Steroid hormone and Water Balance Flashcards
Non classical action of Aldosterone
Vasoconstriction of vascular smooth muscle and endothelial cells
What is C27 Sterol
Cholesterol
C 18 steroid
Oestradiol
C21 SEX steroid
Progesterone
Functional group of Cortisol
OH
Difference between testosterone and oestradiol
C19 v C18- CH3 removed
First step of steroid synthesis
C27 to C21 (SCC, CYP 11A1)
First product in steroid synthesis
Pregnenolone
Where does 11B-HSD-1 work and which direction
HSD-2?
In liver, bi direction
In kidney, to cortisone only
Which vertebral level are the adrenals located around
T12
What adrenal androgens does Zona Reticularis produce
DHEA and androstenedione
What provides all the oestrogens in women post menopause
DHEA
What is pregnenolone concerted to and through what enzyme
Progesterone, 3B-HSD
What is the role of 17a hydroxylase
Converted progesterone and pregnenolone to 17OH..
What is the role of 17-20 lysase
17-OH pregnenolone to DHEA
17-OH progesterone to Androstenedione in ZR
Role of 21-hydroxylase
Converts progesterone or 17-OH progesterone into deoxycorticosterone or 11- Deoxycortisol
Role of Aldo-synthase
Concerts DOC all the way to aldosterone
What converts 11-deoxycortisol to its product
11B-hydroxylase, cortisol
What converts Androstenedione to what and where
17B HSD, in peripheral tissues
What five hormones get secreted more as plasma glucose level falls
Glucagon
Growth Hormone
Adrenaline and Na
Cortisol
Which nuclei in the hypothalamus secrete CRH
PVN
What factors stimulate release of CRH
5HT
ACh
Encephalin
AVP
What factors inhibit release of CRH
A adrenergic agonists
GABA and Endorphins
DA
CORTISOL negative feedbak
How is AP hormone production stimulated by CRH
CRH binds to GPCR (cAMP and adenyl cyclase) and stimulates production of POMC which is cleaved into ACTH and other peptides
Process of production of Cortisol when ACTH binds to ACTH receptor
cAMP, Adenyl cyclase– cholesterol estet hydrolase increases so more cholesterol is free and transported into mitochondria, where sTAR protein bring cholesterol in and then SCC converts it into pregnenolone and eventually cortisol
effect of cortisol on acid secretion and what happens in excess
stimulates acid secretion, gastric ulcers in excess
effect of cortisol on appetite
increases appetite
effect of cortisol on sexual characteristics
can increase adrenal androgens and cause hirsutism, acne, altered hair pattern, menstrual disturbance
What causes Endometriosis? (Genetic Basis)
Alteration of DNA methylation that causes ERB overexpression and reduced PR expression
What receptor signaling is involved in breast cancers
ERa and PR B
Role of testosterone in male reproductive functions
Spermatogenesis, prostate secretions
when should the hpg axis be tested and how
during puberty in patients with concerns about puberty delay or teticular function, give GnRH and see how much Gns are produced
Role of testosterone in foetal life
for virilisation of genitatlia, esp external genitalia and some internal accessory structuree
What does testosterone get converted to in male foetuses and by what
5a reductase converts it to dihydrotestosterone
What cells produce AMH in males
sertoli cells
normal age of puberty in males and females
8-13 and 9-14
TDS vs DSD- which is environmental
TDS- testicular dysgenesis syndrome
Disorders of Sex Development is genetic
one disorder part of DSD and not TDS
Ambiguous genitalia
Genes involved in DSD
SRY and Sox 9
which chromosome should be sequenced for PAIS
X chromosome
what hormones to measure for puberty test, how to measure max production of hormones
Gns and Test
Do GnRH stimulation test to see if puberty had begun
Kalmann’s vs Kleinfelter’s
Kallman’s- Hypog Hypog, may have anosmia. Kleinfelter’s- 47XXY- HYPERhypog- genetic cause of testicular dysfunction
Inducing puberty vs fertility
Testosterone vs Gn
Tumour markers for testicular cancer
hCG, AFP, LDH
When does the gonadotropin regulated growth phase start
preantral follicle
what cells produce inhibin and AMH
Inhibin- granulosa and theca
AMH- granulosa of largerr follicles
what stimulates LH binding sites on outer layers of granulosa cells
FSH and estradiol
What is the effect of Gn and steroid hormones on AMH
No effect, hence AMH is reliable reflection of growing follicles
what cells proliferate in endometrium in secretory stage and what chemicals/ hormones are there are an abundance of
NK cells, prolactin, growth factors, IGFBP1, IL-15
How many days ddoes it take for CL to regress
7-8 days after high progesterone - degenerates after 14 days
what cells contract as a result of oxytocin
myoepithelial cells
4 causes of high LH
Premature ovarian failure
PCOS!!
Asherman’s syndrome
Gonadotroph tumour
3 causes of high Test
PCOS
Congenital adrenal Hyperplasia
Androgen secreting tumour
3 causes of low E2
Hypog Hypog
premature ovarian failure
Hyperprolactinaemia
What is Turner’s Syndrome
A cause of Premature ovarian failure- no eggs even before puberty
History for Asherman’s Syndrome
Previous termination of pregnancy, miscarraige
Is SHBG high or low in PCOS
low
What conditions likely to have oligomenorrhea
PCOS, CAH, hyperprolactinaemia
problems with pcos and why
may have TIID as androgens are associated with insulin resistance and endometrial hyperplasia
treatment for hyperprolactinaemia
DA agonist like bromocriptine or surgery
treatment for pcos if pregnancy wanted and how
clomefine citrate- estrogen antagonist
5 days from 3-7 or fsh injections
need to give progesterone and take it away 4 times a year for woman to have period
how does congenital adrenal hyperplasia raise test levels
21 hydroxylase has problem so cant make cortisol and substrates used to make testosterone instead
treatment of cah
glucorticoid replacement
what does progesterone do for ovarian cancers
antagonises estrogen action by repressing estrogen induced gen expression and enhances apoptosis of epithelial and cancer cells
What does E2 induce in breast cancers
Rapid ERa signalling which faciliatates cell migratory functions and metastasis- drives excessive cell proliferation
How does tamoxifen affect endometrial cancers
Partial estrogen agonist which stimulates endometrial growth`
How does adipose tissue affect endometrial growth
Leads to excess estrogen
How does anovulation affect endometrial growth
Reduced progesterone production, endometrial growth and hyperplasia
What mechanism does aldosterone use to increase ECF
Genomic mechanism
What is the action of aldosterone in the kidney
Which part of nephron
DCT and collecting ducts of nephron
Increases synthesis of ENaC to increase sodium retention and Na takes water with it
H2O reabsorbed via aquaporin channels
Increased exchange of Na+ with K + and H+
What pathological effects of aldosterone are there
causes vascular smooth muscle hyperplasia and can cause left ventricular hypertrophy and cardiac fibrosis
name a mineralocorticoid antagonist
spironolactone
What is MAP
COx TPR
CO =
HR x SV
What has a permissive effect on vascular tone
Cortisol
What is an inhibitor of RAS (that is not Na+?)
ANP
How does cortisol affect BP (3 ways)
1) Inhibits production of NO (and citrulline) from Arginine by eNOS
2) Potentiate catecholamine action
3) Inappropriately activates kidney MR
What is the most common cause of Addison’s disease
Autoimmune- antibodies to steroid 21-hydroxylase- may be a consequence of adrenocortical damage
Three other main causes of Addison’s
TB, Bilateral adrenalectomy, congenital problems like hypoplasia, CAH, androgens (17-OHP, androstenedione, testosterone), urinary steroids`
what are the common symptoms of addison’s disease
chronic unexplained weight loss, lethargy, weakness, and possibly hypotension
Spot symptom for addison’s and why
pigmentation in skin creases due to ACTH binding to MSH-1 receptors
diagnostic test for Addison’s
9am cortisol wil be low
short synACTHen- measure cortisol at 0 min, and at 30 min after injecting SynACTHen, negligible cortisol in Addison’s
Basal pre-synACTHen ACTH will be high in primary adrenal failure but low in Secondary
Treatment for Addison’s
Hydrocortisone and fludrocortisone for chronic
What are the three main causes of primary hyperaldosteronism
Conn’s Syndrome, Bilateral Adrenal Hyperplasia and Glucocorticoid-remediable Aldosteronism
what are two causes of secondary hyperaldosteronism
Renal artery stenosis and Renin-secreting JG cell tumour.
What is the main similarity between both causes of secondary hyperaldosteronism
BOTH HIGH RENIN
How does plasma ACTH level differentiate Cushing’s syndrome vs Disease
Cushing’s disease will have HIGH ACTH but Syndrome may have high or low- low if adrenal but high if ectopic production of ACTH
What are some symptoms of cushing’s related to blood sugar
Glycosuria and hyperglycaemia
How to exclude Cushing’s syndrome with a test
Dexamethasone suppression test(1mg taken orally at 11pm), plasma cortisol measured at 0am, if plasma cortisol< 40mol/L can exclude
In Cushing’s syndrome cortisol remains high since cortisol secretion no longer under the control of ACTH
24 hr urine cortisol - exclude if <259nmol/day
Treatment of non-iatrogenic cushing’s
Metyrapone +/- Ketoconazole (11B- Hydroxylase blocker) to pre operatively supress symptoms of cortisol excess by reducing cortisol levels
Dexamethasone pre or post operatively to shrink tumours
Surgery
Glucocorticoid Hyperactivity causes- is the genetic cause dom or recessive
Autosomal recessive- loss in function mutation in 11B-HSD2- results in decreased conversion of cortisol to cortisone
Carbenoxolone, glycyrrhizic acid and inhibitors of kidney 11B-HSD2 like liquorice
Treatment for genetic glucocorticoid hyperactivity
MR antagonist again, low Na+, high K+ supplements
What is a pheochromocytoma and what does it cause
Catecholamine-secreting tumour of the adrenal medulla (chromaffin cell tumour)- releases adrenaline
may have hypertension and diabetes mellitus
How does SNS increase blood glucose
Increased glucagon secretion and reduced insulin secretion, increased breakdown of glycogen and lipid breakdown
Diagnosis and treatment of pheochromocytoma
24 hour urinary metanephrines and cathecolamines
a-blockers, B-blockers and surgical
Where is the thirst centre located
hypothalamus
what is normal urine volume
0.6 to 1.5-2 l for 0.9-2 l of input
What is an excessive urine volume
> 2ml/kg/hr (>3.36l/24 hr for 70kg person)
2l when plasma conc of sodium > 145 mmol/l or persistently thirsty
How to investigate polyuria
1) check urine volume
2) Check glucose, ca2+ (osmotic diuresis) and urea and creatinine ( renal function)
3) Check if urine is normally concentrated (>600 mosmol/kg)
4) Water deprivation test
How does water deprivation test work
differentiating between CDI and NDI
up to 8 hrs- to test for DI and distinguish between CDI and NDI (
Check weitght, urine sample( osmolality and volume) and BP every hour , and blood tests (Na+ and plasma osmolality +/-AVP)
Stop if Urine osmolality> 600
Give DDVAP (2 microgram IM ) only when water is depleted (plasma osmolality > 296-300) or Na+ > 145
If urine concentrated on vasopressin, is CDI , otherwise NDI
What does it mean if urine osmolality < 600 even when water is depleted
DI
What is the use of hypertonic saline test
Copeptin or AVP levels should rise normally at higher blood salt conc. If not, is DI
What are some non- genetic causes of CDI
Abnormality in hypothal or pp
Includes:
Neurosurgery
HI
Idiopathic
Diseases eg. tumours and sarcoidosis
Hemorrhage- Sheehan’s syndrome (postpartum) or aneurysm
Genetic causes of CDI
DIDMOAD
Isolated- AVP gene ( autosomal dominant)
NDI acquired causes
Hypercalcaemia and hypokalemia, urinary tract obstructive , psychogenic polydipsia, lithium and demeclocylcine
Inherited causes of NDI
V2R X-linked, AQP2 gened, Ch12- A, recessive or A.dom)
Treatment for CDI
DDAVP( spray/ tablets, injection rately given) and replacement of other hypothalamo-pituitary deficiencies
Treatment for NDI
Treat deficiencies (hypokalemia etc.) or remove treatment (democycline)
Thiazide/ amiloride diuretics to lower urine volumes
Indomethacin to limit renal prostaglandins
Lower salt diet and lower protein diet to limit urinary osmotic load
May try drugs with SIADH tendency like chlorpropamide to increase renal receptors and response to ADH for partial DI
How to compare SIADH with Non SIADH retained water excess
urine osmolality more than 2 X plasma osmolality
Urine osmolality more than 500 mmol/l
when plasma osmolality<280/ Na+ <135 (often means excess ADH)
3 causes of Non SIADH retainwed water excess
low GFR,ACTH/GC deficiency and severe hypothyroidism
Causes of SIADH
Intrathoracic diseases
Intracranial lesions, neoplasmas esp mediastinal/ lungs
drugs like antipsychotics (phenothiazines),
sedative (morphine, barbarituates)
5 c’s -chlorpropamide, clofibrate,
chlorpromazine,carbamazepine, chlorothiazide
Nicotine, pain, nausea, hypoglycaemia
Treatment for SIADH
Fluid restriction to 1l/day then 0.8l/day if needed, then increase solute intake via salt supplements(hypetonic saline for urgent ot moderate hyponatramia)
Normalise chronic hyponatremia slowly ( Na conc. less than 10nmol/day)
May use democylcine that can cause partial NDI
What is the dual action of cortisol
Anabolic in liver to promote gluconeogenesis but catabolic in peripheral muscle to promote protein and lipid breakdown
Which chromosome is involved in Glucocrticoid Remediated Aldosteronism
Chromosome 8
Treatment for renal artery stenosis
MR blockers, balloon angioplasty +/- stents, statins, anti-platelet agents
renin and aldosterone in cushings
Low for both
Symptoms of pheochromocytoma
Palpitations, headache, episodic sweating, anxiety, hypertension, diabetes
Two causes of polyuria
BOTH DIABETES
Does Osmotic Diuresis cause hypo or hypernatremia
Hyponatremia
One lung related cause of dehydration
CF
What is involved in the decidualization of the endometrium
Increasing progesterone (and estradiol)
How to analyse semen
WIthin 60 mins of ejaculation, 2 samples 4-12 weeks apart
Most common genetic cause of infertility
Kleinfelter’s
What Y chromosome deletions may be involved in infertility
AZF A,B, C
How can CF affect fertility
Thickened secretions or Congenital Bilateral Absence of Vas Deferens
Effect of ANP on RAAS
High ANP inhibits
Rate limiting step of steroid synthesis
sTAR protein- uptake of cholesterol
how does prolactin affects FSH/LH levels
negative feedback
