L6 Disorders of ovulation Flashcards
1
Q
Effect of kisspeptin and KNDy on GnRH
A
- Kisspeptin and the KNDy neurones are potent stimulators of GnRH
2
Q
What are kisspeptin and KNDy stimulated by
A
- Stimulated by high oestrogen and they drive LH production through stimulation of GnRH
3
Q
Where does the first step of ovulation start
A
The first step in ovulation starts at the hypothalamus with the Supra chiasmic nuclei (SCN) which is the master circadian clock that interacts with the Kisspeptin neurones and the KNDy neurones ( neurokinin B and dynorphin )
4
Q
Where are the kisspeptin neurones located
A
The Kisspepetin neurones are located in the Arcuate Nucleus (ARN) and the Anteroventral peri ventricular area (AVPV)
5
Q
Where is GnRH synthesised
A
GnRH is synthesised by neurons in the Pre Optic area (POA)
6
Q
Where do neurons from the pre optic area project into
A
- The neurons project into the median eminence where they release GnRH into the portal system in a pulsatile fashion every 60-90 minutes.
- This in turn drives FSH production from the anterior pituitary gonadotropin cells.
7
Q
Where does FSH act
A
- FSH acts on the primary follicle granulosa cells which start producing oestrogen and inhibin.
- FSH also increases the LH receptors in the granulosa cells
These hormones in turn inhibit FSH (negative feedback)
8
Q
Effect of critically high oestrogen levels
A
- When oestrogen levels get to a critical high level they positively act on the Kisspeptin and KNDy neurones which stimulate the production of GnRH which in turn produces LH (due to increased frequency and amplitude of the pulse from GnRH)
LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells
9
Q
What does FSH cause the follicle to produce
A
FSH causes the follicle to produce oestrogen and inhibin both of which negatively feedback to the hypothalamus and pitutary to decrease FSH.
However as the oestrogen levels rise there is an effect of high levels of oestrogen on the Kisspeptin and KNDy neurones that stimulates GnRH to produce LH in a pulsatile fashion and triggers ovulation ( small rise in FSH at this time).
10
Q
FSH levels in the first half of the menstrual cycle
A
- FSH falls as oestrogen and inhibin rises
- At a critical level, oestrogen positively feeds back to kisspeptin and in turn causes an increase in frequency and amplitude of GnRH which causes the LH surge
11
Q
Changes in hormone levels in the second half of menstrual cycle
A
- As LH now converts the granulosa cells to luteal cells hormone production swaps from oestrogen to progesterone
- Progesterone peaks at day 21 (7 days before the period)
- Progesterone, oestrogen and inhibin inhibit FSH and LH
12
Q
Diagnosis of ovulation
A
Clinical - take a history from the woman
Regular menstruation usually 28 days (check not on hormonal contraception)
- Mid cycle pain at ovulation
- Vaginal discharge alters (increased mucus post ovulation)
13
Q
Biochemical test - diagnosis of ovulation
A
- Day 21 progesterone blood test (7 days before start of next menstrual period)
- LH detection kits - urinary kits bought over the counter
14
Q
Imaging - diagnosis of ovulation
A
Transvaginal pelvic ultrasound - done from day 10, alternate days to demonstrate the developing follicle size and corpus luteum
not basal body temp, cervical mucus change, vaginal epithelium changes nor endometrial biopsies
15
Q
When should the blood test be done for diagnosis of ovulation
A
- If cycle 28 days, then take blood on day 21.
- If cycle longer, then take blood 7 days before expected usual period eg day 28 if cycle 35 days long
16
Q
How often should LH detection kits be used
A
- LH detection kits should be used from day 10 daily
- Once the LH surge is detected, then ovulation occurs 24-36 hours later
17
Q
Features of follicle growth
A
- The follicle grows daily and usually at 20-24mm size ovulation occurs
- Post ovulation, you can visualise the corpus luteum as it looks different to a follicle
18
Q
How thick is the endometrium post ovulation usually
A
Usually > 12mm thick
19
Q
Causes of ovulation problems associated with the hypothalamus (lack of GnRH)
A
- Kiss1 gene deficiency - rare
- GnRH gene deficiency - rare
- Weight loss/stress related/excessive exercise
- Anorexia/bulimia
20
Q
Causes of ovulation problems associated with the pituitary (lack of FSH and LH)
A
- Pituitary tumours (prolactinoma/other tumours)
- Post pituitary surgery/radiotherapy
21
Q
Causes of ovulation problems associated with ovaries(lack of oestrogen/progesterone)
A
- Premature ovarian insufficiency
- Developmental or genetic causes eg Turner’s syndrome
- Autoimmune damage and destruction of ovaries
- Cytotoxic and radiotherapy
- Surgery
- Polycystic Ovarian Syndrome: commonest cause
22
Q
What is amenorrhoea
A
- Lack of a period for more than 6 months
23
Q
Types of amenorrhoea
A
Primary amenorrhoea - never had a period (never went through menarche)
Secondary amenorrhoea - has menstruated before
Polymenorrhoea - periods occurring less than 3 weeks apart
24
Q
What is hirsutism
A
- ‘Androgen-dependent’ hirsutism
- Excess body hair in a male distribution
NOT:
• Androgen-independent hair growth
○ Hypertrichosis
• Familial / racial hair growth
25
Clinical features of polycystic ovarian syndrome (PCOS)
```
Hyperandrogenism
• Hirsutism, acne
Chronic oligomenorrhoea / amenorrhoea
• < or equal to 9 periods / year
• Subfertility
Obesity (but 25% of women with PCOS are “lean”)
```
26
Elements in the diagnosis of PCOS
- Polycystic ovaries
- Androgen excess
- Oligo-/anovulation
27
Relation between insulin resistance and insulin levels
- Insulin resistance increases with insulin levels
28
Effects of insulin resistance on androgen production
- Increase in androgen production by ovarian theca cells
29
What is SHBG (Sex hormone-binding globulin)
- Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens
30
Role of SHBG
- SHBG inhibits the function of testosterone and estradiol
31
Effect of insulin resistance on SHBG production
- Insulin resistance causes a decrease in SHBG production by the liver
32
What condition is more likely to develop with impaired glucose tolerance
- Increase in risk of gestational DM and T2 DM
33
Other abnormalities in PCOS and metabolic syndrome
- Dyslipidaemia
- Vascular dysfunction
- Increase in risk of cardiovascular disease
34
Mechanism via which hirsutism occurs
Increase in GnRH --> pituitary gland --> Increase in LH --> theca cell --> androgen excess --> hirsutism
35
Effect of androgens on steroid negative feedback on LH
- Androgens inhibit steroid negative feedback on LH
36
Mechanism via which anovulation occurs
Increase in GnRH --> pituitary gland --> decrease in FSH --> granulosa cell inhibited by insulin resistance caused by obesity --> follicle arrest --> anovulation
37
Effect of high levels of insulin and androgens on granulosa cells
High levels of Insulin and androgens cause granulosa cells to become less functional ( less oestrogen) and the follicle to arrest, also causes increased LH levels which drives thecal cells to increase androgens
38
Appearance of polycystic ovaries in ultrasound scans
> 10 subcapsular follicles 2-8mm in diameter
- Arranged around a thickened ovarian stroma
- Not all women with PCOS will have USS appearance
39
Definition of cyst
- Mass > 3cm
| NOT cysts in polycystic ovaries despite name
40
LH and FSH levels in PCOS
- Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1
41
Androgen and free testosterone levels in PCOS
- Raised androgens and free testosterone
42
SHBG levels in PCOS
- Reduced sex hormone binding globin levels
43
Oestrogen levels in PCOS
- Oestrogen usually low but can be normal
44
Where is SHBG produced
- Liver
45
What does SHBG bind to
- Binds to testosterone and oestradiol
| - If testosterone bound - not converted to active component dihydrotestosterone ie not 'free'
46
What are SHBG levels increased by
- Oestrogens
47
What are SHBG levels reduced by
- Testosterone thus releasing more free testosterone
48
Reproductive effects of PCOS
- PCOS is maybe associated with varying degrees of infertility
- Associated with increased miscarriages
- Increased risk of gestational diabetes
49
What percentage of all causes of infertility are due to lack of ovulation
- 15%
50
What percentage of lack of ovulation is due to PCOS
- 80%
51
Link between PCOS and endometrial cancer
- Increased endometrial hyperplasia and cancer
| - Lack of progesterone on the endometrium
52
What other conditions are associated with endometrial cancer
- Type 2 diabetes
- Obesity
- High frequency eating disorders (bulimia associated with PCOS)
53
Life-style modifications - treatment of PCOS
- Diet and exercise
| - Stop smoking
54
Results of life-style modifications in treating PCOS
- Decrease in insulin resistance
- Increase in [SHBG]
- Decrease in [free testo]
- Improved fertility/pregnancy outcomes
- Improve metabolic syndrome risk factors
- Lean women with PCOS should try not to get fat!
55
Effect of combined oral contraceptives on SHBG and free testosterone levels
- Increases SHBG and thus decreases free testosterone
56
Effect of combined oral contraceptives on FSH and LH
- Decreases FSH and LH and therefore ovarian stimulation
57
Effect of combined oral contraceptives on the menstrual cycle
- regulates cycle & decreases endometrial hyperplasia
58
Adverse effects of combined oral contraceptives
- may cause weight gain, venous thrombosis, adverse effects on metabolic risk factors
59
What are anti-androgens given with usually
• With COCP / other form of secure contraception
60
Examples of anti-adrogens
- Cyproterone acetate (oral tablet)
| - Spironolactone (oral tablet)
61
Action of cyproterone acetate
• inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors
62
Action of spironolactone (oral tablet)
• anti mineralocorticoid and anti androgen properties
63
Hair removal treatment - pcos
Photoepilation (laser) / electrolysis etc
Eflornithine cream (non-NHS)
• Inhibits ornithine decarboxylase enzyme in hair follicles
64
Drug used to target insulin resistance in PCOS
Metformin (biguanide)
• decrease in insulin resistance, decrease in insulin levels, decrease in ovarian androgen production
• May help with weight loss / diabetes prevention
• May increase ovulation (with clomifene), safe in pregnancy
• Less helpful for hirsutism & oligomenorrhoea, but may be an option for obese PCOS women
65
How might primary ovarian insufficiency present
- Primary or secondary amenorrhoea
- Secondary amenorrhoea may be associated with hot flushes and sweats
other terms used:
- Premature ovarian failure
- Premature menopause
66
Primary ovarian insufficiency - aetiology
Autoimmunity - may be associated with other autoimmune endocrine conditions
X chromosomal abnormalities - turner syndrome, fragile X associated
Genetic predisposition
- Premature menopause
Iatrogenic
- Surgery, radiotherapy or chemo
67
Investigations - Premature ovarian failure
- History/examination
- Increase in LH and FSH
- ? karyotype
- Consider pelvic USS
- Consider screening for other autoimmune endocrine disease - thyroid function tests, glucose, cortisol
68
Management of premature ovarian failure
- Psychological support
- HRT
- Monitor bone density(DEXA scan)
- Fertility (IVF with donor egg)
69
How long should HRT be continued for in premature ovarian failure
- Continue till around 52
70
Genetic features of turner syndrome
- Complete/partial x monosomy in some/all cells
- 50% of cases will be XO
- Rest: partial absence of X or mosaicism
- 1:2000 - 1:2500 live-born girls
71
Presentation of turner syndrome
- May be diagnosed in the neonate
- May present with short stature in childhood
- May present with primary/secondary amenorrhoea
72
Turner syndrome - associated problems
- Short stature (consider GH treatment)
- CV system (coarctation of aorta, bicuspid aortic valve, aortic dissection, hypertension in adults)
- Renal (congenital abnormalities)
- Metabolic syndrome
- Hypothyroidism
- Ears/hearing problems
- Osteoporosis (lack HRT)
73
Differential diagnosis of hirsutism
95% - PCOS or 'idiopathic hirsutism'
1% - Non-classical congenital adrenal hyperplasia (CAH)
<1% cushing's syndrome
<1% adrenal/ovarian tumour
74
Prevalence of polycystic ovarian syndrome
5-10% women
75
When to worry - PCOS
- Sudden onset of severe symptoms
- Virilisation (frontal balding, deepening of voice, male-type muscle mass, clitoromegaly)
- Possible cushing's syndrome
76
Congenital adrenal hyperplasia (CAH) - genetic features
- Carrier frequency 1:60
- Most patients are compound heterozygotes
- Different mutations on two alleles
77
What are most cases of CAH caused by
95% of CAH cases are caused by 21-hydroxylase deficiency
78
Other causes of CAH
- Cortisol deficiency
- May have aldosterone deficiency
- Androgen excess
- Depends on degree of enzyme deficiency
79
Mechanism via which excess adrenal androgen production occurs
Defect in cortisol biosynthesis --> raised CRH/ACTH (lack of negative feedback) --> drives excess adrenal androgen production
80
How can 21-hydroxylase deficiency be confirmed
- High concentrations of 17-hydroxyprogesterone
| - Can confirm with synacthen test
81
CAH presentation - childhood
- Salt wasting - hypovolaemia, shock
- Virilisation - ambiguous genitalia in girls, early virilsation in boys
- Precocious puberty
- Abnormal growth - accelerated early, premature fusion
82
Features of CAH presentation - childhood
- 'Classic' / 'severe'
- Salt-losing (2/3rd)
- Non-salt losing (1/3rd)
- Simple virilising
83
Features of CAH presentation - adulthood
- 'Non-classic' / 'mild'
| - 'Late-onset'
84
CAH presentation - adulthood (mild)
- Hirsutism
- Oligo/amenorrhoea
- Acne
- Subfertility
- Similar to 'pcos' presentation
85
CAH treatment
- Glucocorticoid and mineralocorticoid replacement (hydrocortisone and fludrocortisone)
- Glucocorticoids suppress CRH/ACTH
- Supraphysiological glucocorticoid doses may be needed to suppress adrenal androgen production
- Surgical management for ambiguous genitalia
- Non-classical CAH in adult women (mild) - can treat as for PCOS with COCP +/- anti-androgen
86
What needs to be monitored if supraphysiological glucocorticoid doses are used
- Monitor [17-OH-P] / androstenedione
| - Monitor growth in childhood
87
Effect of excess glucocorticoid treatment
- May inhibit growth
