Steroid Hormone Biosynthesis and Congenital Adrenal Hyperplasia Flashcards
_________ Peptide Hormones Stimulate the _______ to Release Peptide Hormones that control _______ and _______ steroidogenesis
Hypothalamic Peptide Hormones Stimulate the Anterior Pituitary to Release Peptide Hormones that control adrenal and gonadal steroidogenesis
GnRH sequence
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).
ACTH targets the ________to stimulate the synthesis of _______
ACTH targets the adrenal cortex (zona fasiculata and zona reticularis) to stimulate the synthesis of glucocorticoids
LH targets the ______ to stimulate the synthesis of ____, and ______ cells for ______ production
LH targets the Leydig cell of the testes to stimulate the synthesis of testosterone, and ovarian theca cells for androgen production
FSH targets the ______ to stimulate the synthesis of ______
FSH targets the ovarian granulosa cells to stimulate the synthesis of estrogen
GnRH recpetor name in anterior pituitary
GnRHR
LH and FSH recpetors on Leydig cells and ovarian granulosa cells, respectively
LHR and FSHR
GnRH-receptor interaction activates _____signaling leading to activation of the _______ second messenger cascade.
GnRH-receptor interaction activates Gαq/11 signaling leading to activation of the phospholipase C –diacylglycerol – IP3 - calcium (PLC-DAG-IP3-Ca2+) second messenger cascade.
CRH-CRHR1 interaction activates _____ and _______ signaling pathways resulting in increased calcium.
CRH-CRHR1 interaction activates Gs (primary) and Gq signaling pathways resulting in increased calcium.
What is the response secondary to hormone release
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.
LH and FSH hormone
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.
Are steroid hormones stored anywhere?
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.
The cellular response of steroidogenic cells to PKA activation is two-fold:
1) cholesterol delivery to mitochondria and
2) increased gene expression of the enzymes that metabolize cholesterol to a steroid hormone
Steps in cholesterol delivery to mitochondria
- Cytochrome P450 cholesterol side chain cleavage (Chol SCC) catalyzes first step in mitochondrial matrix
- Cholesterol in HDL and LDL is stored as choleterol ester (CE)
- Free cholesterol released from CE by AMP-PKA dependent activation of cholesterol ester hydrolase (CE hydrolase).
- Free cholesterol is then transported to the mitochondria outer membrane by lipid carrier proteins
- 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.
Hormone feedback regulation for estradiol, testosterone, and cortisol
Steroid hormones are classified based on _______ and ________
Steroid hormones are classified based on the number of carbons (C21, C19, C18) and the nuclear receptor they bind
C21
steroids that are end products of the adrenal are in the mineralocorticoids (aldosterone) and glucocorticoids (cortisol) classes
C19
steroids are the major product of the testes, and are synthesized in the ovary and serve as the precursor for estrogens.
C18
Type of steroids that are the major product of the ovary, and are in the estrogen class
Only the _____ produces C21 steroids
Only the adrenal produces C21 steroids
Steroid hormones are ______ so require _____ in circulation
Hydrophobic, plasma binding proteins
The biosynthesis of steroid hormones requires the action of _____ and _______ enzymes.
The biosynthesis of steroid hormones requires the action of cytochrome P450s (CYPs) and hydroxysteroid dehydrogenases (HSD) enzymes.
Two locations of C P450 and difference in electron chain
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.
Function of Hydroxysteroid Dehydrogenases (HSD)
oxidation (dehydration) of hydroxysteroids to produce ketosteroids
3β -hydroxysteroid dehydrogenase (3βHSD, HSD3B) catalyzes what reaction
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.
delta-5 refers to steroids …
derived from pregnenolone that has the C5-C6 double bond
delta-4 refers to steroids
derived from progesterone that has the C4-C5 double bond
Is The 3βHSD reaction is reversible
No, irreversible
17β -hydroxysteroid dehydrogenase (17βHSD, HSD17B) catalyzes ….
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.
The major steroid products of the ZG (adrenal)
Mineralcorticoids like aldosterone … salt
The major steroid products of the ZF
Glucocorticoids, like those stimulated by ACTH
The major steroid products of the ZR
Adrenal androgens, weak sex hormones
Which are the adernal specific enzymes
Cytochrome P450 21α-hydroxylase, 11β-hydroxylase, and aldosterone synthase
Which enzymes are present and absent in the ZG
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
Enzymes present and absent in ZF
The presence of 17α-hydroxylase, 17,20 lyase combined with the absence of aldosterone synthase leads to cortisol being produced.
What enzymes are in the ZR
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
High circulating DHEA and androstenedione levels are an indicator of
an adrenal disorder
Elevated levels of C17 keto steroids in urine is diagnostic for
excess adrenal androgen production.
Elevated DHEA/androstenedione levels can lead to
elevated sex hormone levels due to metabolism by the adipose tissue
What are the precursors for testosterone synthesis
C17 keto steroids DHEA and androstenedione
Where is estrogen sythesized in males
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.
Where is estrogen produced in females
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
Major hormones of adrenal gland
aldosterone, cortisol, C17 keto steroids (androgens)
Major hormones of ovary
estradiol, progesterone, testosterone
Major hormones of testes leydig cells
testosterone
Major hormones produced in peripheral (adipose) tissue
use adrenal androgens to produce testosterone or estradiol
What is congenital adrenal hypoplasia (CAH)
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.
What is a major indicator of CAH
an indicator for CAH is high ACTH and low Cortisol
A 21α-hydroxylase deficiency can be differentiated by
high 17α-hydroxyprogesterone levels
What finding implicate 17α-hydroxylase deficiency
Low 17OHP levels (17α-hydroxyprogesterone)
What is the most common form of CAH and what gene mutation causes it
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.
What is salt wasting
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”.
What occurs in the simple virilization form of 21 CAH
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.
What occurs in non-classical CAH
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
17α-hydroxylase / 17,20 lyase deficiencies affect
both the adrenal and gonadal steroidogenic pathways
Treatment for adrenal disorders, metabolic disorders (overproduction of cortisol), and cancer targets both ….
steroid biosynthesis and steroid action (activation of a steroid nuclear receptor)
