Adrenal Disorders

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Case 1
• A 45-year-old man presents to a clinical pharmacist for
asthma education.
• His medical history is significant for hypertension,
hyperlipidemia, and asthma.
• He complains of insomnia, fatigue, and erectile dysfunction.
• Physical examination reveals an obese (BMI 39 kg/m2) man
with truncal obesity, dorsocervical fat, and facial plethora.
• His current medications include valsartan, atorvastatin,
fluticasone/vilanterol inhaler, and albuterol inhaler.

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• His fluticasone/vilanterol inhaler dose has increased
over the last 2 years in the setting of asthma
exacerbations.
• He has had several walk-in clinic visits this year for
asthma
exacerbations
• He was treated with a high-dose prednisone
protocol each time. The clinical pharmacist suggests
evaluation for possible Cushing syndrome.

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1. Which findings are suggestive of Cushing
syndrome?
2. Aside from Cushing syndrome, what are some
major differential diagnoses for clinical
presentation?
3. The patient is diagnosed with drug-induced
Cushing syndrome after evaluation and
diagnostic testing by the endocrinologist. What
patient education points should be provided?

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Introduction

• The adrenal glands are important in the synthesis

and regulation of key human hormones
• They play a crucial role in
• Water and electrolyte homeostasis,
• Regulation of blood pressure,
• Carbohydrate and fat metabolism,
• Physiologic response to stress, and
• Sexual development and differentiation

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Introduction…

• Located extraperitoneally to the upper poles of each

kidney
• Weighs 4 g each and is 2 to 3 cm in width and 4 to 6
cm in length
• Nourished by small arteries from the abdominal
aorta and renal and phrenic arteries
• Drainage occurs via the renal vein on the left and
the inferior vena cava on the right

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Adrenal Gland Anatomy

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Normal Cortisol Production

Aldosterone:
• Maintains electrolyte and volume homeostasis by
altering
• Potassium and magnesium secretion and
• Renal tubular sodium reabsorption
Cortisol
• Responsible for the regulation of fat, carbohydrate,
and protein metabolism
Adrenal androgen
• Influence the reproductive system
• Modulate primary and secondary sex characteristics

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Normal Cortisol Production…
• Normally, the production of cortisol follows a
precise chain of events
• First, the hypothalamus sends corticotropin
releasing hormone (CRH) to the pituitary gland
• CRH causes the pituitary to secrete ACTH
(adrenocorticotropin), a hormone that stimulates the
adrenal glands
• Adrenals receive the ACTH, then respond by
releasing cortisol into the bloodstream Serotonin
and norepinephrine

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Corticosteroids

• Three classes (by effect):

• Mineralcorticoids
• Glucocorticoids
• Androgenic steroids

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Cortisol

• 25mg produced daily (non-stressed)

• 5-10% free and physiologically active
• Remainder bound to cortisol-binding globulin
• Becomes uncoupled in times of stress
• Negatively feeds back to control hypothalamus
• Role in adrenal insufficiency

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Functions of Cortisol

• Maintain blood pressure and cardiovascular function

• Reduces the immune system's inflammatory response
• Regulates the metabolism of proteins, carbohydrates,
and fats
• Help the body to respond to stress
• High in women in their last 3 months of pregnancy,
trained athletes, depression, alcoholism, malnutrition
and panic disorders

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Mineralocorticoids

• Aldosterone:
• the main mineralocorticoid produced by the adrenal
glands
• Helps to regulate the body’s
• Sodium and potassium levels
• Blood volume, and
• Blood pressure

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Adrenal Androgens

• Significant source of androgens in females

• Can cause signs/symptoms seen in adrenal
insufficiency
• Testosterone, dehydroepiandrosterone (DHEA), and
DHEA sulfate, are present in both men and women
• Promote the development of sexual characteristics
• Important for women's libido (sex drive)

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Adrenal Gland Disorders

• Hyperfunction of the adrenal glands occurs in

Cushing’s syndrome, a disorder caused by excessive
secretion of cortisol by the adrenal gland
(hypercortisolism).
Hyperaldosteronism excess aldosterone in the
serum(1o or 2ry)
• Hypofunction is associated with:
Primary (Addison’s dx) or
Secondary adrenal insufficiency

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Hyperfunction Adrenal Gland

Cushing’s Syndrome
• Results from the effects of supraphysiologic
(hypercortisolism) levels of glucocorticoids
(cortisol) either from
• Exogenous administration or
• Endogenous overproduction less common

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Cushing’s Syndrome Can be categorized

ACTH-dependent: usually originates from

overproduction of ACTH by the pituitary gland
• which chronically stimulates the adrenal glands causing
bilateral adrenal hyperplasia (BAH).
• ≈80% of all Cushing’s syndrome cases
• Predominant (85%) cause is pituitary adenoma
Other causes: Ectopic ACTH-secreting tumors
(pancreas, thyroid, or lung), non-neoplastic
corticotropin hyper-secretion)

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• ACTH independent: abnormal adrenocortical
tissues regardless of ACTH stimulation
• Adrenal adenomas and
• Adrenal carcinomas

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Clinical Presentation

General
• Most common findings (90%): central obesity and
facial rounding
Symptoms
• Myopathies: 65%
• Muscular weakness: 58%

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Laboratory Tests

• Establishing the presence of hypercortisolism

• A midnight plasma cortisol
• Late-night salivary cortisol
• 24-hour urinary free cortisol (UFC)
• low-dose dexamethasone suppression test (DST)
• 1 mg dexamethasone for the overnight test or
• 0.5 mg/6 hours for the classic 2-day study
• Adrenal nodules and masses are identified using
high-resolution CT scanning or MRI.

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Cushing’s syndrome

• Iatrogenic (exogenous) Cushing’s syndrome

• Oral, inhaled, intranasal, intraarticular, and topical
glucocorticoids
• Progestins (medroxyprogesterone acetate and
megestrol acetate)
• Disease severity correlates: potency, dose,
frequency, route, and treatment duration

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Treatment

Desired Outcomes
• To limit detrimental outcomes
• To return the patient to a normal functional state
• To minimize pituitary or adrenal deficiencies

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Non pharmacological

• Surgical resection of offending tumors is treatment of choice

for both ACTH dependent and ACTH-independent Cushing
syndrome
• Transsphenoidal resection of the pituitary tumor
• Pituitary irradiation provides clinical improvement in ~50%
of patients within 3 to years, but improvement may not be
seen for 6 to 12 months
• Laparoscopic adrenalectomy may be preferred in patients
with
• unilateral adrenal adenomas or
• for whom transsphenoidal surgery and pituitary radiotherapy have
failed or cannot be used.

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Treatment

Iatrogenic (exogenous) Cushing’s syndrome

• Discontinuation of the offending agent
• However, abrupt withdrawal of the glucocorticoid
can result in adrenal insufficiency or exacerbation
of the underlying disease.
• Glucocorticoid doses less than 7.5 mg/day of prednisone
or its equivalent for less than 3 weeks….. Tapering not
needed
• However, in pts receiving glucocorticoids for
prolonged periods, gradual tapering to near
physiologic levels (5–7.5 mg/day of prednisone or
its equivalent) should precede drug discontinuation
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Pharmacologic Therapy
• Generally used as second-line treatments in patients
• who are not surgical candidates and
• may also be used for preoperative patients or as adjunctive
therapy in postoperative patients awaiting response
• Four categories based on the anatomic site of action
of the agent:
• Steroidogenesis inhibitors
• Adrenolytic agents
• Neuromodulators of ACTH release, and
• Glucocorticoid-receptor blocking agents

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Steroidogenesis Inhibitors
• Block the production of cortisol
• Metyrapone, ketoconazole, etomidate, and
aminoglutethimide

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Metyrapone

• It inhibits 11β-hydroxylase: the enzyme responsible for

converting 11-deoxycortisol to cortisol
• Decrease in cortisol levels occurs within hours
• Compensatory rise in plasma ACTH concentrations
• Adrenal steroidogenesis efforts shunted toward androgen
production
Side effects
• Androgenic side effects: hirsutism and increased acne
• Blood pressure and electrolyte level variations
• Nausea, vomiting, vertigo, headache, dizziness, abdominal
discomfort, and allergic

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Ketoconazole
• Exhibits antiandrogenic activity
• Inhibit 11β-hydroxylase and 17α-hydroxylase
• Benefits achieved only after several weeks of
therapy
• Beneficial in female patients
• Cause gynecomastia and hypogonadism in males
• lower total and LDL cholesterol levels
• May be co-administered with metyrapone
• Side effects: hepatotoxicity, GI discomfort and
dermatologic

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Etomidate
• Parenteral formulation
• Used in patients with acute hypercortisolemia
Aminoglutethimide
• Inhibits the conversion of cholesterol to pregnenolone
• Inhibit the production of cortisol, aldosterone, and
androgens
• Not used commonly: severe side effects
• Side effects: severe sedation, nausea, ataxia, and skin rashes

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Adrenolytic Agents

Mitotane (A cytotoxic drug)

• Inhibits the 11-hydroxylation of 11-desoxycortisol and
11- desoxycorticosterone in the cortex
• Inhibit cortisol and corticosterone synthesis
• Takes weeks to months to exert beneficial effects
• Sustained cortisol suppression occurs result in atrophy of
the adrenal cortex
• Side effects: neurologic (lethargy and somnolence), GI,
nausea and diarrhea, hypercholesterolemia, prolongation
of bleeding times

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Neuromodulatory Agents

• Include: cyproheptadine, ritanserin, ketanserin,

bromocriptine, cabergoline,valproic acid, octreotide,
lanreotide, rosiglitazone, and tretinoin
• None of the neuromodulatory agents has
demonstrated consistent clinical efficacy for treating
Cushing’s syndrome.
• Cyproheptadine should be reserved for non surgical
candidates who fail more conventional therapy.
• Because the response rate is no more than 30%, pts
should be followed closely for relapses.

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Glucocorticoid-Receptor Blocking Agents

Mifepristone
• A potent progesterone- and glucocorticoid-receptor
antagonist
• Adverse effects: fatigue, nausea, headache,
arthralgia, peripheral edema, endometrial thickening
(with or without vaginal bleeding), and significant
reductions in serum potassium

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Personalized Pharmacotherapy
Consider gender in drug selection
• Metyrapone: secondary choice in women
• Ketoconazole: secondary choice in men
• Pregnancy: metyrapone
• Avoid mitotane in women desiring pregnancy
within the next 5years

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Hyperaldosteronism

• Excess aldosterone secretion

categorized as
• Primary aldosteronism: stimulation for
aldosterone secretion arises from within the adrenal
gland
• Secondary aldosteronism: extra-adrenal
stimulation of aldosterone secretion

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Primary Aldosteronism

Etiology
• BAH: 65%
• Aldosterone-producing adenoma:30%
• Unilateral (primary) adrenal hyperplasia
• Adrenal cortex carcinoma
• Renin-responsive adrenocortical adenoma

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Clinical Presentation

Symptoms
• Patients may complain of muscle weakness, fatigue,
paresthesias, and headache
Signs
• Hypertension
• Tetany/paralysis
• Polydipsia/nocturnal polyuria

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Laboratory Tests

• A plasma-aldosterone-concentration–to–plasma-renin-
activity (PAC–to–PRA) ratio, or aldosterone-to-renin
ratio (ARR) greater than 20 is suggestive of PA
• Suppressed renin activity
• Elevated plasma aldosterone concentrations (PACs)
• Hypernatremia, Hypokalemia, Hypomagnesemia
• Elevated bicarbonate concentration (>31 mEq/L), and
• Glucose intolerance

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Therapeutic Management

Aldosterone receptor antagonists

• Spironolactone: nonselective aldosterone receptor
antagonist Also inhibit aldosterone synthesis within
the adrenal gland:
• high dose Doses: 25-400 mg/day
• Wait 4 to 8 weeks before reassessing urinary
electrolytes and blood pressure control

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Eplerenone
• Selective aldosterone receptor antagonist
• High affinity for the aldosterone receptor and low
affinity for androgen and progesterone receptors
• Dose: 50-100 mg
• Titrate at 4- to 8-week intervals
Amiloride
• Dose: 5- 30 mg/day
• Less effective than spironolactone

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Secondary Aldosteronism

• An appropriate response to excessive stimulation of the

zona glomerulosa by an extra adrenal factor: usually
RAAS Causes
• Excessive potassium intake
• Oral contraceptives
• Pregnancy
• Menses
• Congestive heart failure, cirrhosis, renal artery stenosis, and
Bartter’s syndrome
• Treatment dictated by etiology
• Spironolactone: mainstay of treatment until an exact etiology
can be located

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• Adrenal Virilism
• Excessive secretion of androgens from the adrenal gland
• Development of male secondary sexual characteristics
• Females affected more often than males
• Hirsutism: the dominant feature
• Additional coexisting features: voice deepening,
acne, increased muscle mass, menstrual
abnormalities, clitoral enlargement, redistribution of
body fat and loss of female body contour, breast
atrophy, and hair recession and crown balding

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Adrenal Virilism

• Treatment: suppression of the pituitary–adrenal

axis with exogenous glucocorticoids
• Dexamethasone: 0.25 to 0.5 mg
• Prednisone: 2.5 to 5 mg
• Hydrocortisone: 10 to 20 mg

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Hypofunction Of The Adrenal Gland

Addison disease (or Addison's disease)

• Adrenocortical insufficiency due to the destruction
or dysfunction of the entire adrenal cortex
• Affects glucocorticoid and mineralocorticoid function
• Onset of disease usually occurs when 90% or more
of both adrenal cortices are dysfunctional or
destroyed

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Epidemiology and Etiology
• Adrenal insufficiency generally refers to the
inability of the adrenal glands to produce adequate
amounts of cortisol for normal physiologic
functioning or in times of stress.
• The condition is usually classified as primary,
secondary, or tertiary, depending on the etiology
• The estimated prevalence of primary adrenal
insufficiency and secondary adrenal insufficiency

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• Approximately 60 to 143 and 150 to 280 cases per 1
million persons, respectively.
• Whereas primary adrenal insufficiency is usually
diagnosed in the third to fifth decade of life,
secondary adrenal insufficiency is commonly
detected
during the sixth decade
• Adrenal insufficiency is more prevalent in women
than in men, with a ratio of 2.6:1.1 Chronic adrenal
insufficiency is rare.

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Pathophysiology

• Primary adrenal insufficiency (Addison’s dx)

most often involves the destruction of all regions of
the adrenal cortex.
• There are deficiencies of cortisol, aldosterone, and the
various androgens.
• Medications that inhibit cortisol synthesis (e.g.,
ketoconazole) or accelerate cortisol metabolism
(e.g., phenytoin, rifampin, phenobarbital) can also
cause primary adrenal insufficiency.

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• 20 adrenal insufficiency most commonly results
from exogenous corticosteroid use, leading to
suppression of the HPA-axis & decreased release of
ACTH,
• resulting in impaired androgen & cortisol production
• Secondary dx typically presents with normal
mineralocorticoid conc.

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Clinical Presentation
• Symptoms
• Weakness
• Weight loss
• GI symptoms
• Craving for salt
• headaches, memory impairment, depression, and
• Postural dizziness

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• Laboratory Tests
• The short cosyntropin stimulation test
• Other Diagnostic Tests
• Other tests include the insulin hypoglycemia test, the
metyrapone test, and the CRH stimulation test

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Treatment

• Goal Of Therapy
• To establish the lowest effective dose
• To mimic the normal diurnal adrenal rhythm
• To reduce side effects of medications

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Treatment…

Corticosteroids
• Hydrocortisone, cortisone, and prednisone are the
glucocorticoids of choice, administered bid.
• Recommended starting total daily doses are
hydrocortisone 15 mg, cortisone acetate 20 mg, or
prednisone 2.5 mg.
• Two-thirds of the dose is given in the morning & 1/3rdis
given in the evening.
• Add 5 to 10 mg of hydrocortisone: before strenuous
activities

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Treatment…
• primary insufficiency:
• fludrocortisone acetate can be used to supplement
mineralocorticoid loss………… to minimize
development of hyperkalemia ……not used for 2 0
insufficiency
• Dose: 0.05 to 0.2 mg PO QD
• Adverse effects: gastric upset, edema,
hypertension, hypokalemia, insomnia, excitability,
and diabetes mellitus
• Monitor: Patient weight, blood pressure, and
electrocardiogram

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• Because most adrenal crises occur due to
• glucocorticoid dose reductions or
• lack of stress-related dose adjustments,
• pts receiving corticosteroid replacement therapy
should add 5 to 10 mg hydrocortisone (or
equivalent) to their normal daily regimen shortly
before strenuous activities such as exercise.
• During times of severe physical stress (e.g., febrile
illnesses, after accidents), pts should be instructed
to double their daily dose.

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Acute Adrenal Insufficiency
Adrenal crisis or Addisonian crisis
• An acute adrenocortical insufficiency
• Can be precipitated by: Stressful situations, surgery,
infection, and trauma
• Most common cause: abrupt withdrawal of
exogenous
glucocorticoids ……resulted in HPA–axis
suppression

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Diagnosis

• Short corticotropin stim test

• Get baseline level
• Inject 250gm cosyntropin (IV or IM)…ACTH
• Measure plasma cortisol level in 60 minutes
• Excluded if
• basal or test level is > 525 nmol/L
• Plasma cortisol levels between 8am-9am
• Level <83 nmol/L rules IN
• Level >525 nmol/L rules OUT

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Treatment…
• Hydrocortisone given parenterally is the
corticosteroid of choice b/c of its combined
glucocorticoid and mineralocorticoid activity
• Dose: 100 mg IV rapid infusion, followed by a
continuous infusion (10 mg/h) or intermittent bolus
100 to 200 mg q24 hrs
• IV administration: 24 to 48 hours then oral 50 mg
every 6 to 8 hrs
• A hydrocortisone taper is then initiated until the
dosage is 30 to 50 mg/day in divided doses.

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Treatment…

• Fluid replacement
• often is required and can be accomplished with IV 5%
dextrose at a rate to support BP.
• If hyperkalemia is present after the hydrocortisone
maintenance phase, additional mineralocorticoid
usually is required
• Fludrocortisoneacetate 0.1 mg orally once daily is the
agent of choice.

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Treatment…

• They should also have easy access to injectable

hydrocortisone or glucocorticoid suppositories in
case of an emergency or during times of physical
stress, such as febrile illness or injury.

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Evaluation of Therapeutic Outcomes

• The end point of therapy for adrenal insufficiency is

difficult to assess in most patients, but
• a reduction in excess pigmentation is a good clinical
marker.
• Development of features of Cushing syndrome
indicates excessive replacement.

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