Physiologically, progesterone normally exerts antimineralocorticoid activity.

Clinical Manifestations

• Clinical hallmark: hypokalemic hypertension; however, only 50% of patients with primary aldosteronism exhibit hypokalemia.
• Serum sodium tends to be normal due to concurrent fluid retention.
• Hypomagnesemia is also a common finding.
• Hypokalemia can be exacerbated by thiazide drug treatment (increased delivery of sodium to the distal renal tubule, driving potassium excretion).
• Severe hypokalemia can be associated with muscle weakness, overt proximal myopathy, or even hypokalemic paralysis.
• Severe alkalosis contributes to muscle cramps and, in severe cases, can cause tetany.
• Excess activation of MR leads to potassium depletion and increased sodium retention → expansion of extracellular and plasma volume.
• Increased ENaC activity also results in hydrogen depletion → metabolic alkalosis.
• Aldosterone also has direct effects on the vascular system: increases cardiac remodeling and decreases compliance.
• Aldosterone excess may cause direct damage to the myocardium and the kidney glomeruli, in addition to secondary damage due to systemic hypertension.
• Patients with primary aldosteronism show increased rates of osteoporosis, type 2 diabetes, and cognitive dysfunction.
• A significant proportion of patients suffer from concurrent mild autonomous cortisol excess (MACE), termed "Connshing syndrome."

Diagnosis

• Diagnostic screening for mineralocorticoid excess is NOT currently recommended for all patients with hypertension but should be restricted to those who exhibit hypertension associated with:
  1. Drug resistance
  2. Hypokalemia
  3. An adrenal mass
  4. Onset of disease before age 40 years
• Accepted screening test: concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone-renin ratio (ARR).
• Serum potassium needs to be normalized prior to testing.
• MR antagonists need to be ceased at least 4 weeks prior to ARR measurement.
• Beta blocker treatment can cause false-positive results.
• ACE/AT1R inhibitors can cause false-negative results in milder cases (Table 386-4).

TABLE 386-4: Effects of Antihypertensive Drugs on ARR

• ARR positive if ratio >750 pmol/L per ng/mL per hour with concurrently high normal or increased aldosterone.
• Some labs measure plasma renin activity, whereas others measure plasma renin concentrations.
• ARR screen positive if ARR >750 pmol/L: ng/mL/h AND aldosterone >450 pmol/L

1. Saline infusion test: IV administration of 2 L of physiologic saline over a 4-h period. Failure of aldosterone to suppress <140 pmol/L (5 ng/dL) is indicative of autonomous mineralocorticoid excess.
2. Oral sodium loading test: 300 mmol NaCl/d for 3 days
3. Fludrocortisone suppression test: 0.1 mg q6h with 30 mmol NaCl q8h for 4 days; can be difficult because of the risk of profound hypokalemia and increased hypertension.

• In patients with overt hypokalemic hypertension, strongly positive ARR, and concurrently increased aldosterone levels, confirmatory testing is usually NOT necessary.

Differential Diagnosis and Treatment

• Fine-cut CT scanning of the adrenal region is the method of choice.
• Most aldosterone-producing adenomas are <1 cm.
• CT will readily identify larger tumors suspicious of malignancy but may miss lesions <5 mm.

• Should only be carried out in surgical candidates with either no obvious lesion on CT or evidence of a unilateral lesion but with age >40 years (because the latter patients have a high likelihood of harboring a coincidental, endocrine-inactive adrenal adenoma).
• Requires concurrent measurement of cortisol to document correct placement; should demonstrate a cortisol gradient >3 between the vena cava and each adrenal vein.
• Lateralization is confirmed by an aldosterone/cortisol ratio that is at least twofold higher on one side than the other.
• Right adrenal vein can be difficult to cannulate correctly, which, if not achieved, invalidates the procedure.
• No agreement as to whether the two adrenal veins should be cannulated simultaneously or successively and whether ACTH stimulation enhances the diagnostic value.

• Patients <40 years with confirmed mineralocorticoid excess and a unilateral lesion on CT can go straight to surgery.
• Laparoscopic adrenalectomy is the preferred approach.
• Patients not surgical candidates, or with evidence of bilateral hyperplasia, should be treated medically.

• MR antagonist spironolactone: started at 12.5-50 mg bid, titrated up to a maximum of 400 mg/d. Side effects: menstrual irregularity, decreased libido, gynecomastia.
• Eplerenone (more selective MR antagonist): doses start at 25 mg bid, can be titrated up to 200 mg/d.
• Amiloride (sodium channel blocker): 5-10 mg bid.

• Based on documentation of suppressed renin and suppressed aldosterone in the presence of hypokalemic hypertension.
• Best carried out by urinary steroid metabolite profiling by gas chromatography/mass spectrometry (GC/MS).
• Increased free cortisol over free cortisone ratio is suggestive of SAME and can be treated with dexamethasone.

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APPROACH TO THE PATIENT: INCIDENTALLY DISCOVERED ADRENAL MASS

Definition and Prevalence

• Incidentally discovered adrenal masses, commonly termed adrenal "incidentalomas", prevalence of 2-5% in the general population (CT and autopsy series).
• Prevalence increases with age: 1% of 40-year-olds and 7% of 70-year-olds harboring an adrenal mass.

Etiology

• Most solitary adrenal tumors are monoclonal neoplasms.
• Genetic syndromes with adrenal tumors: MEN 1 (MEN1), MEN 2 (RET), Carney's complex (PRKAR1A), and McCune-Albright (GNAS1).
• Majority of adrenal nodules are endocrine-inactive adrenocortical adenomas.
• Larger series suggest that up to 25% of adrenal nodules are hormonally active.
• ACC is rare but is the cause of an adrenal mass in 5% of patients.

TABLE 386-5: Classification of Unilateral Adrenal Masses

Diagnostic Evaluation

• Patients with an adrenal mass >1 cm require a diagnostic evaluation.
• Two key questions:
  1. Does the tumor autonomously secrete hormones that could have a detrimental effect on health?
  2. Is the adrenal mass benign or malignant?
• Exclusion of catecholamine excess from a pheochromocytoma arising from the adrenal medulla is a mandatory part of the diagnostic workup (Fig. 386-13).

• Plasma metanephrines or 24-h urine for metanephrine excretion (mandatory - pheochromocytoma exclusion)
• Dexamethasone 1 mg overnight test; if positive, also perform plasma ACTH, midnight salivary cortisol (≥2x), 24-h urine for free cortisol excretion (≥2x)
• Plasma aldosterone and plasma renin in patients with hypertension and/or hypokalemia
• If tumor >4 cm: Serum 17-hydroxyprogesterone, androstenedione, and DHEAS

• Unenhanced CT is the procedure of choice for imaging the adrenal glands.
• Diagnosis of ACC, pheochromocytoma, and benign adrenal myelolipoma becomes more likely with increasing diameter.
• Size alone is of poor predictive value, with only 80% specificity for differentiation of benign from malignant masses when using a 4-cm cutoff.
• Metastases are rare but are found with similar frequency in adrenal masses of all sizes.
• Tumor attenuation value on unenhanced CT: many adrenocortical adenomas are lipid rich → low attenuation values (i.e., densities <20 Hounsfield units [HUs]).
• Similar numbers of adrenocortical adenomas are lipid poor and present with higher HUs, making it difficult to differentiate them from ACCs as well as pheochromocytomas, both of which invariably have high attenuation values (i.e., densities >20 HU on precontrast scans).
• Benign lesions are rounded and homogenous; most malignant lesions appear lobulated and inhomogeneous.
• Pheochromocytoma and adrenomyelolipoma may also exhibit lobulated and inhomogeneous features.
• MRI chemical shift analysis: malignant tumors rarely showing loss of signal on opposed-phase MRI; may also be observed in a proportion of benign adrenocortical adenomas.
• MRI is preferred in children, young adults, and during pregnancy (no ionizing radiation).

• FNA or CT-guided biopsy of an adrenal mass is very rarely indicated.
• FNA of a pheochromocytoma can cause a life-threatening hypertensive crisis.
• FNA of an ACC violates the tumor capsule and can cause needle track metastasis.
• FNA should only be considered in a patient with a history of nonadrenal malignancy and a newly detected adrenal mass, after careful exclusion of pheochromocytoma, and if the outcome will influence therapeutic management.
• In 25% of patients with a previous history of nonadrenal malignancy, a newly detected mass on CT is NOT a metastasis.
• FNA can diagnose extra-adrenal malignancies but has very limited ability to differentiate between benign and malignant adrenocortical lesions and hence should NOT be used for diagnosis of ACC.
• FNA is a feasible option if looking for metastases of an extra-adrenal primary or other adrenal tumor entities, such as ganglioneuroma.

• Confirmed hormone excess or suspected malignancy: usually treated surgically.
• Normal endocrine biochemistry at diagnosis and radiodensity of <20 HU on unenhanced CT: can be considered benign and do NOT require further follow-up.
• Suspicious imaging findings (>20 HU): further tests and surgery are feasible options.

• Recently introduced diagnostic test.
• Has a twofold higher positive predictive value than imaging in detecting adrenocortical carcinoma.
• Based on a distinct "steroid fingerprint" with accumulating precursor steroids in 24-h urine.

• Rare and most frequently seen in the context of ACC, as are increased levels of steroid precursors such as 17OHP.

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ADRENOCORTICAL CARCINOMA (ACC)

• ACC is a rare malignancy with an annual incidence of 1-2 per million population.
• ACC is generally considered a highly malignant tumor; however, it presents with broad interindividual variability with regard to biologic characteristics and clinical behavior.

Genetics

• Somatic mutations in the tumor-suppressor gene TP53 are found in 25% of apparently sporadic ACC.
• Germline TP53 mutations are the cause of Li-Fraumeni syndrome associated with multiple solid organ cancers including ACC.
• Germline TP53 mutations are found in 25% of pediatric ACC cases.
• The TP53 mutation R337H is found in almost all pediatric ACC in Brazil.
• Other genetic changes in ACC: alterations in the Wnt/β-catenin pathway and in the insulin-like growth factor 2 (IGF2) cluster.
• IGF2 overexpression is found in 90% of ACCs.

Diagnosis and Staging

• Patients with large adrenal tumors suspicious of malignancy should be managed by a multidisciplinary specialist team.
• FNA is NOT indicated in suspected ACC: (1) cytology and histopathology of a core biopsy cannot differentiate between benign and malignant primary adrenal masses; (2) FNA violates the tumor capsule and may cause needle canal metastasis.

1. High nuclear grade
2. Mitotic rate (>5/HPF)
3. Atypical mitosis
4. <25% clear cells
5. Diffuse architecture
6. Presence of necrosis
7. Venous invasion
8. Invasion of sinusoidal structures
9. Invasion of tumor capsule

• Presence of three or more elements suggests ACC.
• There is no established grading system for ACC, and the Weiss score carries no prognostic value.
• The most important prognostic histopathologic parameter is the Ki67 proliferation index:
  • Ki67 <10%: indicative of slow to moderate growth velocity
  • Ki67 ≥10%: associated with poor prognosis including high risk of recurrence and rapid progression.
• 60-70% of ACCs show biochemical evidence of steroid overproduction, but in many patients, this is not clinically apparent due to relatively inefficient steroid production.
• Excess production of glucocorticoids and adrenal androgen precursors are most common and indicative of malignancy.

TABLE 386-6: ENSAT Staging of ACC

• Staging requires scanning of chest and abdomen for local organ invasion, lymphadenopathy, and metastases.
• Intravenous contrast medium is necessary for maximum sensitivity for hepatic metastases.
• 18-Fluoro-2-deoxy-D-glucose positron emission tomography (18-FDG-PET) is highly sensitive for detection of malignancy; can detect small metastases or local recurrence that may not be obvious on CT. However, FDG-PET has limited specificity and therefore cannot be used for differentiating benign from malignant adrenal lesions.
• Metastasis in ACC most frequently occurs to liver and lung.

Treatment of ACC

• Cure of ACC can only be achieved by early detection and complete surgical removal.
• Capsule violation during primary surgery, metastasis at diagnosis, and primary treatment in a nonspecialist center and by a nonspecialist surgeon are major determinants of poor survival.
• If primary tumor invades adjacent organs, en bloc removal of kidney and spleen should be considered to reduce risk of recurrence; regional lymph node dissection may further reduce this risk.
• Surgery can also be considered in a patient with metastases if there is severe tumor-related hormone excess. This needs to be carefully weighed against surgical risk, including thromboembolic complications, and the resulting delay in introduction of other therapeutic options.

• Patients with confirmed ACC and successful removal of the primary tumor should receive adjuvant treatment with mitotane (o,p'DDD), particularly in patients with high risk of recurrence:
  • Tumor size >8 cm
  • Histopathologic signs of vascular invasion
  • Capsule invasion or violation
  • Ki67 proliferation index ≥10%
• Adjuvant mitotane should be continued for at least 2 years, if side effects are tolerated.
• Regular monitoring of plasma mitotane levels is mandatory: therapeutic range 14-20 mg/L; neurotoxic complications more frequent at >20 mg/L.
• Mitotane is usually started at 500 mg tid, with stepwise increases to a maximum dose of 2000 mg tid in days (high-dose saturation) or weeks (low-dose saturation) as tolerated.
• Once therapeutic range plasma mitotane levels are achieved, dose can be tapered to maintenance doses mostly ranging from 1000-1500 mg tid.
• Mitotane treatment results in disruption of cortisol synthesis and thus requires glucocorticoid replacement.
• Glucocorticoid replacement dose should be at least double of that usually used in adrenal insufficiency (i.e., 20 mg tid) because mitotane induces hepatic CYP3A4 activity, resulting in rapid inactivation of glucocorticoids.
• Mitotane also increases circulating CBG, thereby decreasing the available free cortisol fraction.

• Single metastases: surgically or with radiofrequency ablation.
• If tumor recurs or progresses during mitotane treatment: cytotoxic chemotherapy should be considered.
• Established first-line chemotherapy regimen: combination of cisplatin, etoposide, and doxorubicin plus continuing mitotane.
• Painful bone metastasis responds to irradiation.
• Overall survival in ACC is still poor, with 5-year survival rates of 30-40% and a median survival of 15 months in metastatic ACC.

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ADRENAL INSUFFICIENCY

Prevalence

• Prevalence of well-documented, permanent adrenal insufficiency: 5 in 10,000 in the general population.
• Hypothalamic-pituitary origin (secondary/central): 3 in 10,000 (most frequent).
• Primary adrenal insufficiency: 2 in 10,000 (approximately one-half acquired, mostly by autoimmune destruction; other one-half genetic, most commonly CAH).
• Adrenal insufficiency arising from suppression of the HPA axis as a consequence of exogenous glucocorticoid treatment is much more common, occurring in 0.5-2% of the population in developed countries.

Etiology - Primary Adrenal Insufficiency

• Most commonly caused by autoimmune adrenalitis.
• Isolated autoimmune adrenalitis: accounts for 30-40%.
• Autoimmune polyglandular syndromes (APSs): 60-70% develop adrenal insufficiency as part of APSs.

• Underlying cause in 10% of patients affected by APS.
• Transmitted in an autosomal recessive manner.
• Caused by mutations in the autoimmune regulator gene AIRE.
• APS1 patients invariably develop chronic mucocutaneous candidiasis, usually manifested in childhood and preceding adrenal insufficiency by years or decades.
• Associated conditions: total alopecia, primary hypoparathyroidism, and in rare cases lymphoma.

• Much more prevalent; polygenic inheritance.
• Confirmed associations with HLA-DR3 gene region in the major histocompatibility complex and distinct gene regions involved in immune regulation (CTLA-4, PTPN22, CLEC16A).
• Coincident autoimmune disease most frequently includes: thyroid autoimmune disease, vitiligo, and premature ovarian failure.
• Less commonly: type 1 diabetes and pernicious anemia caused by vitamin B12 deficiency.

• Incidence of 1:20,000 males.
• Caused by mutations in the X-ALD gene encoding the peroxisomal membrane transporter protein ABCD1.
• Disruption results in accumulation of very-long-chain (>24 carbon atoms) fatty acids.
• ~50% of cases: manifest in early childhood with rapidly progressive white matter disease (cerebral adrenoleukodystrophy).
• ~35%: present during adolescence or in early adulthood with neurologic features of adrenomyeloneuropathy (AMN) (myelin and peripheral nervous system involvement).
• ~15%: adrenal insufficiency is the sole manifestation of disease.
• Distinct mutations manifest with variable penetrance and phenotypes within affected families.

TABLE 386-7: Causes of Primary Adrenal Insufficiency (Key entries)

• Adrenal metastases rarely cause adrenal insufficiency; this occurs only with bilateral, bulky metastases.
• Inborn causes of primary adrenal insufficiency other than CAH are rare, causing <1% of cases.
• Tuberculous adrenalitis is still a frequent cause of disease in developing countries.
• Mutations causing primary adrenal insufficiency include factors regulating: adrenal development and steroidogenesis (DAX-1, SF-1), cholesterol synthesis, import and cleavage (DHCR7, StAR, CYP11A1), elements of the adrenal ACTH response pathway (MC2R, MRAP), and factors involved in redox regulation (NNT, TXNRD2) and DNA repair (MCM4, CDKN1C).

Etiology - Secondary (Central) Adrenal Insufficiency

• Consequence of dysfunction of the hypothalamic-pituitary component of the HPA axis.
• Excluding iatrogenic suppression, the overwhelming majority of cases are caused by pituitary or hypothalamic tumors or their treatment by surgery or irradiation.
• Rarer causes: pituitary apoplexy (infarcted pituitary adenoma or transient reduction in blood supply during surgery or after rapid blood loss associated with parturition - Sheehan's syndrome).
• Isolated ACTH deficiency is rarely caused by autoimmune disease or pituitary infiltration.

TABLE 386-8: Causes of Secondary Adrenal Insufficiency (Key entries)

Clinical Manifestations

TABLE 386-9: Signs and Symptoms of Adrenal Insufficiency

• Fatigue, lack of energy
• Weight loss, anorexia
• Myalgia, joint pain
• Fever
• Normochromic anemia, lymphocytosis, eosinophilia
• Slightly increased TSH (due to loss of feedback inhibition of TSH release)
• Hypoglycemia (more frequent in children)
• Low blood pressure, postural hypotension
• Hyponatremia (due to loss of feedback inhibition of AVP release)

• Abdominal pain, nausea, vomiting
• Dizziness, postural hypotension
• Salt craving
• Low blood pressure, postural hypotension
• Increased serum creatinine (due to volume depletion)
• Hyponatremia
• Hyperkalemia

• Lack of energy
• Dry and itchy skin (in women)
• Loss of libido (in women)
• Loss of axillary and pubic hair (in women)

• Hyperpigmentation (primary adrenal insufficiency only) - due to excess of POMC-derived peptides
• Alabaster-colored pale skin (secondary adrenal insufficiency only) - due to deficiency of POMC-derived peptides

• Distinguishing feature of primary adrenal insufficiency: hyperpigmentation, caused by excess ACTH stimulation of melanocytes.
• Hyperpigmentation most pronounced in skin areas exposed to increased friction or shear stress and is increased by sunlight.
• Conversely, in secondary adrenal insufficiency, skin has an alabaster-like paleness due to lack of ACTH secretion.
• Hyponatremia is a characteristic biochemical feature in primary adrenal insufficiency, found in 80% of patients at presentation.
• Hyperkalemia is present in 40% of patients at initial diagnosis.
• Hyponatremia is primarily caused by mineralocorticoid deficiency but can also occur in secondary adrenal insufficiency due to diminished inhibition of ADH release by cortisol → mild SIADH.
• Glucocorticoid deficiency also results in slightly increased TSH concentrations that normalize within days to weeks after initiation of glucocorticoid replacement.
• Adrenal crisis is usually triggered after a prolonged period of nonspecific complaints.
• An adrenal crisis can be triggered by: intercurrent illness, surgical or other stress, or increased glucocorticoid inactivation (e.g., hyperthyroidism).
• Adrenal insufficiency may mimic features of acute abdomen with abdominal tenderness, nausea, vomiting, and fever.
• Primary presentation may resemble neurologic disease, with decreased responsiveness progressing to stupor and coma.
• Prospective data indicate 8.3 adrenal crises and 0.5 adrenal crisis-related deaths per 100 patient-years.
• Hypothalamic-pituitary disease can lead to additional clinical manifestations due to involvement of other endocrine axes (thyroid, gonads, GH, prolactin) or visual impairment with bitemporal hemianopia caused by chiasmal compression.
• Iatrogenic adrenal insufficiency caused by exogenous glucocorticoid suppression: patients will appear clinically cushingoid as a result of the preceding overexposure to glucocorticoids.

Diagnosis of Adrenal Insufficiency

• Established by the short cosyntropin test: a safe and reliable tool with excellent predictive diagnostic value.
• Cutoff for failure: cortisol levels of <450-500 nmol/L (16-18 µg/dL) sampled 30-60 min after ACTH stimulation (exact cutoff is dependent on the locally available assay, with generally lower cutoffs for mass spectrometry-based assays).
• During the early phase of HPA disruption (e.g., within 4 weeks of pituitary insufficiency): patients may still respond to exogenous ACTH stimulation → ITT is an alternative choice.
• Random serum cortisol measurements are of limited diagnostic value because baseline cortisol levels may be coincidentally low due to the physiologic diurnal rhythm.
• Many patients with secondary adrenal insufficiency have relatively normal baseline cortisol levels but fail to mount an appropriate cortisol response to ACTH.
• Importantly, tests to establish the diagnosis of adrenal insufficiency should NEVER DELAY TREATMENT.
• In a patient with suspected adrenal crisis: draw baseline cortisol levels, provide replacement therapy, and defer formal stimulation testing until a later time.
• Once adrenal insufficiency is confirmed: measurement of plasma ACTH is the next step, with increased levels defining primary and inappropriately low levels defining secondary origin.
• In primary adrenal insufficiency: increased plasma renin will confirm the presence of mineralocorticoid deficiency.
• At initial presentation, patients with primary adrenal insufficiency should undergo screening for steroid autoantibodies as a marker of autoimmune adrenalitis.
• If autoantibodies are negative: adrenal imaging by CT is indicated to investigate possible hemorrhage, infiltration, or masses.
• In male patients with negative autoantibodies: very-long-chain fatty acids should be measured to exclude X-ALD.
• Patients with inappropriately low ACTH in the presence of confirmed cortisol deficiency should undergo hypothalamic-pituitary imaging by MRI.

Treatment

Acute Adrenal Insufficiency (Adrenal Crisis):

• Requires immediate initiation of rehydration, usually carried out by saline infusion at initial rates of 1 L/h with continuous cardiac monitoring.
• Glucocorticoid replacement should be initiated by bolus injection of 100 mg hydrocortisone, followed by the administration of 200 mg hydrocortisone over 24 h, preferably by continuous infusion or alternatively by bolus IV or IM injections.
• Mineralocorticoid replacement can be initiated once the daily hydrocortisone dose has been reduced to <50 mg because at higher doses hydrocortisone provides sufficient stimulation of MRs.

Chronic Adrenal Insufficiency:

• Glucocorticoid replacement: oral administration of 15-25 mg hydrocortisone in two to three divided doses.
• Pregnancy may require an increase in hydrocortisone dose by 50% during the last trimester.
• In all patients, at least one-half of the daily dose should be administered in the morning.
• Currently available glucocorticoid preparations fail to mimic the physiologic cortisol secretion rhythm.
• Long-acting glucocorticoids such as prednisolone or dexamethasone are NOT preferred because they result in increased glucocorticoid exposure due to extended GR activation at times of physiologically low cortisol secretion.

• 1 mg hydrocortisone = 1.6 mg cortisone acetate = 0.2 mg prednisolone = 0.25 mg prednisone = 0.025 mg dexamethasone

• Mainly based on history and examination; assessment of body weight and blood pressure.
• Plasma ACTH, 24-h urinary free cortisol, or serum cortisol day curves reflect whether hydrocortisone has been taken or not but do NOT convey reliable information about replacement quality.
• In patients with isolated primary adrenal insufficiency: monitoring should include screening for autoimmune thyroid disease, and female patients should be made aware of possibility of premature ovarian failure.
• Supraphysiologic glucocorticoid treatment with doses equivalent to 30 mg hydrocortisone or more will affect bone metabolism → regular bone mineral density evaluation.

• Doubling the routine oral glucocorticoid dose in the case of intercurrent illness with fever and bed rest.
• Immediate IV or IM injection of 100 mg hydrocortisone followed by intravenous infusion of 200 mg hydrocortisone/24 h in cases of prolonged vomiting, surgery, or trauma.
• All patients should carry a hydrocortisone self-injection emergency kit, in addition to their usual steroid emergency cards and bracelets, and should receive training in its use.
• Patients living or traveling in regions with delayed access to acute health care should particularly carry this kit.

Mineralocorticoid Replacement:

• Should be initiated at a dose of 100-150 µg fludrocortisone.
• Monitoring: blood pressure sitting and standing (detect postural drop → hypovolemia); serum sodium, potassium, and plasma renin.
• Renin levels should be kept in the upper normal reference range.
• Changes in glucocorticoid dose may also impact mineralocorticoid replacement as cortisol also binds the MR; 40 mg of hydrocortisone is equivalent to 100 µg of fludrocortisone.
• Prednisone and prednisolone have reduced mineralocorticoid activity; dexamethasone has none.
• In patients living or traveling in areas with hot or tropical weather conditions: the fludrocortisone dose should be increased by 50-100 µg during the summer.
• Mineralocorticoid dose may also need to be adjusted during pregnancy due to the antimineralocorticoid activity of progesterone, but this is less often required than hydrocortisone dose adjustment.
• Plasma renin cannot serve as a monitoring tool during pregnancy because renin rises physiologically during gestation.

Adrenal Androgen Replacement:

• An option in patients with lack of energy despite optimized glucocorticoid and mineralocorticoid replacement.
• May also be indicated in women with features of androgen deficiency, including loss of libido.
• Achieved by once-daily administration of 25-50 mg DHEA.
• Treatment is monitored by measurement of DHEAS, androstenedione, testosterone, and sex hormone-binding globulin (SHBG) 24 h after the last DHEA dose.

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CONGENITAL ADRENAL HYPERPLASIA (CAH)

• CAH is caused by mutations in genes encoding steroidogenic enzymes involved in glucocorticoid synthesis (CYP21A2, CYP17A1, HSD3B2, CYP11B1) or in the cofactor enzyme P450 oxidoreductase that serves as an electron donor to CYP21A2 and CYP17A1.
• Invariably, patients affected by CAH exhibit glucocorticoid deficiency.
• Depending on the exact step of enzymatic block, they may also have excess production of mineralocorticoids or deficient production of sex steroids.
• Diagnosis is readily established by measurement of steroids accumulating before the distinct enzymatic block, either in serum or in urine, preferably by the use of mass spectrometry-based assays.

21-Hydroxylase Deficiency (21-OHD)

• Mutations in CYP21A2 are the most prevalent cause of CAH, responsible for 90-95% of cases.
• 21-Hydroxylase deficiency disrupts glucocorticoid and mineralocorticoid synthesis (Fig. 386-1), resulting in diminished negative feedback via the HPA axis.
• Leads to increased pituitary ACTH release, which drives increased synthesis of adrenal androgen precursors and subsequent androgen excess.
• The degree of impairment of glucocorticoid and mineralocorticoid secretion depends on the severity of mutations.

• Classic CAH (neonatal presentation): Major loss-of-function mutations → combined glucocorticoid AND mineralocorticoid deficiency
• Simple virilizing CAH (neonatal or early childhood presentation): Less severe mutations → affect glucocorticoid synthesis only
• Nonclassic CAH: Mildest mutations → least severe clinical phenotype, usually presenting during adolescence and early adulthood with preserved glucocorticoid production.

• Androgen excess is present in all patients and manifests with broad phenotypic variability.
• Severe virilization of the external genitalia in neonatal girls (46,XX disordered sex development [DSD]).
• Hirsutism and oligomenorrhea resembling polycystic ovary syndrome in young women with nonclassic CAH.
• In countries without neonatal screening for CAH: boys with classic CAH usually present with life-threatening adrenal crisis in the first few weeks of life (salt-wasting crisis).
• Simple-virilizing genotype: precocious pseudo-puberty and advanced bone age in early childhood.
• Men with nonclassic CAH are usually detected only through family screening.

TABLE 386-10: Variants of Congenital Adrenal Hyperplasia

• FIGURE 386-17: CT scans showing homogenous bilateral hyperplasia in young patient with classic CAH AND macronodular bilateral hyperplasia in middle-aged patient with classic CAH with longstanding poor disease control.
• Bilateral testicular adrenal rest tumors (TART): shown on MRI as bilateral lesions in rete testis in young patient with salt-wasting CAH.

Treatment of CAH

• Hydrocortisone is a good treatment option for prevention of adrenal crisis, but longer-acting prednisolone may be needed to control androgen excess.
• In children, hydrocortisone is given in divided doses at 1-1.5 times the normal cortisol production rate (~10-13 mg/m2 per day).
• In adults, if hydrocortisone does not suffice, intermediate-acting glucocorticoids (e.g., prednisone) may be given, using the lowest dose necessary to suppress excess androgen production.
• For achieving fertility, dexamethasone treatment may be required but should only be given for the shortest possible time period to limit adverse metabolic side effects.
• The recent introduction of modified and delayed-release hydrocortisone, which mimics the endogenous physiologic cortisol release pattern, is promising.
• Glucocorticoid treatment is more complex than for other causes of primary adrenal insufficiency as it not only needed to replace missing glucocorticoids but also to control the increased ACTH drive and subsequent androgen excess.

• Childhood: optimization of growth and pubertal development, prevention of adrenal crisis, treatment of 46,XX DSD.
• Adults: preserving fertility and preventing side effects of glucocorticoid overtreatment (metabolic syndrome and osteoporosis).

• Fertility can be compromised in women due to oligomenorrhea/amenorrhea with chronic anovulation as a consequence of androgen excess.
• Men may develop testicular adrenal rest tissue (TART) (Fig. 386-17):
  • Consists of hyperplastic cells with shared adrenal and gonadal characteristics located in the rete testis.
  • Should NOT be confused with testicular tumors.
  • TART can compromise sperm production and induce testicular fibrosis that may be irreversible.

• Can result in adrenocortical hyperplasia - may present as macronodular hyperplasia subsequent to long-standing ACTH excess.
• The nodular areas can develop autonomous adrenal androgen production and may be unresponsive to glucocorticoid treatment.
• Prevalence of adrenomyelolipomas is increased in CAH; these are benign but can require surgical intervention due to lack of self-limiting growth.

• Should include androstenedione and testosterone, aiming for the normal sex-specific reference range.
• 17OHP is a useful marker of overtreatment: 17OHP levels within the normal range of healthy controls indicates overtreatment.
• Glucocorticoid overtreatment may suppress the hypothalamic-pituitary-gonadal axis.
• Stress-dose glucocorticoids should be given at double or triple the daily dose for surgery, acute illness, or severe trauma.

• Change during life and are higher in children (due to relative mineralocorticoid resistance that diminishes with ongoing maturation of the kidney).
• Children with CAH usually receive mineralocorticoid and salt replacement.
• Young adults with CAH should undergo reassessment of their mineralocorticoid reserve.
• Plasma renin should be regularly monitored and kept within the upper half of the normal reference range.

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⭐ HIGH-YIELD MCQ POINTS FOR NEET SS ⭐

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ANATOMY & PHYSIOLOGY

1. Normal adrenal gland weight: 6-11 g each
2. Right suprarenal vein → drains into vena cava; Left suprarenal vein → drains into left renal vein
3. Adrenals separate from gonads/kidneys at 6th week of gestation; cortex starts producing cortisol and DHEA at 7th-9th week (time of sexual differentiation)
4. SF1 (NR5A1) and DAX1 (NR0B1) are key orphan nuclear receptors for adrenal development
5. StAR protein shuttles cholesterol from outer to inner mitochondrial membrane (initiation of steroidogenesis)
6. Cortisol circulates at 1000-fold higher concentration than aldosterone, yet both bind MR with equal affinity → only rapid inactivation by 11β-HSD2 prevents MR flooding by cortisol
7. 11β-HSD1 activates cortisone to cortisol (prereceptor activator); 11β-HSD2 inactivates cortisol to cortisone (prereceptor inactivator, mainly in kidney)
8. 11β-HSD1 requires NADPH provided by H6PDH in the endoplasmic reticulum lumen
9. Cortisol circadian rhythm: Acrophase = 0830 h (peak); Nadir = 0015 h; MESOR = 5.25 µg/dL (145 nmol/L)
10. CYP17A1 uniquely catalyzes two reactions: 17α-hydroxylase AND 17,20 lyase activities
11. Mitochondrial CYP enzymes: CYP11A1, CYP11B1, CYP11B2; ER CYP enzymes: CYP17A1, CYP21A2, CYP19A1
12. GR transactivation (via GREs) = anti-metabolic effects; GR transrepression (via AP-1/NF-κB) = anti-inflammatory effects
13. In rodents: corticosterone is the major glucocorticoid (not cortisol)
14. 17-hydroxylase deficiency: lack of cortisol compensated by corticosterone accumulation
15. POMC (241 amino acids) → cleaved to ACTH (39 amino acids); first 24 amino acids are sufficient for adrenal response
16. SGK-1 phosphorylates Nedd4 → reduces Nedd4-ENaC interaction → ENaC traffics to cell surface → sodium retention
17. DOC also exerts mineralocorticoid activity; DOC accumulation in 11β-hydroxylase or 17α-hydroxylase deficiency can cause mineralocorticoid excess

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CUSHING'S SYNDROME

1. Cushing's disease = pituitary corticotrope adenoma (specific term)
2. ACTH-dependent: 90% (Cushing's disease 75%, ectopic ACTH 15%) | ACTH-independent: 10%
3. Cushing's disease: Female:Male = 4:1 | Ectopic ACTH: Female:Male = 1:1
4. At least 90% of Cushing's disease = microadenoma; macroadenomas (>1 cm) = only 5-10%
5. USP8 mutations in Cushing's disease pituitary adenomas → constitutive EGF signaling → POMC upregulation
6. PRKACA somatic mutations = 40% of cortisol-producing adrenocortical adenomas
7. ARMC5 tumor-suppressor gene mutations = prevalent cause of bilateral macronodular adrenal hyperplasia Cushing's
8. PRKAR1A germline mutations = PPNAD + Carney's complex (cardiac myxomas, hyperlentiginosis, Sertoli cell tumors)
9. PDE11A and PDE8B mutations = bilateral adrenal hyperplasia with Cushing's
10. GNAS-1 activating mutations = McCune-Albright syndrome (polyostotic fibrous dysplasia, unilateral café-au-lait spots, precocious puberty)
11. Food-dependent Cushing's = ectopic GIP receptors in PBMAH → meal → cortisol rise
12. Most common cause overall = iatrogenic Cushing's (glucocorticoid use for inflammatory disorders)
13. Ectopic ACTH: most frequent source = lung (bronchial carcinoid), also thymus and pancreas
14. Broad (>1 cm) purplish striae = specific for Cushing's
15. Proximal myopathy = most obvious when standing from chair without hands / climbing stairs
16. Ectopic ACTH syndrome: hyperpigmentation of knuckles/scars (from POMC cleavage products)
17. DVT risk is a major acute complication in Cushing's; hypercoagulable state
18. Eosinopenia (NOT eosinophilia) in Cushing's

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CUSHING'S DIAGNOSIS - CRITICAL NUMBERS

1. Overnight 1 mg dexamethasone suppression: give at 11 pm; check cortisol at 8-9 am → failure if cortisol >50 nmol/L
2. 24-h UFC: must be elevated in three separate collections (≥2x normal)
3. Midnight salivary cortisol >5 nmol/L (≥2x) = loss of diurnal rhythm
4. Low dose DEX test: 0.5 mg q6h for 2 days; failure = cortisol >50 nmol/L
5. CRH test: CRH 100 µg IV; ACTH increase >40% at 15-30 min + cortisol increase >20% at 45-60 min = positive (favors pituitary)
6. High dose DEX test: 2 mg q6h for 2 days; suppression >50% = favors pituitary (Cushing's disease)
7. MRI pituitary may not show abnormality in up to 40% of cases (tumors too small)
8. IPSS ratio >2 at baseline, >3 at 2-5 min after CRH injection = indicative of Cushing's disease
9. No cortisol-lowering agents should be used prior to IPSS (critical)
10. IPSS cannot be used for lateralization (broad interindividual variability in pituitary venous drainage)
11. CYP3A4-inducing drugs (antiepileptics, rifampicin) → rapid dexamethasone inactivation → false positive suppression test
12. Oral contraceptives raise CBG → fail suppression; repeat after 4-6 weeks off estrogens
13. Pituitary corticotrope adenomas fail to enhance on gadolinium T1-weighted MRI

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CUSHING'S TREATMENT - KEY DRUGS AND DOSES

1. Metyrapone: starting dose 500 mg tid; maximum 6 g; mechanism = inhibits 11β-hydroxylase (CYP11B1)
2. Ketoconazole: starting dose 200 mg tid; maximum 1200 mg; mechanism = inhibits early steroidogenesis steps
3. Osilodrostat: potent 11β-hydroxylase inhibitor; also strongly inhibits aldosterone synthase (CYP11B2)
4. Mitotane (o,p'DDD): adrenolytic agent; low-dose for benign Cushing's = 500-1000 mg/d
5. Etomidate: blocks 11β-hydroxylase AND aldosterone synthase; given by continuous IV infusion in low, nonanesthetic doses for severe cortisol excess
6. Pasireotide (somatostatin receptor agonist): subcutaneous administration for Cushing's disease
7. Pituitary surgery cure rate: 70-80% (by highly experienced surgeon)
8. HPA axis recovery post-cure: Ectopic ACTH = 80%; Cushing's disease = 60%; Adrenal Cushing's = 40%

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MINERALOCORTICOID EXCESS

1. Bilateral micronodular hyperplasia = more common cause than unilateral adenoma (60% vs 40%)
2. KCNJ5 (GIRK4) mutations = 40% of aldosterone-producing adenomas; also ATP1A1, ATP2B3, CACNA1D, CACNA1H
3. Benign aldosterone-producing adenomas usually measure <2 cm
4. GRA: CYP11B1-CYP11B2 chimeric gene → ACTH drives aldosterone → suppressible by dexamethasone; autosomal dominant; associated with early-onset hypertension and strokes
5. Liddle's syndrome: mutant ENaC β or γ subunits; autosomal dominant; very sensitive to amiloride but NOT MR antagonists
6. SAME: HSD11B2 inactivating mutations; severe hypokalemic hypertension in childhood; licorice ingestion has similar effect
7. Only 50% of primary aldosteronism patients have hypokalemia (NOT all)
8. Hypokalemia exacerbated by thiazide drugs (increase sodium delivery to distal tubule → drive potassium excretion)
9. Connshing syndrome: concurrent mild autonomous cortisol excess (MACE) in patients with primary aldosteronism
10. ARR screening: stop MR antagonists at least 4 weeks prior; β-blockers → false positive ARR; ACE/AT1R inhibitors → false negative ARR
11. ARR positive: >750 pmol/L per ng/mL/h with aldosterone >450 pmol/L
12. Saline infusion test: 2 L physiologic saline over 4 h IV; failure to suppress aldosterone <140 pmol/L (5 ng/dL) = autonomous excess
13. Fludrocortisone suppression test risk: profound hypokalemia and worsened hypertension
14. Cortisol gradient >3 between vena cava and each adrenal vein for valid AVS; lateralization = aldosterone/cortisol ratio ≥ 2-fold higher on one side
15. Age >40 years with unilateral lesion on CT → must do AVS before surgery (risk of coincidental inactive adenoma)
16. Age <40 years with unilateral lesion → can go straight to surgery
17. Spironolactone: start 12.5-50 mg bid, titrate to maximum 400 mg/d; side effects: menstrual irregularity, gynecomastia, decreased libido
18. Eplerenone: start 25 mg bid, titrate to 200 mg/d (more selective MR antagonist)
19. Amiloride: 5-10 mg bid (sodium channel blocker)
20. Aldosterone has direct damage to myocardium and kidney glomeruli (beyond systemic HTN)

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ADRENAL INCIDENTALOMA

1. Adrenal incidentaloma prevalence: 2-5% general population; 1% of 40-year-olds; 7% of 70-year-olds
2. 25% of adrenal nodules are hormonally active; ACC is cause in 5% of adrenal masses
3. Most frequent metastases to adrenal: breast and lung
4. Exclusion of pheochromocytoma is MANDATORY in all adrenal incidentalomas
5. Adrenal masses >1 cm require diagnostic evaluation; if tumor >4 cm: also check 17OHP, androstenedione, DHEAS
6. Benign lesions: rounded and homogenous, lipid-rich → <20 HU on unenhanced CT → can be discharged, no follow-up required
7. >20 HU on unenhanced CT = indeterminate/suspicious → further workup
8. ACCs and pheochromocytomas invariably have >20 HU on precontrast scans
9. 4-cm cutoff for malignancy has only 80% specificity
10. FNA of pheochromocytoma → life-threatening hypertensive crisis (contraindicated)
11. FNA of ACC → violates tumor capsule → needle track metastasis (contraindicated)
12. FNA only indicated: known extra-adrenal malignancy + new adrenal mass + pheochromocytoma excluded + outcome will change management
13. 25% of patients with nonadrenal malignancy: new adrenal mass on CT is NOT a metastasis
14. Urine steroid metabolomics: twofold higher positive predictive value than imaging for detecting ACC

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ADRENOCORTICAL CARCINOMA (ACC)

1. ACC annual incidence: 1-2 per million population
2. TP53 somatic mutations: 25% of sporadic ACC; germline TP53 mutations → Li-Fraumeni syndrome; TP53 R337H = almost all pediatric ACC in Brazil
3. IGF2 overexpression: found in 90% of ACCs (most common molecular abnormality)
4. Weiss score: 3 or more of 9 criteria → suggests ACC; mitotic rate >5/HPF is one criterion
5. Weiss score carries NO prognostic value
6. Ki67 <10% = slow to moderate growth; Ki67 ≥10% = poor prognosis, high recurrence risk
7. 60-70% of ACCs show biochemical evidence of steroid overproduction
8. ENSAT Staging: Stage I = T1 (≤5 cm), N0, M0; Stage II = T2 (>5 cm), N0, M0; Stage III = N1 or T3-T4; Stage IV = M1 (distant metastases)
9. Most frequent metastasis from ACC: liver and lung
10. FDG-PET: highly sensitive for ACC malignancy, limited specificity (cannot differentiate benign from malignant)
11. Adjuvant mitotane indicated after surgery in high-risk ACC: tumor >8 cm, vascular invasion, capsule invasion, Ki67 ≥10%
12. Adjuvant mitotane: continue for at least 2 years; therapeutic plasma range = 14-20 mg/L; neurotoxic at >20 mg/L
13. Mitotane starting dose: 500 mg tid → stepwise increase to max 2000 mg tid; maintenance 1000-1500 mg tid
14. Mitotane induces CYP3A4 → rapid glucocorticoid inactivation → glucocorticoid replacement dose must be at least double usual AI dose (20 mg tid)
15. Mitotane increases circulating CBG → decreases free cortisol fraction
16. First-line chemotherapy for metastatic ACC = cisplatin + etoposide + doxorubicin + mitotane
17. 5-year survival in ACC: 30-40%; median survival in metastatic ACC: 15 months

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ADRENAL INSUFFICIENCY

1. Prevalence of permanent AI = 5 in 10,000; secondary AI = 3/10,000 (most frequent); primary AI = 2/10,000
2. Iatrogenic AI = 0.5-2% of population in developed countries (most common form overall)
3. Primary AI: isolated autoimmune adrenalitis = 30-40%; part of APS = 60-70%
4. APS1 (AIRE gene; autosomal recessive): candidiasis appears in childhood, precedes adrenal insufficiency by years to decades; 10% of all APS
5. APS2 (HLA-DR3, CTLA-4; polygenic): thyroid disease, vitiligo, premature ovarian failure
6. X-ALD (ABCD1 gene): very-long-chain fatty acids (>24 carbon atoms); incidence 1:20,000 males
7. Inborn causes (other than CAH) = <1% of cases
8. Adrenal metastases cause AI ONLY with bilateral, bulky metastases
9. Tuberculosis = frequent cause of AI in developing countries
10. CPHD (PROP-1 mutation): hormone deficiencies develop in order GH → PRL → TSH → LH/FSH → ACTH (ACTH last)
11. TBX19 (Tpit) mutations = congenital isolated ACTH deficiency
12. POMC mutations: early-onset obesity, red hair pigmentation (POMC-derived peptides include MSH)
13. Triple A syndrome (AAAS gene): Alacrima, Achalasia, Adrenal insufficiency, neurologic impairment
14. IMAGe syndrome (CDKN1C): Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia, Genital anomalies

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ADRENAL INSUFFICIENCY - CLINICAL PEARLS

1. Hyperpigmentation = primary AI only (excess ACTH/POMC peptides stimulate melanocytes); most pronounced in areas of friction, increased by sunlight
2. Alabaster-like pale skin = secondary AI only (deficiency of POMC peptides)
3. Hyponatremia in primary AI: found in 80% at presentation
4. Hyperkalemia in primary AI: present in 40% at initial diagnosis
5. Slightly elevated TSH in AI (loss of cortisol feedback on TRH/TSH) → normalizes days to weeks after glucocorticoid replacement
6. Adrenal crisis rate: 8.3 per 100 patient-years; crisis-related deaths: 0.5 per 100 patient-years
7. Iatrogenic AI: patients will appear cushingoid (preceding overexposure) but have symptoms of glucocorticoid deficiency if steroids are stopped abruptly
8. ITT is CONTRAINDICATED in diabetes mellitus, cardiovascular disease, and history of seizures
9. Tests should NEVER DELAY TREATMENT in suspected adrenal crisis
10. During early HPA disruption (<4 weeks of pituitary insufficiency): patient may still respond to cosyntropin test → use ITT instead for reliable diagnosis
11. In male patients with negative autoantibodies: measure very-long-chain fatty acids to exclude X-ALD
12. Cosyntropin test cutoff: cortisol <450-500 nmol/L (16-18 µg/dL) at 30-60 min = failure (assay-dependent)

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ADRENAL INSUFFICIENCY TREATMENT - CRITICAL NUMBERS

1. Acute adrenal crisis: saline infusion at 1 L/h + 100 mg hydrocortisone IV bolus + 200 mg hydrocortisone/24 h continuous infusion
2. Mineralocorticoid replacement can be started once hydrocortisone dose <50 mg/day
3. Chronic AI replacement: 15-25 mg hydrocortisone in 2-3 divided doses; at least HALF the dose in the morning
4. Long-acting glucocorticoids (prednisolone, dexamethasone) are NOT preferred for AI (unphysiologic – extend GR activation during low cortisol periods)
5. Dose equivalencies: 1 mg HC = 1.6 mg cortisone acetate = 0.2 mg prednisolone = 0.25 mg prednisone = 0.025 mg dexamethasone
6. Pregnancy: increase hydrocortisone by 50% during the last trimester
7. Supraphysiologic dose ≥30 mg hydrocortisone equivalent → affects bone metabolism → regular BMD evaluation
8. Stress dose: double routine oral dose for fever/bed rest; 100 mg IM/IV bolus + 200 mg/24 h infusion for vomiting/surgery/trauma
9. Mineralocorticoid: fludrocortisone 100-150 µg; keep renin in upper normal range
10. 40 mg hydrocortisone = 100 µg fludrocortisone (mineralocorticoid equivalence)
11. Dexamethasone has NO mineralocorticoid activity; prednisolone/prednisone have reduced mineralocorticoid activity
12. Hot/tropical climate: increase fludrocortisone by 50-100 µg during summer
13. Plasma renin cannot be used to monitor mineralocorticoid replacement during pregnancy (physiologically rises)
14. Adrenal androgen replacement: DHEA 25-50 mg once daily (for women with loss of libido/energy); monitor DHEAS, androstenedione, testosterone, SHBG at 24 h post-dose

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CAH - CRITICAL FACTS

1. 21-OHD = 90-95% of all CAH (CYP21A2 gene)
2. Classic CAH: combined GC + MC deficiency; Simple virilizing: GC deficiency only; Nonclassic: presents in adolescence/adulthood, preserved GC production
3. Boys with classic CAH (no neonatal screening) → life-threatening salt-wasting crisis in first few weeks of life
4. 11β-OHD (CYP11B1): GC deficiency + MC excess (DOC accumulation) + androgen excess → hypertension (not salt-wasting)
5. 17α-OHD (CYP17A1): MC excess + androgen deficiency (and absent sex steroid production)
6. 3β-HSDD (HSD3B2): adrenal androgen excess in females AND males; gonadal androgen deficiency in males
7. PORD (P450 oxidoreductase): prenatal androgen excess BUT postnatal androgen deficiency + skeletal malformations (Antley-Bixler-like phenotype)
8. TART (testicular adrenal rest tumors): located in rete testis; NOT testicular tumors; can cause irreversible testicular fibrosis
9. 17OHP is a marker of overtreatment (if 17OHP is in the normal range of healthy controls → over-replaced)
10. CAH children: hydrocortisone at 1-1.5× normal cortisol production rate (~10-13 mg/m2/day)
11. Stress dose in CAH: double or triple daily dose for surgery/acute illness/severe trauma
12. CAH mineralocorticoid requirements higher in children (relative mineralocorticoid resistance, diminishes with kidney maturation)
13. Plasma renin in CAH: should be kept in upper half of normal reference range
14. Adrenomyelolipomas: increased prevalence in CAH; benign but can require surgery (lack self-limiting growth)
15. Androgen excess marker in CAH monitoring: androstenedione and testosterone (aim for normal sex-specific range)

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