Endocrinology Flashcards
What stimulates the production of IGF-1 and where is it made?
GH and in the liver
What is the cause of Laron dwarfism?
GH receptor defect
Two exaqmples of GnRH deficiency
Kallman’s syndrome Prader-Willi
What is the gold standard GH Provocation test?
Insulin Tolerance test - Give iv insulin. Should be followed by GH spike
(others = GHRH +Arginine
Glucagon im
Exercise)
What is the replacement hormone for ACTH
Hydrocortisone
What is the replacement hormone for GH
Recombinant GH = Somatotrophin
What are the symptoms of GH deficiency in adults?
Reduced lean mass inc. adiposity inc hip:waist dec. muscle Dec. HDL inc. HDL
What are the drugs of choice in acromegaly
Somatostatin analogues such as lanreotide and octreotide are the drugs of choice in acromegaly.
What are the metabollic effects of acromegaly?
Gh stimulates an inc. in blood glucose -> inc plasma insulin -> insulin resistance -> impaired glucose tolerance test - > diabetes mellitus
What is the test for GH HYPERsecretion?
Glucose induced supression of growth hormone (give glucose -> inhibit GH release. In acromegaly = paradoxical rise in GH)
Name 2 commonly used Dopamine receptor antagonists
Bromocriptine (oral) and Cabergoline (oral - longer t1/2)
What is the principle action of vasopressin
Antidiuretic
What are the signs and symptoms of Diabetes insipidus ?
Lack of vasopressin. Hypo-osmolar polyuria and polydipsia. (peeing large volumes of very dilute water). dehydration if intake not maintained. Electrolyte imbalance
How do you test for diabetes insipidus?
Fluid deprivation test?
What results would you expect to see in an individual with DI after a fluid deprivation test?
No real change in urine osmolarity
How do you test the difference between nephrogenic and central DI
Administer DDAVP (desmopressin). Central DI will be able to concentrate urine and urine osmolarity will rise.
What is SIADH
Syndrome of inapropriate ADH
What is the main result of SIADH
hyponatraemia due to increased watrer reabsorption diluting the plasma
What are the symptoms of hyponatraemia
Generalised weakness Poor mental function Nausea Confusion coma death
What is exogenous Vasopressin called
Argipressin
Other than water reabsorption, what other effect does vasopressin have
V1 - Vascular smooth muscle - contraction Non- vascular smooth muslce - contraction (gut motility) Liver Platelets CNS - Increased ACTH secretion V2 - Increased VIII and von Willebrand factor production
Name a V2 selection Vasopressin receptor agonist and how is it administered
desmopressin (Nasally/orally)
How do you treat nephrogenic DI
Thiazides (inhibit Na+/Cl- transport in the distal convoluted tubule).
What is the name given to primary hypothyroidism
Myxoedema
What sign and symptoms will you see in myxoedema
BMR fall Bradycardia Weakness Cold intolerance Weight gain Constipation
Thyroxine = T4 or T3?
T4 = Thyroxine `
What is the normal thyroid hormone replacement therapy ?
Levothyroxine Sodium (t4) Rearely T3 is used Liothyronine Sodium
What is the binding hormone globulin for T3 +T4 called?
TBG (Thyroid Binding Globulin)
What Graves disease?
Hyperthyroidism with autoimmune antibodies to the antibodies to the receptor for thyroid-stimulating hormone (TSH)
Smooth goitre = Plummers or Graves?
Graves
What is the treatment of hyperthyroid disorders?
PTU (Propylthiouracil)
CBZ (Carbimazole)
Why might the clinical effect of Thionamide drugs take weeks to show clinical effects?
Large storage in the colloid
What might be a third cause of hyperthyroidism?
Viral thyroidistis -(ie de Quervain’s syndrome) Damages the thyroid follicles and all the stored thyroxine gets RELEASED
Patient has thyrotoxicosis but with no uptake of iodine.
Four weeks later, the stored thyroxine will be exhausted so the patient will be hypothyroid.
After another month, the cells will have recovered and will start to produce thyroxine again so they will return to normal
What is the difference between Cushings disease and Cushing’s syndrome
Disease = pituitary tumour. Syndrome = all other causes of high cortisol
How do you test for Cushing’s ?
- 24hr urine collection
- Secret midnight blood test - to test for diurnal cortisol levels
- Low dose dexamethasone suppression test (GOLD STANDARD)
Dexamethasone = artificial steroid . Someone with Cushing’s Syndrome will have a high level of cortisol even after the low dose dexamethasone suppression test
What is the drug treatment of Cushing’s ?
Metyrapone (+Ketoconazole)
Inhibits 11-beta hydroxylase in the zona fasciculata.
(mineralocorticoid effect = hypertension
Increase adrenal androgens can cause hirsiutism)
What is the name given to the syndrome resulting from a benign tumour of zona glomerulosa and waht is the result?
Conn’s syndrome
Tumour secretes aldosterone leading to hypertension and Hypokalaemia
What is the treatment give to sufferers of Conn’s syndrome
Mineraloocorticoid Receptor Antagonist
eg SPIRONOLACOTNE. However can cause menstrual irregularities (F) and gynaecomastion (M) due to androgen effect
EPLERONONE (fewer progesterone and androgen effects)
What is a phaeochromocytoma?
Tumour of the medulla that secretes catecholamines (adrenaline and noradrenaline)
Can cause SUDDEN massive rise in BP, anxiety, panic.
Stroke, sudden death
Fill in the hydroxylases
Fill in the missing steroids
What are the main causes of adrenocortical failure ?
Tuberculous Addisons
Auto immune Addisons
Congenital Adrenal hyperplasia
What are the signs and symptoms of Addisons and why?
Lack of aldosterone
Low BP
Na loss in the urine
high plasma K+
No cortisol
Low glucose
High ACTH
hyperpigmentation
Also- Weight loss, anorexia
How do you test for Addison’s?
Short synACTHen test
=
- 250 ug synacthen IM
- Measure cortisol response
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency
What is the hallmark of 21-hydroxylase deficiency
Excess sex-steroids
In adrenocortical failure what hormones need to be replaced?
Cortisol and aldosterone must be replaced
Androgens do not need to be replaced as the gonads are the main source and they can take over sufficiently
What hormones binds to the mineralocorticoid receptor and which has the greatest affiinity?
Aldosterone and cortisol
Cortisol has higher affinity
Where are glucocorticoid receptors located?
Wide distribution in the body
Where are mineralocorticoid receptors located?
In the kidney
(discrete distribution)
What is the principal action of aldosterone?
the reabsorption of sodium and excretion of potassium
How is cortisol prevented from binding to aldosterone receptors?
The enzyem 11βHSD (11β-hydroxysteroid dehydrogenase 2) converts cortisol to cortisone which is inactive
Why do patients with Cushing’s syndrome have hypertension and hypokalaemia?
High cortisol, eventually 11β-HSD becomes saturated and can’t convert any more cholesterol so the cortisol binds to the mineralocorticoid receptors
= ↑ Na⁺ resorption, ↑ water resorption, ↑ K⁺ excretion
= hypertension, hypokalaemia
What is the receptor selectivity of hydrocortisone, prednisolone and dexamethasone?
(=Synthetic cortisol)
Hydrocortisone = Glucocorticoid with mineralocorticoid activity at high doses
Prednisolone = Glucocorticoid with weak mineralocorticoid
Dexamethasone = = Glucocorticoid. No mineralocorticoid
What is Fludrocortisone?
Alodsterone analogue
What drugs are used to treat Addison’s disease ie primary adreonocortical failure?
Treat with hydrocortisone (replaces cortisol) and fludrocortisone (replaces aldosterone)
What drugs are used to treat secondary adreonocortical failure ie ACTH deficiency?
Treat with hydrocortisone only (replaces cortisol) everything else is either done by RAS system or gonads
How would oyu treat an Addisonian Crisis?
- IV saline to rehydrate patient, replace salt and restore volume
- High-dose hydrocortisone to replace cortisol
- 5% dextrose if hypoglycaemic
What is therelationship between oestrogen and LH and FSH?
At low concentration Oestrogen = negative feedback on FSH and LH
As levels rise = +ve feedback (especially LH)
Which hormone stimulates ovulaiton
LH Surge
What hormone dominate in the luteal phase of the menstrual cycle?
Luteal phase is the release of an egg and the subsequent hormonal change. Large progesterone spike (plus oestradiol and inhibin) peaking at the middle of the Luteal phase. As progesterone release decreases it initiates menstration
What are the 2 primary reason for infertility?
Primary gonadal failure
Hypothalamic/Pituitary disease
What investigations are conducted if male hypogonadism is suspected?
1) LH, FSH, testosterone
- if all low MRI pituitary
2) Prolactin
3) Sperm count
- Azoospermia = absence of sperm in ejaculate
- Oligospermia = reduced numbers of sperm in ejaculate
4) Chromosomal analysis (Klinefelter’s XXY)
What are the products of tissue-specific processing of testosterone? What receptor do these products act on?
1) Dihydrotestosterone (DHT)
acts via the androgen receptor
2) 17β-oestradiol
acts via the oestrogen receptor
What enzymes process testosterone?
5alpha - reductase = DHT
Aromatase (found in brain and adipose tissue) = 17beta-oestradiol
What are the causes of Ovarian failure
- premature ovarian failure (eary menopause)
- ovariectomy
- chemotherapy
- ovarian dysgenesis (Turner’s 45 X)
What investigations are conducted in a patient with amenorrhoea?
Pregnancy test
LH, FSH, oestradiol
Day 21 progesterone
Prolactin, thyroid function tests
Androgens (testosterone, androstenedione, DHEAS)
Chromosomal analysis (Turner’s 45 X)
Ultrasound scan ovaries / uterus
What is the criteria to diagnose PCOS?
Need 2 of the following:
- polycystic ovaries on ultrasound scan
- oligo- / anovulation
- clinical / biochemical androgen excess
What are the clinical features of PCOS
1) Hirsuitism
2) Menstrual cycle disturbance
3) Increased BMI
What is the treatment for PCOS with regard to fertility?
- *Metformin**
- *Clomiphene** anti-oestrogen in the hypothalamus pituitary axis. Blocks oestrogen receptors in the hypothalamus so blocks negative feedback which increases secretion of GnRH.
- *Gonadotrophin therapy as part of IVF treatment**
What investigations would be performed on a woman of 30 who has not had a period for 3 months and has a BMI of 18?
Pregnancy test
Blood test (prolactin, LH, FSH, oestrogen, hyper/hypothyroid, androgens- PCOS)
High prolactin- pituitary MRI
Low oestrogen, high LH and FSH = something wrong with ovaries
What is another name for Addison’s disease?
Primary adrenal insufficiency/hypocortisolism. It is a long-term endocrine disorder in which the adrenal glands do not produce enough Cortisol and aldosterone hormones.
Which drugs might cause Hyperprolactinaemia?
Metoclopramide (anti-emetic)
Phenothiazines (anti-psychotics)
What night be the drug treatment of hyperprolactinoma?
Dopamine agonist
- Bromocriptine
- Cabergoline
What complications are associated with menopause?
Osteoporosis: oestrogen deficiency
Cardiovascular disease: women are protected against CVD before menopause, but have the same risk as men by 70 years
What are the different types of HRT? When are they used? Give an example of each drug.
Oestrogen-only: Used for women who have had a hysterectomy.
e.g. Premarin
Combined: Used to prevent endometrial hyperplasia in all other women.
e.g. PremPro, CEEs and medroxyprogesterone
What are the 4 options for HRT formulations
- Oral estradiol = low bioavailability
- Transdermal patch oestradiol
- intravaginal
- Oral conjugated equine oestrogen = Estrone suphate.
What are the different types of SERMs? What do they do? Give examples.
Selective oEstrogen Receptor Modulators:
1) Tissue-selective ER antagonist
e. g. tamoxifen
- Antagonises ERs in breast but has oestrogenic activity in bone
- Oestrogenic effects on endometrium limit it’s use in osteoporosis management
2) Tissue selective ER agonist
e. g. raloxifen (further developed for it’s selectivity on bone)
- Oestrogenic activity in bone. Anti-oestrogenic at breast and uterus
- Risks include VTE and stroke
How does a combined oral contraceptive work to prevent pregnancy?
- ive feedback actions of progesterone in the hypothalamus and pituitary supresses ovulation.
- Progesterone thickens cervical mucus which provides hostile environment to sperm
- Oestrogen up-regulates progesterone receptors, enhancing sensitivity to progesterone
- Oestrogen counteracts the androgenic effects of synthetic progesterone, preventing masculinisation
- Oestrogen contributes to negative feedback at hypothalamus and pituitary, by synergising with progesterone
What emergency contraception may be taken?
Levonogesterel (within 72 hrs)
Ulipristal (up to 120hrs after intercourse)
-delay ovulation by up to 5 days, impairs implantation
What hormone controls tubular fluid reabsorption within the male reproductive tract?
Oestrogen = increased concentration of sperm
What enzyme converts androgens to oestrogens?
Aromatase
Where is seminal fluid produced?
Small contribution from
- Epididymis/testis
Mainly from accessory sex glands
- Seminal vesicle
- Prostate
- also bulbourethral glands
What is capacitation of the sperm? What is the process?
Maturation of the sperm so it can achieve fertilising capability
- Loss of glycoprotein coat
- Change in the surface membrane characteristics
- Whiplash movements of the tail
What hormone is capacitation of sperm dependent on? Where does it occur?
Oestrogen-dependent
Takes place in ionic and proteolytic environment of the fallopian tube
Ca²⁺ dependent mechanism
What is the acrosome reaction?
1) Sperm binds to the ZP3 receptors on the glycoprotein coating of the ovum (zona pellucida)
2) This causes a Ca²⁺ influx into the sperm (stimulated by progesterone)
3) The sperm then releases hyaluronidase and proteolytic enzymes
4) Sperm then penetrates the zona pellucida
What is the cortical reaction and what triggers it?
It is triggerered by fertilization. Cortical granues release molecules that degrade the zona pellucida , preventing further sperm from binding
What are polar bodies?
Produced from unequeal division of the ovum, contains only genetic material. No cytoplasm
How long can a fertilised ovum survive before implantation as it travels down the fallopian tube? How does it receive nutrients?
Can last around 9-10 days
Receives nutrients from uterine secretions
What are the 2 phases of implantation ?
1) Attachement phase- outer trophoblast cells make contact with the uterine epithelium
2) Decidualizaton process that occurs in the endometrium because of progesterone
What molecules are secreted from the secretory glands in the endometrial lining that promote adhesion of the blastocyst?
LIF (leukaemia inhibitory factor) -stimulates adhesion of the blastocyst to endometrial cells
IL11 - released into uterine fluid .
What changes occur during decidualization of the endometrium ?
Glandular epithelium secretion
INcreased glycogen accumulation in stromal cell cytoplams
growth of capillaries
increased vascular permeability
What is the first hormone to peak during pregnancy
hCG
human chorionic gonadotrophin
At what point during pregnancy does the fetoplacental unit take over oestrogen production? and specifically which one
From day 40 - mainly oestriol (weaker than eastradiol but produced in greater amounts)
What maternal hormones rise during pregnancy (5)
ACTH -(pregnant cushings)
Iodothyronines
Prolactin
Adrenal steroids
PTHrp (related peptide)
Which hormones fall during pregnancy ?
Gonadotrophins
TSH (T4/3 production driven by hCG)
hGH
Which hormone stimulates milk synthesis and which stimulates milk ejection?
Milk synthesis = Prolactin
Ejection = oxytocin
What is the key brain area involved in the regulation of food intake?
The arcuate nucleus
What are the two neural populations in the arcuate nucleus?
1) Stimulatory (of appetite) = (NPY/Agrp neurons)
2) Inhibitory = (POMC neuron)
What receptor do these neurons use for signalling?
MC4R
(melanocortin 4 receptor)
What is the overall effect of MC4R stimulation ?
Decrease in food intake
How do POMC and Agrp/NPY act on the MC4R?
POMC is cleaved to produce α-MSH, an agonist of MC4R = decreases food intake
Agrp = antagonist of MC4R = increased food intake
How does a POMC mutation present?
Hungry all the time
No cortisol regulation
Pale skin and red hair
What effect does Leptin have on POMC/Agrp?
Activates POMC, inhibits Agrp
What effect does ghrelin have on neurons in the arcuate nucleus?
- Stimulates NPY/Agrp neurons
- Inhibits POMC neurons
- Increases appetite
Where is Ghrelin released and how is it activated?
It is released in the stomach, activated by GOAT
What effect does ghrelin have on neurons in the arcuate nucleus?
- Increases appetite, levels go up when fasted. Stimulates NPY/Agrp neurons
- Inhibits POMC neurons
What do L cells secrete?
PYY and GLP-1
What effect does PYY have on neurons in the arcuate nucleus?
- Inhibits NPY release
- Stimulates POMC
- Decreases appetite
What does glucagon-like peptide-1 do?
Important in stimulating glucose-stimulated insulin release (incretin role) and also reduces food intake
What is the synthetic (long-acting) GLP-1-like peptide that is approved for the treatment of obesity?
Saxenda
