Setting: office
CC: “My face is getting fat and hairy.”
VS: BP: 153/98 mm Hg; P: 74/minute; T: 97.2°F
HPI: A 27-year-old woman comes to your office concerned that her face is getting “fatter and rounder” despite the fact that she exercises and restricts her diet. She has an increasing acne problem. She was referred to you by her dermatologist who she was seeing for the acne and thinning hair on her scalp.
PMHX:
Infertility, irregular menstruation
Borderline hypertension
Vertebral compression fracture
Medications: none
PE:
General appearance: somewhat obese abdomen
Skin: striae on flanks, bruises on thin arms
Head, ears, eyes, nose, throat (HEENT): excess hair over lip and at chin
Cardiovascular: normal
What is the best initial test to look for hypercortisolism?
a. A 24-hour urine cortisol
b. Adrenocorticotropic hormone (ACTH) level
c. Magnetic resonance imaging (MRI) of the head
d. High-dose dexamethasone suppression
e. Random serum cortisol
Answer a. A 24-hour urine cortisol
Cortisol levels have tremendous fluctuation during the day. Randomly testing for blood or urine cortisol is useless and always the wrong answer. Every time you get anxious or get a parking ticket, your cortisol level goes up. The 24-hour urine cortisol test tells the average cortisol level over the past day.
The “1-mg overnight dexamethasone suppression test” is too nonspecific. If the morning cortisol level remains elevated, it can be from anxiety, depression, or alcoholism. A normal test result excludes hypercortisolism.
Never start with a head MRI in endocrine disorders.
Initial Orders:
Comprehensive metabolic panel (CHEM-20)
Lipid panel
UA
24-hour urine cortisol collection
Which of the following is the only hormone made continuously?
a. Cortisol
b. Testosterone
c. T4
d. Growth hormone (GH)
e. ACTH
Answer c. T4
All hormones are made in pulsatile fashion except for T4 and T3, which are made continuously. They are all subject to feedback inhibition—after production, they go back and shut off their own stimulatory hormone. Cortisol does feedback inhibition on the pituitary and hypothalamus to shut off ACTH and corticotropin-releasing hormone (CRH).
Cortisol is glucuronidated or “sugar coated” to come off the binding protein and be excreted in the urine.
Move the clock forward 1 to 2 weeks to have the result of the 24-hour urine test.
CHEM-20: potassium borderline low; bicarbonate elevated; glucose 185 mg/dL
Lipid panel: LDL and triglycerides elevated
UA: normal
24-hour urine cortisol collection: elevated
What is the mechanism of low potassium and high bicarbonate?
a. Volume depletion
b. Mineralocorticoid effects of cortisol
c. 11-Deoxycorticosterone elevation
d. ACTH effect on kidney
Answer b. Mineralocorticoid effects of cortisol
Adrenal hormones are not purely of one single effect. Cortisol has some mineralocorticoid or aldosterone-like effect. That is also why the potassium level is low. Aldosterone levels are likely low in hypercortisolism. This is because cortisol raises BP.
1. High BP shuts off renin.
2. No Renin = No ANGII
3. No ANGIII + Low Potassium = No Aldosterone Synthesis
Mineralocorticoid (aldosterone) effect
• Potassium (K+) excretion
• Hydrogen (H+) excretion
• Sodium reabsorption
The patient is relieved to know that she has a diagnosis that can explain her facial fatness and truncal obesity.
The patient wants to know if the acne and hirsutism are also related to this same problem. What do you tell her?
a. Yes, she is secreting more testosterone.
b. Yes, adrenal androgen excess accompanies Cushing syndrome.
c. Yes, cortisol suppresses estrogen production.
d. No, unfortunately you must find a second tumor.
Answer b. Yes, adrenal androgen excess accompanies Cushing syndrome (Figure 3-5). Dehydroepiandrosterone (DHEA) and androstenedione are cosecreted with hypercortisolism. In addition, there is some androgen-like effect of cortisol. Acne, male pattern hair loss, and excess hair on the face in women is part of hypercortisolism. This is the same reason this patient is infertile. Excess androgens are interfering with her ovulatory cycles.
Figure 3-5. Diagnostic evaluation of Cushing syndrome and procedures for determining the cause. Boxes enclose clinical diagnoses, and ovals enclose diagnostic tests. ACTH, adrenocorticotropic hormone. (Reproduced with permission from Felig P, Baxter JD, eds. Endocrinology and Metabolism, 2nd ed. New York: McGraw-Hill; 1987, as redrawn in McPhee SJ, Hammer GD. Pathophysiology of Disease: An Introduction to Clinical Medicine, 6th ed. New York: McGraw-Hill; 2010.)
Excess androgen levels cause acne. Sebaceous glands have testosterone receptors.
The patient is delighted that she can get “one stop shopping” to fix her fat face, obese trunk, acne, and restore her periods and fertility. She wants to know where the lesion is.
What test do you order next?
a. ACTH level
b. MRI of head
c. CT of adrenals
Answer a. ACTH level
If the ACTH level is high, then the source is the pituitary or an ectopic focus, such as the lungs. If the ACTH level is low, then the source is the adrenal glands.
High Cortisol = High Lipids
Cortisol causes lipolysis.
The patient returns in 1 week. Always follow BP in any person who was hypertensive. Her BP is 148/94 mm Hg. The laboratory test results show:
ACTH: elevated
Glucose: 176 mg/dL
What is the mechanism of hypertension?
a. Cortisol increases the number of α-receptors in the vasculature.
b. Hyperglycemia increases osmotic pressure in vessels.
c. Increasing norepinephrine accompanies hypercortisolism.
Answer a. Cortisol increases the number of α-receptors in the vasculature.
There is an increased effect of catecholamines, not an increased level. Cortisol has a permissive effect on catecholamines in the vasculature. This is by the direct effect of alpha-1-receptors on vasoconstriction. Glucocorticoids increase the number of alpha-1-receptors as well as potentiating the effect on norepinephrine and epinephrine at currently existing receptors. This is why a bolus of steroids in sepsis has such an immediate effect in raising BP. There is a slower aldosterone-like effect at the kidney, increasing sodium reabsorption.
Hypercortisolism causes striae and easy bruising.
Skin is made of collagen protein.
Cortisol breaks down proteins to use the amino acids for gluconeogenesis.
After you have established the presence of hypercortisolism with a 24-hour urine cortisol collection, use the ACTH level to determine the location. When the ACTH level is proven elevated, then do a high-dose dexamethasone suppression test to distinguish between a pituitary source and an ectopic source.
Order:
High-dose dexamethasone suppression test
Response to high-dose dexamethasone:
• The pituitary gland will suppress the ACTH level.
• Ectopic foci will not suppress the ACTH level.
The patient has suppression of the ACTH level. You now order an MRI of the head to find a lesion. All of this testing is so that you will remove the correct part of the body. Because 10% of the population has an abnormal pituitary on MRI, you must never start with a scan. You might end up removing the pituitary inappropriately if the source is really elsewhere.
Cortisol causes osteoporosis by directly breaking down bone.
Cortisol increases osteoclast activity.
The MRI shows a lesion in the pituitary. You consult a neurosurgeon for removal.
What is the most likely histology?
a. Hyperplasia
b. Adenoma
c. Neoplasia
Answer b. Adenoma
Most functional pituitary tumors are adenomas. They retain the ability to be suppressed by feedback inhibition but only with high-dose dexamethasone administration.
Bone matrix is protein and is broken down to amino acids for gluconeogenesis.
Which of the following is the greatest or major mechanism of how cortisol increases serum glucose level?
a. Increasing gluconeogenesis
b. Decreasing glucose excretion at kidney
c. Having a permissive action on glucagon
d. Blocking uptake into tissues like muscle and adipose
Answer d. Blocking uptake into tissues like muscle and adipose
Although cortisol does increase gluconeogenesis and breaks down glycogen by permissive action on glucagon, the major mechanism is blocking uptake into peripheral tissues.
Move the clock forward to follow up after removal of the pituitary lesion. Make sure you replace thyroid hormone and sex hormones in addition to giving prednisone or hydrocortisone. Recheck the patient’s chemistry looking for a normal glucose, potassium, sodium, and bicarbonate levels.