The Adrenal Gland

Question 2

What are the regions of the adrenal gland?

Answer 2

The adrenal gland is divided into the adrenal cortex and adrenal medulla

Question 3

Outline the zones of the adrenal cortex and their secretions.

Answer 3

1. Zona Glomerulosa: produces aldosterone (salt)
2. Zona Fasciculata: produces cortisol (sugar)
3. Zona Reticularis: produces adrenal androgens e.g. DHEA (sex)

Question 4

What regulates the adrenal gland?

Answer 4

The hypothalamus and pituitary gland regulate the adrenal gland. The pituitary releases ACTH which stimulates the adrenal gland to produce cortisol.

Question 5

What does the adrenal medulla produce?

Answer 5

The adrenal medulla produces catecholamines (adrenaline & noradrenaline).

Question 6

What are the causes of androgen excess in women?

Answer 6

1. Congenital Adrenal Hyperplasia (CAH) (rare)
2. Polycystic Ovary Syndrome (PCOS) (most common)
3. Adrenal Tumour (e.g. adrenal incidentaloma, adrenocortical carcinoma, phaeochromocytoma).

Question 7

What is CAH?

Answer 7

CAH is not one disorder but a collection of disorders caused by gene mutations resulting in a lack of enzymes needed to produce aldosterone, cortisol, and androgens. It is inherited in an autosomal recessive manner.

Question 8

Describe the adrenal steroidogenesis pathway.

Answer 8

All start with cholesterol which branches out into pathways to make mineralocorticoids, glucocorticoids, and androgens. The most common cause of CAH is 21-hydroxylase deficiency (CYP21A2).

Question 9

What happens if there is a block in CYP21A2?

Answer 9

If CYP21A2 is not functioning, both glucocorticoid and mineralocorticoid synthesis will be impaired, leading to a lack of aldosterone and cortisol production, while androgen production remains normal.

Question 10

How does CAH present itself in female babies?

Answer 10

CAH causes an overabundance of androgens and adrenal insufficiency, leading to virilisation of external genitalia in female newborns, potentially causing them to be mistaken for boys.

Question 11

How does CAH affect the pituitary-adrenal axis?

Answer 11

Due to the enzymatic defect in CAH, insufficient cortisol is produced, reducing negative feedback to the hypothalamus and pituitary gland, leading to increased ACTH production and excess androgen production.

Question 12

What key marker do we look for in CAH 21 hydroxylase block?

Answer 12

17 OHP is the steroid immediately before the enzymatic block and accumulates in the blood, used to diagnose CAH. Elevated levels indicate the condition.

Question 13

Outline the 3 forms of CAH and their symptoms.

Answer 13

1. Non-classic: androgen excess.
2. Classic simple-virilising: androgen excess, cortisol deficiency.
3. Classic salt-wasting: androgen excess, cortisol deficiency, aldosterone deficiency.

Question 14

Which of the 3 forms of CAH is the most severe?

Answer 14

Classic salt-wasting CAH is the most severe, while non-classic is the mildest.

Question 15

Signs and symptoms of non-classic CAH?

Answer 15

Mildest form with slight upregulation of ACTH. Symptoms include oligomenorrhea, early pubarche, hirsutism, subfertility, and male pattern baldness.

Question 16

Signs and symptoms of classic simple-virilising CAH?

Answer 16

Females will have virilized genitalia at birth, while males show no signs at birth. Stunted growth due to overproduction of androgens.

Question 17

Signs and symptoms of classic salt-wasting CAH?

Answer 17

Females will have virilized genitalia at birth, while males show no signs at birth. Symptoms include weight loss, vomiting, failure to thrive, and poor feeding.

Question 18

Describe 46, XX disordered sex development (DSD).

Answer 18

Female infants with CAH may have external genitalia that appear male due to excess androgen production, with the severity depending on the amount of androgens produced.

Question 19

How do we treat CAH?

Answer 19

Treatment involves balancing cortisol and aldosterone deficiencies with glucocorticoids to suppress excess androgens, as glucocorticoids exert negative feedback on ACTH production.

Question 20

What are the two main principles of CAH therapy?

Answer 20

1. Replacement of deficient corticosteroids (mineralocorticoid and glucocorticoid).
2. Suppression of ACTH-driven androgen excess through higher glucocorticoid doses.

Question 21

Why does CAH glucocorticoid treatment have to be carefully balanced?

Answer 21

Too much hydrocortisone can cause Cushing-like effects, while too little can lead to excess androgens.

Question 22

How can CAH and CAH treatment affect female fertility?

Answer 22

Excess glucocorticoids can suppress LH and FSH, leading to oligomenorrhea or amenorrhea, while insufficient glucocorticoids can cause androgen excess and anovulation.

Question 23

How can CAH treatment affect female fertility?

Answer 23

Giving too much glucocorticoid can lead to suppression of LH and FSH, causing menstrual cycle cessation, oligo/amenorrhea, iatrogenic Cushing’s, and hypogonadism. Not enough glucocorticoids can result in androgen and progesterone excess, anovulation, oligomenorrhea, and failure of fertilized egg implantation.

Question 24

How can CAH affect male fertility?

Answer 24

Testicular adrenal rest tissue (TART) can develop in men due to ACTH stimulation in CAH, expanding and compressing normal spermatogenesis, particularly in patients with poor control of CAH. This can impair fertility and may become irreversible if untreated.

Question 25

What are the three clinical characteristics for diagnosing PCOS?

Answer 25

1. Chronic (or intermittent) anovulation: failure to produce an egg, defined as frequent bleeding <21 days or infrequent bleeding >35 days. 2. Androgen excess: clinical signs include hirsutism, acne, androgenic alopecia; biochemical evidence is increased serum testosterone. 3. Polycystic ovarian appearance on ultrasound: presence of 12+ follicles 2-9 mm in diameter and/or increased ovarian volume >10 mL.

Question 26

What are the general symptoms of PCOS?

Answer 26

Symptoms include irregular menstrual cycles, hirsutism, acne, weight gain, and infertility.

Question 27

What is the PCOS diagnostic criteria?

Answer 27

The Rotterdam criteria, which includes the presence of two out of three of the following: oligo/anovulation, clinical/biochemical signs of hyperandrogenism, and polycystic ovaries.

Question 28

What is the worldwide prevalence of PCOS?

Answer 28

PCOS has a worldwide prevalence of 3-22% of all women, depending on the diagnostic criteria used.

Question 29

How can PCOS be a metabolic disorder?

Answer 29

Insulin resistance is a key feature of PCOS, with androgen excess potentially increasing insulin resistance and vice versa.

Question 30

How does PCOS change through life?

Answer 30

PCOS affects 1 in 10 women and is a lifelong metabolic disorder. Symptoms may develop with age, including androgen excess and irregular periods, along with increased incidence of insulin resistance and cardio-metabolic conditions.

Question 31

Why are there suggestions that PCOS should be renamed?

Answer 31

PCOS is a misnomer as it implies the ovary is the culprit, while it affects multiple systems. Androgen excess and insulin resistance are central, leading to risks like dyslipidemia, type 2 diabetes, hypertension, fatty liver disease, and cardiovascular disease. The proposed name is FAME: Female AndroMEtabolic Syndrome.

Question 32

What needs to be excluded prior to the diagnosis of PCOS?

Answer 32

Congenital adrenal hyperplasia, adrenal cancer, adrenal adenoma, Cushing’s disease, ovarian hyperthecosis, and ovarian tumors must be excluded before diagnosing PCOS.

Question 33

What are adrenal incidentalomas?

Answer 33

Adrenal incidentalomas are incidentally discovered adrenal tumors found during imaging for other reasons, with 5-10% of people having a nodule that is usually harmless.

Question 34

What are the first important questions when diagnosing adrenal incidentalomas?

Answer 34

1. Does it produce hormones (Is there hormonal excess)? 2. Is the adrenal mass malignant?

Question 35

What is adrenocortical carcinoma?

Answer 35

Adrenocortical carcinoma (ACC) is a highly malignant tumor, rare with a poor prognosis, accounting for 5% of adrenal masses, with <50% survival past 5 years.

Question 36

How is adrenocortical carcinoma differentiated from adenomas?

Answer 36

Differentiation relies on imaging, which can be poor in sensitivity and specificity. Adenomas typically appear darker than liver due to higher fat content, while carcinomas are larger, heterogeneous, and may show hemorrhages and necrosis.

Question 37

What imaging characteristics of an adrenal incidentaloma do we look at?

Answer 37

Key characteristics include tumor size, lipid content, laterality, homogeneity, and local invasion.

Question 38

What factors are key to determine when looking at imaging?

Answer 38

Tumors <4cm have a low risk of malignancy (<10%), while those >4cm have a higher risk.

Question 39

What are Hounsfield units?

Answer 39

Hounsfield units (HU) are a quantitative measurement of radiodensity used in CT imaging, comparing tissue density to distilled water.

Question 40

How do tumor radiodensity values vary among different tumors?

Answer 40

Adenomas often have negative Hounsfield units due to fat content, while lipid-poor adenomas and other tumors may have positive values, complicating the distinction between benign and malignant.

Question 41

How do we investigate hormone excess?

Answer 41

Exclude cortisol excess using a 1mg overnight dexamethasone suppression test (1mg-DST) and measure serum cortisol at 8-9 a.m. Levels higher than 50 indicate cortisol excess.

Question 42

How do we investigate hormone excess?

Answer 42

Exclude cortisol excess by performing a 1mg overnight dexamethasone suppression test (1mg-DST) and measuring serum cortisol at 8-9 a.m. Cortisol levels higher than 50 indicate cortisol excess.

Question 43

How do we exclude aldosterone excess?

Answer 43

Measure blood pressure; if elevated, measure renin, aldosterone, and serum potassium. This is particularly important in patients with high blood pressure or low potassium.

Question 44

How do we exclude adrenal androgen excess?

Answer 44

Test for serum DHEAS, androstenedione, and 17OHP (in tumors >4cm).

Question 45

How do we exclude pheochromocytoma?

Answer 45

Measure plasma metanephrine.

Question 46

What is MACE and how is it categorized?

Answer 46

MACE refers to mild autonomous cortisol excess/secretion. It is categorized using the 1mg dexamethasone overnight suppression test, with outcomes including Non-functioning adrenal tumors (NFAT), Mild autonomous cortisol secretion (MACS), and Clinically overt cortisol excess (Cushing's syndrome).

Question 47

How do we differentiate between MACS and clinically overt cortisol excess?

Answer 47

If a patient has biochemical evidence of cortisol excess and abnormal dexamethasone suppression but lacks Cushing’s features, it is classified as MACS.

Question 48

What cortisol levels indicate normal and MACS?

Answer 48

Cortisol levels <50 are normal; levels >50 are consistent with MACS.

Question 49

What cardio-metabolic comorbidities is MACE associated with?

Answer 49

MACE is associated with an increased risk of hypertension, obesity, type 2 diabetes, cardiovascular events, and chronic kidney disease.

Question 50

What are pheochromocytomas?

Answer 50

Pheochromocytomas are tumors from the adrenal medulla.

Question 51

What is the textbook description of pheochromocytoma?

Answer 51

Textbook presentation includes hypertension and hyperadrenergic spells (headaches, palpitations, profuse sweating) caused by catecholamine excess. Nowadays, most cases are incidental findings.

Question 52

What do we measure for pheochromocytoma diagnosis?

Answer 52

Measure plasma metanephrines, which are metabolites of catecholamines and circulate longer in the blood. 24-hour urinary metanephrines can also be measured.

Question 53

What is the treatment for pheochromocytoma?

Answer 53

Patients must receive α-blockers before surgery to mitigate catecholamine effects. Surgery requires special anesthesia and fluid resuscitation.

Question 54

What causes the vast majority of pheochromocytomas?

Answer 54

The majority are associated with germline mutations and are the most hereditary form of cancer known.

Question 55

What germline mutations are associated with pheochromocytomas?

Answer 55

1. RET protooncogene: Multiple Endocrine Neoplasia (MEN) type 2. 2. VHL gene: Von Hippel Lindau Syndrome. 3. NF-1 gene: Neurofibromatosis type 1. 4. Succinyl Dehydrogenase Complex Subunit B and D mutations: familial pheochromocytoma.

Question 56

What key things need to be excluded when an adrenal tumor is found?

Answer 56

Exclude hormone excess (primary aldosteronism, Cushing’s syndrome, adrenal androgen excess, pheochromocytoma) and exclude adrenal cortical carcinoma (ACC) if tumor diameter >4cm and attenuation >20HU on unenhanced CT.