Biochemistry-Steroid Synthesis Flashcards
5 classes of steroid hormones
1) Progesterons (21C) 2) Glucocorticoids (21C) 3) Mineralocorticoids (21C) 4) Androgens (19C) 5) Estrogens (18C)
Where are most steroid receptors located?
Since steroids are lipophilic, receptors are found intracellularly in the cytosol or in the nucleus
How does cortisol turn genes on?
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
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?
ACTH (ant. pit), FSH (ant. pit), LH (ant. pit), Angiotensin (kidney) and oxytocin (hypothalamus)
What is the target tissue of the hormone listed below?
*
How does angiotensin II stimulate cellular signaling to increase aldosterone production?
ATII -> Gq -> PLC -> PIP2 -> IP3 (opens Ca channels) and DAG (activates PKC which stimulates aldosterone production)
How do ACTH/FSH/LH stimulate cellular signaling to increase steroid synthesis?
Hormone -> G-protein -> Adenylyl cyclase -> cAMP -> PKA -> Steroid synthesis
What types of steroid hormones are secreted by the adrenal cortex?
Aldosterone (zona glomerulosa, “salt steroid”), Cortisol (zona fasciculata, “sugar steroid”) and Androgens (zona reticularis, “sex steroid” in males)
HPA axis
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.
What effect does cortisol have on muscle glucose uptake, glucose use, protein synthesis, glucose output, ketogenesis and glycogenolysis?
Increased glucose output, ketogenesis and glycogenolysis. Decreased muscle glucose uptake, glucose use and protein synthesis.
3 symptoms of glucocorticoid deficit
Hypoglycemia (insulin uninhibited and glucagon unstimulated), fatigue (low glucose/gluconeogenesis) and infection (loss of inflammation & infection control)
Distal tubule reaction to aldosterone
Increased water and Na uptake and K excretion
Kidney response to decreased BP
Juxtaglomerular cells secrete the enzyme renin -> AT -> ATI -> ATII by ACE -> ATII causes aldosterone release from adrenal cortex -> salt and water retention -> increased BP
3 symptoms of mineralocorticoid deficit
Electrolyte imbalance (hyponatremia, hyperkalemia), Dehydration & diarrhea (Na excretion) and low BP (RAAS ineffective)
3 effects of testosterone
Anabolic (muscle/bone growth), androgenic (secondary sex characteristics in males) and promotes differentiation of spermatogonia
2 types of testosterone
Testosterone and DHT (more potent)
What causes progesterone synthesis and what are its effects?
FSH stimulates corpus luteum and placenta to make progestagens. Progesterone prepares uteral lining during ovulation and maintains pregnancy
3 types of estrogens
Estradiol (E2 is most predominant, most potent), estriol (E3, made in placenta), estrone (E1, major source in post-menopausal women)
Where does steroid synthesis take place after PKA is activated?
Smooth ER and mitochondria
Sources of cholesterol for steroid synthesis
1) LDL (80%), also from scratch and cholesterol ester droplets
What stimulates LDL receptors to bring in more cholesterol for steroid synthesis?
Binding of hormone to receptor. Note that binding of the receptor also stimulates upregulation of CYP450 side chain cleaving enzyme for steroid synthesis
Rate limiting and committed step for steroid synthesis?
Cholesterol (C27) -> Pregnenolone (C21) by CYP450 side chain cleaving enzyme
As an overview how does steroid synthesis progress?
More oxidation as the pathway goes on and loss of carbons to form androgens and estrogens.
Precursor for mineralocorticoid and glucocorticoid synthesis
Progesterone. Remember that aldosterone has an aldehyde at C18 and that cortisol has an alcohol at C17.
Precursor for sex hormone synthesis
Androstenedione
Location of DHEA and 1/2 of androstenedione secretion
Adrenal gland
What enzyme makes testosterone potent that reacts in target tissues prior to binding to the receptor?
5-alpha-reductase (Takes testosterone to DHT)
How do you get estradiol and estrone?
Both require aromatization of ring A in the steroid nucleus. Estradiol comes from testosterone and estrone comes from androstenedione.
A patient presents with trunk obesity, moon facies, buffalo hump, muscle weakness and frequent infections. What are likely etiologies of his condition?
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)
A patient presents with tan skin, weight loss, dehydration and hypoglycemia. What are likely etiologies of his condition?
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.
Most common enzymes mutated in congenital adrenal hyperplasia (CAH)? Which is most common?
CYP21, CYP17 and CYP11B1, CYP21 deficiency being most common.
What type of mutation is CAH?
Autosomal recessive
A patient presents with hyponatremia, hirsutism (too much hair), menstrual irregularity and enlarged adrenal glands. What is causing this patient’s condition?
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).
A patient presents with hirsutism (too much hair), menstrual irregularity, hypertension and enlarged adrenal glands. What is causing this patient’s condition?
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.
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?
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.
How do you diagnose CAH? How do you treat?
Test for altered hormone levels depending on the suspected enzyme deficiency. Treat with daily administration of prednisone to suppress overproduction of ACTH
A patient presents with severe hypertension and hypokalemia. She has a history of binge eating licorice. What is causing her symptoms?
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.
