ENDO; Lecture 9, 10 and 11 - Therapeutic use of adrenal steroids, Endocrine infertility and Menopause, HRT and oral contraceptives Flashcards
How is the production of adrenal steroids controlled?
Hyperkalaemia and hyponatraemia, reduced RBF and b1 stimulation causes angiotensinogen release into aldosterone secretion
What are the principal physiological actions of adrenal steroids?
Cortisol- essential for life, aldosterone - promotes Na retention and K loss, androgens/oestrogens - main source from gonads
What are the 2 types of corticosteroid receptors?
Glucocorticoid receptor (cortisol) and mineralocorticoid receptor (Aldosterone)
How do the glucocorticoid and mineralocorticoid receptors compare?
How are the mineralocorticoid receptors protected from cortisol?
By 11 beta-hydroxysteroid dehydrogenase which converts cortisol into cortisone -> cortisol can activate both GR and MR in HEALTH -> explains why hypokalaemia can occur in cushing’s syndrome, as when cortisol is very high it overwhelms 11bHSD, so activates MR = also explains why they’re hypertensive
Which receptor is hydrocortisone selective to?
GR/MR; Glucocorticoid with mineralocorticoid activity (overwhelmed 11bHSD) at high doses
Which receptor is prednisolone selective to?
GR, weak MR; Glucocorticoid with weak mineralocorticoid activity
Which receptor is dexamethosone selective to?
GR; Synthetic glucocorticoid with no mineralocortiod activity
Which receptor is fludrocortisone selective to?
MR; Aldosterone analogue used as aldosterone substitute
Which corticosteroid drugs are administered orally?
Hydrocortisone, prednisolone, dexamethasone and fludrocortisone
Which corticosteroid drugs are administered parenterally (IV, IM)?
Hydrocortisone and dexamethasone -> when quick administration is needed
How are corticosteroid drugs distributed?
They bind to CBG and albumin as circulating cortisol does
How long do hydrocortisone, prednisolone and dexamethasone act for?
Hydrocortisone = 8h; prednisolone = 12h; dexamethasone = 40h
Which conditions need corticosteroid replacement therapy?
Primary adrenocortical failure (Addison’s disease); secondary adrenocortical failure (ACTH deficiency); Acute adrenocortical failure (Addisonian crisis); congenital adrenal hyperplasia
How is Addison’s disease treated and what symptoms do they have?
Patients lack cortisol and adosterone -> treat with hydrocortisone and fludrocortisone by mouth
How do you treat the symptoms of ACTH deficiency?
Patients lack cortisol but have normal aldosterone -> treat with hydrocortisone
How would you treat an Addisonian crisis?
IV saline (0.9% NaCl) to rehydrate patient (due to lack of retention) and high dose hydrocortisone -> IV infusion/IM every 6h (overwhelming 11betaHSD so don’t need to wrry about aldosterone replacement as it will continue to activate MR until enzyme is less overwhelmed); 5% dextrose if hypoglycaemic
What is congenital adrenal hyperplasia?
Congenital lack of enzymes needed for adrenal steroid synthesis -> majority due to 21 hydroxylase deficiency
What is the objective of therapy for congenital adrenal hyperplasia?
Replace cortisol, suppress ACTH suppressing adrenal androgen production, replace aldosterone in salt wasting forms
What drugs are needed for congenital adrenal hyperplasia?
Dexamethasone (1/d pm) or hydrocortisone (2-3/day, high dose pm) to try and reduce ACTH which will reduce the amount of adrenal androgens and aldosterone made and fludrocortisone which replaces aldosterone
How do you monitor corticosteroid replacement therapy in congenital adrenal hyperplasia?
17OH progesterone, clinical assessment, BUT cushingoid (GC dose too high) and hirsuitism (GC dose too low, hence ACTH has risen) can occur
What additional measures can be taken in subjects with adrenocortical failure?
Normal cortisol production = 20mg/day and in stress 200-300 mg/day -> increase glucocorticoid dosage when patients are vulnerable to stress or has an illness (needs to double dose)
When do you increase glucocorticoid dosage in corticosteroid replacement therapy?
In minor illness (2x normal dose), after surgery -> hydrocortisone, IM, with pre-med and at 6-8h intervals, oral once eating and drinking
How does the pituitary-gonadal axis work in men?
How does the pituitary-gonadal axis work in women?
Different as it is a 28-day menstrual cycle with follicular phase, ovulation, luteal phase
How does the pituitary-gonadal axis work in women during folllicular phase?
How does the pituitary-gonadal axis work in women during ovulation?
What happens during the luteal phase in women?
If implantation doesn’t occur then endometrium is shed; otherwise pregnancy occurs
What is infertility?
Inability to concieve after 1y of regular unprotected sex -> 1:6 couples caused by abnormalities in males(30%), females (45%), or unknown (25%)
What is primary gonadal failure?
No testosterone/oestradiol so no negative feedback
What is hypopituitary disease?
x
What are the 4 causes of male hypogonadism?
Hypothalamic-pituitary disease, primary gonadal disease, hyperprolactinaemia, androgen receptor deficiency
What are the symptoms of Kallman’s syndrome?
Stature low, testes descend late, anosmia, low GnRH
What are the different kinds of hypothalamic-pit diseases?
Hypopituitarism, Kallmans syndrome (anosmia and low GnRH), illness/ underweight
What are the different primary gonadal diseases?
Congenital: Kleinfelters syndrome (XXY); acquired: testicular torsion, chemotherapy
What investigations would you carry out for male hypogonadism?
LH, FSH, testosterone (if all low then pit MRI); prolactin; sperm count; chromosomal analysis (Klinefelters)
What is azoospermia?
Absence of sperm in ejaculate
What is oligospermia?
Reduced numbers in sperm in ejaculate
What is the treatment for male hypogonadism?
Replacement for testosterone for all patients; for fertility: if hypo/pit disease then subcutaneous gonadotrophins (LH/FSH); hyperprolactinaemia (DA agonist)
What are the endogenous sites of production of androgens?
Interstitial Leydig cells of testes, adrenal cortex, ovaries, placenta, tumours
What are the main actions of testosterone?
Development of the male genital tract, maintains fertility in adulthood, control of secondary sexual characteristics, anabolic effects (muscle, bone)
How is testosterone circulating in the blood and what does it act on in the body?
What are the clinical uses of testosterone?
In adulthood: increases lean body mass, muscle size and strength, bone formation and bone mass (in young men), libido and potency -> doesn’t restore fertility (requires gonadotrophin treatment)
What are the disorders in the female?
Amenorrhoea, polycystic ovarian syndrome, hyperprolactinaemia
What is amenorrhoea?
Absence of periods
What is primary amenorrhoea?
Failure to begin spontaneous menstruation by age of 16y
What is secondary amenorrhoea?
Absence of menstruation for 3 months in a woman who has previously had cycles
What is oligomenorrhoea?
Irregular long cycles
What are the causes of amenorrhoea?
Pregnancy, lactation, ovarian failure, gonadotrophin failure, hyperprolactinaemia, androgen excess, gonadal tumour
What causes ovarian failure?
Premature ovarian failure, ovariectomy/chemotherapy, ovarian dysgenesis (turner’s 45 XO)
What is Turner’s syndrome?
45 XO -> Short stature, cubitus valgus, gonadal dysgenesis, 1:5000 live F births
What causes gonadotrophin failure?
Hypo/pit disease, Kallmann’s syndrome (anosmia, low GnRH), low BMI, post pill amenorrhoea
How do you investigate amenorrhoea?
Pregnancy test; LH, FSH, oestradiol, Day 21 progesterone (for ovulation), prolactin, thyroid function test, androgens (tesosterone, androstenedione, DHEAS), chromosomal analysis (turners 45XO), US ovaries/uterus
How do you treat amenorrhoea?
Treat cause; primary ovarian failure (infertile - HRT), hypo/pit disease (HRT for oestrogen replacement, fertility: LH/FSH for IVF treatment)
What is PCOS?
1:12 women of reproductive age, associated with increased CV risk and insulin resistance
How do you diagnose PCOS?
PCO on US; oligo/anovulation; clinical/biochemical androgen excess
What are the clincial features of PCOS?
Hirsuitism, menstrual cycle disturbance, increased BMI
How do you treat PCOS?
Metformin and clomiphene; gonadotrophin therapy as part of IVF
What is clomiphene?
Anti-oestrogenic in hypo/pit axis
How does clomiphene work?
Bind to oestrogen receptors in the hypothalamus blocking the negative feedback, resulting in increase in the secretion of GnRH and gonadotrophins
What are the causes of hyperprolactinaemia?
DA antagonist drugs (anti-emetics: metoclopramide; anti-psychotics: phenothiazines), prolactinoma, stalk compression due to pit adenoma, PCOS, hypothyroidism, ostrogens, pregnancy, lactation, idiopathic
How is prolactin secretion controlled?
What are the clinical features of hyperprolactinaemia?
Galactorrhoea, reduced GnRH secretion/ LH action > hypogonadism, prolactinoma (headache, visual field defect)
How do you treat hyperprolactinaemia?
Treat cause (stop drugs), DA agonist (bromocriptine, cabergoline), prolactinoma (DA agonist therapy, pit surgery rarely needed)
A male presents to endocrine clinic who has had bilateral orchidectomy (removal of testes). What would you expect his blood results to show: 1. Low LH, Low FSH, Low Testosterone 2. Low LH, high FSH, Low Testosterone 3. high LH, high FSH, Low Testosterone 4. high LH, high FSH, high Testosterone
High LH/FSH and low testosterone
A young woman presents to endocrine clinic who complains of secondary amenorrhea and galactorrhea. Her GP measured her prolactin at 4500 (high). What would you expect her blood results to show: 1. Low LH, Low FSH, Low oestradiol 2. Low LH, high FSH, Low oestradiol 3. high LH, high FSH, Low oestradiol 4. high LH, high FSH, high oestradiol
Low LH/FSH/oestradiol
What are common symptoms of menopause?
Sleep disturbance, increased risk of osteoporosis and fracture, depression, joint pain, decreased libido, hot flushes (head, neck, upper chest), urogenital atrophy and dyspareunia -> diminish with time
What is menopause?
Cessation (permanent) of menstruation -> loss of ovarian follicular activity, at average age of 51 (45-55 range) -> period of transition called climacteric
What occurs to the HPG axis in menopause?
Reduced levels of oestradiol and inhibin B which reduces negative feedback so increases GnRH
What are complications of menopause?
Osteoporosis (oestrogen deficiency, loss of bone matrix, 10x increase of fracture), CVD (protected against CVD before menopause, but have the same risk as men by 70)
How do you control vasomotor symptoms (hot flushes)?
Give HRT -> E+P most used
What are the 2 types of HRT formulations?
Cyclical (E daily and P(12-14 days), continuous combined;
How are oestrogen formulations prepared?
oestrogen prep -> oral estradiol (1mg), oral conjugated equine oestrogen (0.625 mg), transdermal oestradiol (50ug/day), intravaginal
What are the different types of oestrogen placed in HRT and what are their pros/cons?
Estradiol is well absorbed, but low bioavailability; estrone sulphate (conjugated oestrogen); ethinylestradiol (semi synthetic oestrogen -> ethinyl group protects the molecule from first pass metabolism. NB: most oestrogens can be administered via transdermal patches
What are the different types of HRT and what are the risks/benefits?
Oestrogen: endometrial proliferation, risk of endometrial carcinoma; progestogens or both together which reduces endometrial hyperplasia
What are the side effects of HRT?
Breat cancer, VTE, stroke, gallstones -> absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low
What is Tibolone?
Synthetic prohormone; oestrogenic, progestogenic and weak androgenic actions -> reduces fracture risk; increased risk of stroke (RR=2.2), and is questioned about increased risk of breast cancer
What is Raloxifene?
Selective oestrogen receptor modulator -> oestrogenic effect on bone reduces risk of vertebral fractures and anti-oestrogenic effect in breast and uterus reducing breast cancer risk; but increased risk of VTE and fatal stroke
What is Tamoxifen?
Anti-oestrogenic on breast tissue; used to treat oestrogen-dependent breast tumours/metastatic breast cancers
What is premature ovarian insufficiency?
Menopause occurring before the age of 40, in 1% of women
What are the causes of premature ovarian insufficiency?
AI, surgery, chemotherapy, radiation
What are the combined oral contraceptives and when do you take them?
Oestrogen (ethinyl oestradiol) and progestogen (levonorgestrel/norethisterone); take for 21d (or 12 wks) and stop for 7 days
What are the effects of combined oral contraceptives?
E+P = negative feedback actions at hypothalamus/pit; P thickens cervical mucus
When can a progesterone only contraceptive be taken?
When oestrogens are contraindicated (e.g. smoker, >35yo, migraine with aura)
When must a progesterone only contraceptive be taken and why?
Same time each day due to short duration of action; short half life
What is another alternative to oral P contraceptive?
Long acting preps can be given via intrauterine system
What are the different types of emergency contraception and when should they be taken?
Copper IUD (IU contraceptive device - need to exclude pregnancy first and affects sperm and viability), levonorgestrel (within 72h), ulipristal (up to 120h after intercourse - anti progestin activity, delays ovulation by as much as 5 days and impairs implantation)
