Steroid Hormones Flashcards
What is the precursor for steroid hormones?
Cholesterol
What happens to cholesterol during steroid hormone synthesis?
C atoms undergo redox reactions
To what are cytochrome P450 enzymes bound within the cell?
Mitochondrial/endoplasmic reticulum membranes
What do cytochrome P450 enzymes contain?
Haeme group
What type of reaction are cytochrome P450 enzymes involved in during the synthesis of steroid hormones?
Reduction using NADPH
Hydroxylation of C-H bond to C-OH
- For some, coupled with cleavage of C-C bond
What happens in the first step of steroid hormone biosynthesis?
Cholesterol side chain cleavage enzyme (cholestero SCC) converts cholesterol > pregnenolone
What is the first intermediate of steroid hormone synthesis?
Pregnenolone
What do hydroxysteroid dehydrogenases (HSD) do?
Catalyse interconversion of C-OH to C=O
Reduction reaction using NADH
What are the major pituitary hormones regulating steroid hormone synthesis?
ACTH
LH
FSH
What hormone has a negative feedback effect on ACTH?
Cortisol
What hormones have a negative feedback effection LH and FSH?
Testosterone
Oestrogens
What regulates cholesterol import into the mitochondria?
LH in gonads
ACTH in adrenal cortex
What imports cholesterol into cells?
LDL receptor
What imports cholesterol into mitochondria?
Steroidogenic acute regulatory protein (StAR)
What is the acute effect of LH on cholesterol transport?
Formation of cAMP and PKA
PKA phosphorylates and activates StAR
What is the chronic effect of LH on cholesterol transport?
Gene transcription of steroidogenic enzymes; eg: StAR
What are the two endocrine glands of the adrenal glands?
Cortex
Medulla
What are the three regions of the adrenal cortex?
Zona glomerulosa
Zona fasciculata
Zona reticularis
What regulates the zona glomerulosa?
Renin-angiotension
What does the zona glomerulosa secrete?
Minerolcorticoids: aldosterone
What regulates the zona fasciculata?
ACTH
What does the zona fasciculata secrete?
Glucocorticoids: cortisol
What regulates the zona reticularis?
ACTH
What does the zona reticularis secrete?
Androgens
What regulates the adrenal medulla?
Sympathetic nervous system
What does the adrenal medulla secrete?
Adrenaline
Noradrenaline
How much testosterone is produced by the zona reticularis?
Limited because of low enzyme expression under physiological conditions
What does a deficiency in aldosterone synthase cause?
No aldosterone
Aberrant formation of other hormones
What is the two cell model of follicular biosynthesis of oestrogen in the ovaries?
Theca cells stimulated by LH
Make progesterone and androstenedione from cholesterol
Thecal cells secrete androstenedione
Granulosa cells take up androstenedione
FSH stimulates increased expression of aromatase in granulosa cells only
Androstenedione converted to estradiol
Which enzyme is responsible for converting androstenedione into testosterone in the testes?
17 beta-hydroxysteroid hormone dehydrogenase 3 (17beta-HSD 3)
In which cells in the testes is testosterone produced?
Leydig cells
What regulates production of testosterone in the Leydig cells?
LH
What enzyme activates testosterone in some target tissues?
5alpha-reductase
What is the more active form of testosterone?
Dihydrotestosterone (DHT)
How is DHT more active than testosterone?
Higher affinity for androgen receptor than testosterone
Longer half life
What does a 5alpha-reductase deficiency cause?
Failed/incomplete masculinisation of male external genitalia > ambiguous genitalia
What proteins transport steroid hormones in the blood?
Sex-hormone binding globulin (SHBG)
Cortisol binding globulin (CBG)
Albumin
What regulates the expression level of SHBG?
Insulin
Thyroid hormones
Are the steroid hormones bound to plasma proteins active or inactive?
Inactive
What are the physiological effects of glucocorticoids?
Decreased - Glycogen synthesis (in muscles) - Glucose uptake - Glucose oxidation Increased - Beta-cell dysfunction - Apoptosis in pancreas - Insulin secretion - Gluconeogenesis - Glycogen synthesis (in liver)
How is the inactive steroid hormone receptor stabilised in the cytosol?
Bound to chaperone complex
How do steroid hormones stimulate gene transcription?
- Hormone binds to receptor > chaperone complex dissociates
- Homodimerisation of steroid hormone receptors > activation
- Hormone bound receptor dimer enters nucleus > binds to steroid hormone response elements of target genes > recruitment of co-activator complex
What is the response element arrangement of steroid hormone regulated genes?
Reverse
What do the co-activators recruited by the steroid hormone-recepter homodimer do?
Acetylate histones > relaxed nucleosome
What causes adrenal hyperplasia in salt-wasting congenital adrenal hyperplasia (CAH)?
Insufficient level of corticosterone to cause negative feedback inhibition of synthesis and secretion of ACTH from pituitary
Overstimulation of ACTH receptor in adrenal cortex > hyperplasia
What causes virilisation of external genitalia in salt-wasting CAH?
Increased flux of intermediates because of overstimulation by ACTH > accumulation of androstenedione > more testosterone in target tissues > virilisation
Why is CAH caused by a deficiency of 21alpha-hydroxylase called salt-wasting CAH?
Lack of aldosterone > reduced salt re-uptake in kidney
What hormones aren’t produced in salt-wasting CAH?
Aldosterone
Cortisol
What hormones aren’t produced in salt-sparing CAH?
Cortisol
Which enzyme is deficient in salt-wasting CAH?
21alpha-hydroxylase
Which enzyme is deficient in salt-sparing CAH?
11beta-hydroxylase
Why is CAH caused by a deficiency of 11beta-hydroxylase called salt-sparing CAH?
ACTH overstimulation > increased aldosterone level
What causes the profound hyperandrogenism in patients with aromatase deficiency/mutation?
No oestrogen made by granulosa cells
Accumulation of androstenedione > converted to testosterone in other tissues like adrenal cortex
Why do patients with aromatase deficiency/mutation show features of accelerated linear growth?
Testosterone converted to DHT in bone cells
