ENDO; Lecture 9, 10 and 11 - Therapeutic use of adrenal steroids, Endocrine infertility and Menopause, HRT and oral contraceptives Flashcards Preview

Y2 LCRS 1 - Pharm, Endo, Reproduction > ENDO; Lecture 9, 10 and 11 - Therapeutic use of adrenal steroids, Endocrine infertility and Menopause, HRT and oral contraceptives > Flashcards

Flashcards in ENDO; Lecture 9, 10 and 11 - Therapeutic use of adrenal steroids, Endocrine infertility and Menopause, HRT and oral contraceptives Deck (87)
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1
Q

How is the production of adrenal steroids controlled?

A

Hyperkalaemia and hyponatraemia, reduced RBF and b1 stimulation causes angiotensinogen release into aldosterone secretion

2
Q

What are the principal physiological actions of adrenal steroids?

A

Cortisol- essential for life, aldosterone - promotes Na retention and K loss, androgens/oestrogens - main source from gonads

3
Q

What are the 2 types of corticosteroid receptors?

A

Glucocorticoid receptor (cortisol) and mineralocorticoid receptor (Aldosterone)

4
Q

How do the glucocorticoid and mineralocorticoid receptors compare?

A
5
Q

How are the mineralocorticoid receptors protected from cortisol?

A

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

6
Q

Which receptor is hydrocortisone selective to?

A

GR/MR; Glucocorticoid with mineralocorticoid activity (overwhelmed 11bHSD) at high doses

7
Q

Which receptor is prednisolone selective to?

A

GR, weak MR; Glucocorticoid with weak mineralocorticoid activity

8
Q

Which receptor is dexamethosone selective to?

A

GR; Synthetic glucocorticoid with no mineralocortiod activity

9
Q

Which receptor is fludrocortisone selective to?

A

MR; Aldosterone analogue used as aldosterone substitute

10
Q

Which corticosteroid drugs are administered orally?

A

Hydrocortisone, prednisolone, dexamethasone and fludrocortisone

11
Q

Which corticosteroid drugs are administered parenterally (IV, IM)?

A

Hydrocortisone and dexamethasone -> when quick administration is needed

12
Q

How are corticosteroid drugs distributed?

A

They bind to CBG and albumin as circulating cortisol does

13
Q

How long do hydrocortisone, prednisolone and dexamethasone act for?

A

Hydrocortisone = 8h; prednisolone = 12h; dexamethasone = 40h

14
Q

Which conditions need corticosteroid replacement therapy?

A

Primary adrenocortical failure (Addison’s disease); secondary adrenocortical failure (ACTH deficiency); Acute adrenocortical failure (Addisonian crisis); congenital adrenal hyperplasia

15
Q

How is Addison’s disease treated and what symptoms do they have?

A

Patients lack cortisol and adosterone -> treat with hydrocortisone and fludrocortisone by mouth

16
Q

How do you treat the symptoms of ACTH deficiency?

A

Patients lack cortisol but have normal aldosterone -> treat with hydrocortisone

17
Q

How would you treat an Addisonian crisis?

A

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

18
Q

What is congenital adrenal hyperplasia?

A

Congenital lack of enzymes needed for adrenal steroid synthesis -> majority due to 21 hydroxylase deficiency

19
Q

What is the objective of therapy for congenital adrenal hyperplasia?

A

Replace cortisol, suppress ACTH suppressing adrenal androgen production, replace aldosterone in salt wasting forms

20
Q

What drugs are needed for congenital adrenal hyperplasia?

A

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

21
Q

How do you monitor corticosteroid replacement therapy in congenital adrenal hyperplasia?

A

17OH progesterone, clinical assessment, BUT cushingoid (GC dose too high) and hirsuitism (GC dose too low, hence ACTH has risen) can occur

22
Q

What additional measures can be taken in subjects with adrenocortical failure?

A

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)

23
Q

When do you increase glucocorticoid dosage in corticosteroid replacement therapy?

A

In minor illness (2x normal dose), after surgery -> hydrocortisone, IM, with pre-med and at 6-8h intervals, oral once eating and drinking

24
Q

How does the pituitary-gonadal axis work in men?

A
25
Q

How does the pituitary-gonadal axis work in women?

A

Different as it is a 28-day menstrual cycle with follicular phase, ovulation, luteal phase

26
Q

How does the pituitary-gonadal axis work in women during folllicular phase?

A
27
Q

How does the pituitary-gonadal axis work in women during ovulation?

A
28
Q

What happens during the luteal phase in women?

A

If implantation doesn’t occur then endometrium is shed; otherwise pregnancy occurs

29
Q

What is infertility?

A

Inability to concieve after 1y of regular unprotected sex -> 1:6 couples caused by abnormalities in males(30%), females (45%), or unknown (25%)

30
Q

What is primary gonadal failure?

A

No testosterone/oestradiol so no negative feedback

31
Q

What is hypopituitary disease?

A

x

32
Q

What are the 4 causes of male hypogonadism?

A

Hypothalamic-pituitary disease, primary gonadal disease, hyperprolactinaemia, androgen receptor deficiency

33
Q

What are the symptoms of Kallman’s syndrome?

A

Stature low, testes descend late, anosmia, low GnRH

34
Q

What are the different kinds of hypothalamic-pit diseases?

A

Hypopituitarism, Kallmans syndrome (anosmia and low GnRH), illness/ underweight

35
Q

What are the different primary gonadal diseases?

A

Congenital: Kleinfelters syndrome (XXY); acquired: testicular torsion, chemotherapy

36
Q

What investigations would you carry out for male hypogonadism?

A

LH, FSH, testosterone (if all low then pit MRI); prolactin; sperm count; chromosomal analysis (Klinefelters)

37
Q

What is azoospermia?

A

Absence of sperm in ejaculate

38
Q

What is oligospermia?

A

Reduced numbers in sperm in ejaculate

39
Q

What is the treatment for male hypogonadism?

A

Replacement for testosterone for all patients; for fertility: if hypo/pit disease then subcutaneous gonadotrophins (LH/FSH); hyperprolactinaemia (DA agonist)

40
Q

What are the endogenous sites of production of androgens?

A

Interstitial Leydig cells of testes, adrenal cortex, ovaries, placenta, tumours

41
Q

What are the main actions of testosterone?

A

Development of the male genital tract, maintains fertility in adulthood, control of secondary sexual characteristics, anabolic effects (muscle, bone)

42
Q

How is testosterone circulating in the blood and what does it act on in the body?

A
43
Q

What are the clinical uses of testosterone?

A

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)

44
Q

What are the disorders in the female?

A

Amenorrhoea, polycystic ovarian syndrome, hyperprolactinaemia

45
Q

What is amenorrhoea?

A

Absence of periods

46
Q

What is primary amenorrhoea?

A

Failure to begin spontaneous menstruation by age of 16y

47
Q

What is secondary amenorrhoea?

A

Absence of menstruation for 3 months in a woman who has previously had cycles

48
Q

What is oligomenorrhoea?

A

Irregular long cycles

49
Q

What are the causes of amenorrhoea?

A

Pregnancy, lactation, ovarian failure, gonadotrophin failure, hyperprolactinaemia, androgen excess, gonadal tumour

50
Q

What causes ovarian failure?

A

Premature ovarian failure, ovariectomy/chemotherapy, ovarian dysgenesis (turner’s 45 XO)

51
Q

What is Turner’s syndrome?

A

45 XO -> Short stature, cubitus valgus, gonadal dysgenesis, 1:5000 live F births

52
Q

What causes gonadotrophin failure?

A

Hypo/pit disease, Kallmann’s syndrome (anosmia, low GnRH), low BMI, post pill amenorrhoea

53
Q

How do you investigate amenorrhoea?

A

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

54
Q

How do you treat amenorrhoea?

A

Treat cause; primary ovarian failure (infertile - HRT), hypo/pit disease (HRT for oestrogen replacement, fertility: LH/FSH for IVF treatment)

55
Q

What is PCOS?

A

1:12 women of reproductive age, associated with increased CV risk and insulin resistance

56
Q

How do you diagnose PCOS?

A

PCO on US; oligo/anovulation; clinical/biochemical androgen excess

57
Q

What are the clincial features of PCOS?

A

Hirsuitism, menstrual cycle disturbance, increased BMI

58
Q

How do you treat PCOS?

A

Metformin and clomiphene; gonadotrophin therapy as part of IVF

59
Q

What is clomiphene?

A

Anti-oestrogenic in hypo/pit axis

60
Q

How does clomiphene work?

A

Bind to oestrogen receptors in the hypothalamus blocking the negative feedback, resulting in increase in the secretion of GnRH and gonadotrophins

61
Q

What are the causes of hyperprolactinaemia?

A

DA antagonist drugs (anti-emetics: metoclopramide; anti-psychotics: phenothiazines), prolactinoma, stalk compression due to pit adenoma, PCOS, hypothyroidism, ostrogens, pregnancy, lactation, idiopathic

62
Q

How is prolactin secretion controlled?

A
63
Q

What are the clinical features of hyperprolactinaemia?

A

Galactorrhoea, reduced GnRH secretion/ LH action > hypogonadism, prolactinoma (headache, visual field defect)

64
Q

How do you treat hyperprolactinaemia?

A

Treat cause (stop drugs), DA agonist (bromocriptine, cabergoline), prolactinoma (DA agonist therapy, pit surgery rarely needed)

65
Q

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

A

High LH/FSH and low testosterone

66
Q

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

A

Low LH/FSH/oestradiol

67
Q

What are common symptoms of menopause?

A

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

68
Q

What is menopause?

A

Cessation (permanent) of menstruation -> loss of ovarian follicular activity, at average age of 51 (45-55 range) -> period of transition called climacteric

69
Q

What occurs to the HPG axis in menopause?

A

Reduced levels of oestradiol and inhibin B which reduces negative feedback so increases GnRH

70
Q

What are complications of menopause?

A

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)

71
Q

How do you control vasomotor symptoms (hot flushes)?

A

Give HRT -> E+P most used

72
Q

What are the 2 types of HRT formulations?

A

Cyclical (E daily and P(12-14 days), continuous combined;

73
Q

How are oestrogen formulations prepared?

A

oestrogen prep -> oral estradiol (1mg), oral conjugated equine oestrogen (0.625 mg), transdermal oestradiol (50ug/day), intravaginal

74
Q

What are the different types of oestrogen placed in HRT and what are their pros/cons?

A

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

75
Q

What are the different types of HRT and what are the risks/benefits?

A

Oestrogen: endometrial proliferation, risk of endometrial carcinoma; progestogens or both together which reduces endometrial hyperplasia

76
Q

What are the side effects of HRT?

A

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

77
Q

What is Tibolone?

A

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

78
Q

What is Raloxifene?

A

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

79
Q

What is Tamoxifen?

A

Anti-oestrogenic on breast tissue; used to treat oestrogen-dependent breast tumours/metastatic breast cancers

80
Q

What is premature ovarian insufficiency?

A

Menopause occurring before the age of 40, in 1% of women

81
Q

What are the causes of premature ovarian insufficiency?

A

AI, surgery, chemotherapy, radiation

82
Q

What are the combined oral contraceptives and when do you take them?

A

Oestrogen (ethinyl oestradiol) and progestogen (levonorgestrel/norethisterone); take for 21d (or 12 wks) and stop for 7 days

83
Q

What are the effects of combined oral contraceptives?

A

E+P = negative feedback actions at hypothalamus/pit; P thickens cervical mucus

84
Q

When can a progesterone only contraceptive be taken?

A

When oestrogens are contraindicated (e.g. smoker, >35yo, migraine with aura)

85
Q

When must a progesterone only contraceptive be taken and why?

A

Same time each day due to short duration of action; short half life

86
Q

What is another alternative to oral P contraceptive?

A

Long acting preps can be given via intrauterine system

87
Q

What are the different types of emergency contraception and when should they be taken?

A

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)

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