Steroid Hormone Biosynthesis and Congenital Adrenal Hyperplasia

Question 1

_________ Peptide Hormones Stimulate the _______ to Release Peptide Hormones that control _______ and _______ steroidogenesis

Answer 1

Hypothalamic Peptide Hormones Stimulate the Anterior Pituitary to Release Peptide Hormones that control adrenal and gonadal steroidogenesis

Question 2

GnRH sequence

Answer 2

Gonadotropin releasing hormone (GnRH) is secreted from neurons within the hypothalamus/preoptic area (AH- POA) that project into the median eminence. This structure results in release of GnRH into the hypothalamo-pituitary portal system for direct stimulation of the anterior pituitary gonadotropes. This pulsatile release of GnRH stimulates the gonadotropes of the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH).

Question 3

ACTH targets the ________to stimulate the synthesis of _______

Answer 3

ACTH targets the adrenal cortex (zona fasiculata and zona reticularis) to stimulate the synthesis of glucocorticoids

Question 4

LH targets the ______ to stimulate the synthesis of ____, and ______ cells for ______ production

Answer 4

LH targets the Leydig cell of the testes to stimulate the synthesis of testosterone, and ovarian theca cells for androgen production

Question 5

FSH targets the ______ to stimulate the synthesis of ______

Answer 5

FSH targets the ovarian granulosa cells to stimulate the synthesis of estrogen

Question 6

GnRH recpetor name in anterior pituitary

Answer 6

GnRHR

Question 7

LH and FSH recpetors on Leydig cells and ovarian granulosa cells, respectively

Answer 7

LHR and FSHR

Question 8

GnRH-receptor interaction activates _____signaling leading to activation of the _______ second messenger cascade.

Answer 8

GnRH-receptor interaction activates Gαq/11 signaling leading to activation of the phospholipase C –diacylglycerol – IP3 - calcium (PLC-DAG-IP3-Ca2+) second messenger cascade.

Question 9

CRH-CRHR1 interaction activates _____ and _______ signaling pathways resulting in increased calcium.

Answer 9

CRH-CRHR1 interaction activates Gs (primary) and Gq signaling pathways resulting in increased calcium.

Question 10

What is the response secondary to hormone release

Answer 10

ACTH-ACTH receptor (MCR2), LH-LH receptor (LHR), or the FSH-FSH receptor (FSHR) interactions activate the cAMP-protein kinase A (PKA) second messenger pathway that leads to increased transcriptional activation of genes encoding the enzymes in the steroidogenic pathway.

Question 11

LH and FSH hormone

Answer 11

Both LH and FSH are glycoproteins composed of alpha and beta subunits (Fig. 3) . The alpha subunit is common to both LH and FSH while the beta subunit is unique for each hormone and provides the specificity for receptor binding.

Question 12

Are steroid hormones stored anywhere?

Answer 12

Steroid hormones are not stored, but synthesized and immediately released. Therefore the function of the anterior pituitary hormones is to increase the synthesis of steroid hormones.

Question 13

The cellular response of steroidogenic cells to PKA activation is two-fold:

Answer 13

1) cholesterol delivery to mitochondria and
2) increased gene expression of the enzymes that metabolize cholesterol to a steroid hormone

Question 14

Steps in cholesterol delivery to mitochondria

Answer 14

1. Cytochrome P450 cholesterol side chain cleavage (Chol SCC) catalyzes first step in mitochondrial matrix
2. Cholesterol in HDL and LDL is stored as choleterol ester (CE)
3. Free cholesterol released from CE by AMP-PKA dependent activation of cholesterol ester hydrolase (CE hydrolase).
4. Free cholesterol is then transported to the mitochondria outer membrane by lipid carrier proteins
5. At the mitochondria, the Steroidogenic Acute Regulatory protein (StAR) facilitates the transfer of cholesterol across the mitochondrial membranes. This step is dependent upon new synthesis of the StAR protein.

Question 15

Hormone feedback regulation for estradiol, testosterone, and cortisol

Answer 15

Question 16

Steroid hormones are classified based on _______ and ________

Answer 16

Steroid hormones are classified based on the number of carbons (C21, C19, C18) and the nuclear receptor they bind

Question 17

C21

Answer 17

steroids that are end products of the adrenal are in the mineralocorticoids (aldosterone) and glucocorticoids (cortisol) classes

Question 18

C19

Answer 18

steroids are the major product of the testes, and are synthesized in the ovary and serve as the precursor for estrogens.

Question 19

C18

Answer 19

Type of steroids that are the major product of the ovary, and are in the estrogen class

Question 20

Only the _____ produces C21 steroids

Answer 20

Only the adrenal produces C21 steroids

Question 21

Answer 21

Question 22

Steroid hormones are ______ so require _____ in circulation

Answer 22

Hydrophobic, plasma binding proteins

Question 23

The biosynthesis of steroid hormones requires the action of _____ and _______ enzymes.

Answer 23

The biosynthesis of steroid hormones requires the action of cytochrome P450s (CYPs) and hydroxysteroid dehydrogenases (HSD) enzymes.

Question 24

Two locations of C P450 and difference in electron chain

Answer 24

Either the mitochondrial inner membrane or smooth endoplasmic reticulum

In both locations flavoproteins that contain redox prosthetic groups shuttle the electrons.

In the mitochondria, electrons are passed from NADPH to ferrodoxin (Fdx) reductase, a flavin adenine dinucleotide (FAD)-containing flavoprotein. Fdx reductase transfers electrons to the iron-sulfur containing ferrodoxin (Fdx) protein and Fdx shuttles electrons to the P450 enzyme.

In the endoplasmic reticulum, one protein, Cytochrome P450 oxidoreductase protein (CPR), contains two flavin cofactors (FMN and FAD) and shuttles electrons from NADPH to the heme-iron center of the P450 enzyme.

Question 25

Function of Hydroxysteroid Dehydrogenases (HSD)

Answer 25

oxidation (dehydration) of hydroxysteroids to produce ketosteroids

Question 26

3β -hydroxysteroid dehydrogenase (3βHSD, HSD3B) catalyzes what reaction

Answer 26

oxidation of the hydroxyl group at C3 to a keto group. This reaction is coupled with the isomerization of the double bond from C5-C6 to C4-C5.

Question 27

delta-5 refers to steroids …

Answer 27

derived from pregnenolone that has the C5-C6 double bond

Question 28

delta-4 refers to steroids

Answer 28

derived from progesterone that has the C4-C5 double bond

Question 29

Is The 3βHSD reaction is reversible

Answer 29

No, irreversible

Question 30

17β -hydroxysteroid dehydrogenase (17βHSD, HSD17B) catalyzes ….

Answer 30

Reversible oxidation-reduction reactions at C17. Reduction of the C17 keto group to a hydroxyl group generates the potent androgens, and this activity is highest in the gonads and in peripheral tissues such as adipose.

Question 31

The major steroid products of the ZG (adrenal)

Answer 31

Mineralcorticoids like aldosterone … salt

Question 32

The major steroid products of the ZF

Answer 32

Glucocorticoids, like those stimulated by ACTH

Question 33

The major steroid products of the ZR

Answer 33

Adrenal androgens, weak sex hormones

Question 34

Which are the adernal specific enzymes

Answer 34

Cytochrome P450 21α-hydroxylase, 11β-hydroxylase, and aldosterone synthase

Question 35

Which enzymes are present and absent in the ZG

Answer 35

absence of 17α-hydroxylase, 17,20 lyase expression in the ZG drives the pathway toward mineralocorticoid synthesis.

he ZG-specific expression of the enzyme aldosterone synthase that converts corticosterone to aldosterone

Question 36

Enzymes present and absent in ZF

Answer 36

The presence of 17α-hydroxylase, 17,20 lyase combined with the absence of aldosterone synthase leads to cortisol being produced.

Question 37

What enzymes are in the ZR

Answer 37

The adrenal ZR zone lacks expression of any of the adrenal specific enzymes and the steroid hormone biosynthetic pathway in this zone is the same as in the gonads

Question 38

High circulating DHEA and androstenedione levels are an indicator of

Answer 38

an adrenal disorder

Question 39

Elevated levels of C17 keto steroids in urine is diagnostic for

Answer 39

excess adrenal androgen production.

Question 40

Elevated DHEA/androstenedione levels can lead to

Answer 40

elevated sex hormone levels due to metabolism by the adipose tissue

Question 41

What are the precursors for testosterone synthesis

Answer 41

C17 keto steroids DHEA and androstenedione

Question 42

Where is estrogen sythesized in males

Answer 42

Aromatase is expressed in the Leydig, Sertoli, and germ cells of the testis, and peripheral tissue (e.g. adipose). Circulating testosterone can be converted to estrogens in peripheral tissues and drive a local estrogen response via the estrogen receptor.

Question 43

Where is estrogen produced in females

Answer 43

Two ovarian cell types, the theca cells and granulosa cells, coordinate the synthesis of estrogens. The theca cell is the androgen producing cell type and converts cholesterol to androgens (Fig. 16). The androgens diffuse to the adjacent granulosa cells and are converted to estrogens via the action of aromatase

Question 44

Major hormones of adrenal gland

Answer 44

aldosterone, cortisol, C17 keto steroids (androgens)

Question 45

Major hormones of ovary

Answer 45

estradiol, progesterone, testosterone

Question 46

Major hormones of testes leydig cells

Answer 46

testosterone

Question 47

Major hormones produced in peripheral (adipose) tissue

Answer 47

use adrenal androgens to produce testosterone or estradiol

Question 48

What is congenital adrenal hypoplasia (CAH)

Answer 48

CAH is a group of autosomal recessive disorders due to loss of function mutations in genes encoding the enzymes of the steroidogenic pathway.

The low cortisol level classifies CAH as an adrenal insufficiency disorder.

Question 49

What is a major indicator of CAH

Answer 49

an indicator for CAH is high ACTH and low Cortisol

Question 50

A 21α-hydroxylase deficiency can be differentiated by

Answer 50

high 17α-hydroxyprogesterone levels

Question 51

What finding implicate 17α-hydroxylase deficiency

Answer 51

Low 17OHP levels (17α-hydroxyprogesterone)

Question 52

What is the most common form of CAH and what gene mutation causes it

Answer 52

21α-hydroxylase deficiency

CYP21A2 is located in within the major human histocompatibility complex (HLA) on the long arm of chromosome 6. This is a highly complex region with high recombination events. A pseudogene (CYP21A1) that shares 98% sequence identity with CYP21A2 is located 30kb away and recombination is the major mechanism leading to pathogenic variants for 21α-hydroxylase.

Question 53

What is salt wasting

Answer 53

Classical 21α-hydroxylase deficiency

The lack of aldosterone leads to loss of mineralocorticoid effects on the kidney. One target is the loss of regulated Na-K-ATPase and sodium retention, that results in increased Na+ excretion and “salt wasting”.

Question 54

What occurs in the simple virilization form of 21 CAH

Answer 54

Aldosterone production is not diminished but affected individuals have elevated androgens. Prenatal androgen excess results in newborn females with ambiguous genitalia (as observed with the salt-wasting forms). Elevated testosterone levels prior to puberty lead to early virilization (precocious puberty) in boys.

Question 55

What occurs in non-classical CAH

Answer 55

Aldosterone production is not affected and females have no genital ambiguity. Typically endocrine disorders are observed later in life and may present as fertility issues or hirsutism in women.

highest prevalance in groups from european descent

Question 56

17α-hydroxylase / 17,20 lyase deficiencies affect

Answer 56

both the adrenal and gonadal steroidogenic pathways

Question 57

Treatment for adrenal disorders, metabolic disorders (overproduction of cortisol), and cancer targets both ….

Answer 57

steroid biosynthesis and steroid action (activation of a steroid nuclear receptor)