Biochemistry-Steroid Synthesis

Question 1

5 classes of steroid hormones

Answer 1

1) Progesterons (21C) 2) Glucocorticoids (21C) 3) Mineralocorticoids (21C) 4) Androgens (19C) 5) Estrogens (18C)

Question 2

Where are most steroid receptors located?

Answer 2

Since steroids are lipophilic, receptors are found intracellularly in the cytosol or in the nucleus

Question 3

How does cortisol turn genes on?

Answer 3

It binds the glucocorticoid receptor and allows the receptor to dimerize with another receptor. It can then interact with DNA sequences to turn genes on that raise blood glucose levels

Question 4

What stimuli do the brain and kidney send to the adrenal gland (glucocorticoids, mineralocorticoids, and androgens) or gonads (androgens, estrogens or progestagens) to produce steroids?

Answer 4

ACTH (ant. pit), FSH (ant. pit), LH (ant. pit), Angiotensin (kidney) and oxytocin (hypothalamus)

Question 5

What is the target tissue of the hormone listed below?

Answer 5

*

Question 6

How does angiotensin II stimulate cellular signaling to increase aldosterone production?

Answer 6

ATII -> Gq -> PLC -> PIP2 -> IP3 (opens Ca channels) and DAG (activates PKC which stimulates aldosterone production)

Question 7

How do ACTH/FSH/LH stimulate cellular signaling to increase steroid synthesis?

Answer 7

Hormone -> G-protein -> Adenylyl cyclase -> cAMP -> PKA -> Steroid synthesis

Question 8

What types of steroid hormones are secreted by the adrenal cortex?

Answer 8

Aldosterone (zona glomerulosa, “salt steroid”), Cortisol (zona fasciculata, “sugar steroid”) and Androgens (zona reticularis, “sex steroid” in males)

Question 9

HPA axis

Answer 9

Hypothalamus secretes CRH -> Pituitary releases ACTH -> Adrenal releases cortisol. This all happens in response to hypothalamic stimulation by sleep, cold, pain, emotions, hemorrhage, exercise, hypoglycemia, infections, trauma, toxins etc.

Question 10

What effect does cortisol have on muscle glucose uptake, glucose use, protein synthesis, glucose output, ketogenesis and glycogenolysis?

Answer 10

Increased glucose output, ketogenesis and glycogenolysis. Decreased muscle glucose uptake, glucose use and protein synthesis.

Question 11

3 symptoms of glucocorticoid deficit

Answer 11

Hypoglycemia (insulin uninhibited and glucagon unstimulated), fatigue (low glucose/gluconeogenesis) and infection (loss of inflammation & infection control)

Question 12

Distal tubule reaction to aldosterone

Answer 12

Increased water and Na uptake and K excretion

Question 13

Kidney response to decreased BP

Answer 13

Juxtaglomerular cells secrete the enzyme renin -> AT -> ATI -> ATII by ACE -> ATII causes aldosterone release from adrenal cortex -> salt and water retention -> increased BP

Question 14

3 symptoms of mineralocorticoid deficit

Answer 14

Electrolyte imbalance (hyponatremia, hyperkalemia), Dehydration & diarrhea (Na excretion) and low BP (RAAS ineffective)

Question 15

3 effects of testosterone

Answer 15

Anabolic (muscle/bone growth), androgenic (secondary sex characteristics in males) and promotes differentiation of spermatogonia

Question 16

2 types of testosterone

Answer 16

Testosterone and DHT (more potent)

Question 17

What causes progesterone synthesis and what are its effects?

Answer 17

FSH stimulates corpus luteum and placenta to make progestagens. Progesterone prepares uteral lining during ovulation and maintains pregnancy

Question 18

3 types of estrogens

Answer 18

Estradiol (E2 is most predominant, most potent), estriol (E3, made in placenta), estrone (E1, major source in post-menopausal women)

Question 19

Where does steroid synthesis take place after PKA is activated?

Answer 19

Smooth ER and mitochondria

Question 20

Sources of cholesterol for steroid synthesis

Answer 20

1) LDL (80%), also from scratch and cholesterol ester droplets

Question 21

What stimulates LDL receptors to bring in more cholesterol for steroid synthesis?

Answer 21

Binding of hormone to receptor. Note that binding of the receptor also stimulates upregulation of CYP450 side chain cleaving enzyme for steroid synthesis

Question 22

Rate limiting and committed step for steroid synthesis?

Answer 22

Cholesterol (C27) -> Pregnenolone (C21) by CYP450 side chain cleaving enzyme

Question 23

As an overview how does steroid synthesis progress?

Answer 23

More oxidation as the pathway goes on and loss of carbons to form androgens and estrogens.

Question 24

Precursor for mineralocorticoid and glucocorticoid synthesis

Answer 24

Progesterone. Remember that aldosterone has an aldehyde at C18 and that cortisol has an alcohol at C17.

Question 25

Precursor for sex hormone synthesis

Answer 25

Androstenedione

Question 26

Location of DHEA and 1/2 of androstenedione secretion

Answer 26

Adrenal gland

Question 27

What enzyme makes testosterone potent that reacts in target tissues prior to binding to the receptor?

Answer 27

5-alpha-reductase (Takes testosterone to DHT)

Question 28

How do you get estradiol and estrone?

Answer 28

Both require aromatization of ring A in the steroid nucleus. Estradiol comes from testosterone and estrone comes from androstenedione.

Question 29

A patient presents with trunk obesity, moon facies, buffalo hump, muscle weakness and frequent infections. What are likely etiologies of his condition?

Answer 29

Cushing’s DISEASE: hypercortisolemia from pituitary gland hyperplasia or tumor that increases ACTH levels. Cushing’s SYNDROME: hypercortisolemia from oral corticosteroids or adrenal tumor (increases cortisol levels)

Question 30

A patient presents with tan skin, weight loss, dehydration and hypoglycemia. What are likely etiologies of his condition?

Answer 30

Secondary adrenal insufficiency: adrenocortical insufficiency from exogenous steroid use or pituitary adenoma that decreases ACTH. Addison’s disease: adrenocortical insufficiency from destruction of adrenal cortex by autoantibodies, HIV infection or adrenal tumor that all decrease cortisol.

Question 31

Most common enzymes mutated in congenital adrenal hyperplasia (CAH)? Which is most common?

Answer 31

CYP21, CYP17 and CYP11B1, CYP21 deficiency being most common.

Question 32

What type of mutation is CAH?

Answer 32

Autosomal recessive

Question 33

A patient presents with hyponatremia, hirsutism (too much hair), menstrual irregularity and enlarged adrenal glands. What is causing this patient’s condition?

Answer 33

This patient has congenital adrenal hyperplasia (CAH) caused by CYP21 deficiency. This results in lack of aldosterone (hyponatremia) and cortisol. The adrenal gland is enlarged because lack of cortisol causes continued high levels of ACTH from the pituitary. Progesterone backs up and causes increased testosterone (hirsutism and menstrual irregularity).

Question 34

A patient presents with hirsutism (too much hair), menstrual irregularity, hypertension and enlarged adrenal glands. What is causing this patient’s condition?

Answer 34

CAH from CYP11B1 deficiency. In addition to adrenal hyperplasia from overstimulation by ACTH and progesterone back up into testosterone (causes virilization), tons of 11-deoxycortisol (DOC) can activate the MC receptor and cause hypertension.

Question 35

A patient presents with hirsutism (too much hair), menstrual irregularity, severe hypertension and enlarged adrenal glands. You determine that she needs estrogen supplementation and if she were a boy would need testosterone shots. What is causing this patient’s condition?

Answer 35

CAH from CYP17 deficiency. Now that hydroxylase and lyase function is gone, only aldosterone is left and hypertension is worse. Also, sex hormones cannot be produced and supplementation is necessary. Finally, cortisol is absent so there is continued ACTH stimulation causing adrenal hyperplasia.

Question 36

How do you diagnose CAH? How do you treat?

Answer 36

Test for altered hormone levels depending on the suspected enzyme deficiency. Treat with daily administration of prednisone to suppress overproduction of ACTH

Question 37

A patient presents with severe hypertension and hypokalemia. She has a history of binge eating licorice. What is causing her symptoms?

Answer 37

She has Apparent Mineralocorticoid Excess (AME). Normally glucocorticoid levels in plasma are much greater than mineralocorticoids. To prevent high levels of cortisol from mass activating mineralocorticoid receptors and causing hypertension and hypokalemia, CYP11beta-HSD2 converts cortisol to cortisone in the kidney. When this enzyme is defective, patients have intense retention of Na and excretion of K, causing hypertension and hypokalemia.