T2 L6: Disorders of Ovulation Flashcards
what does GnRH stimulate FSH to do
Act on the primary follicle granulosa cells which start producing oestrogren & Inhibin
FSH increases the LH receptors but in which cells
granulosa cells
when does oestrogen act positively on Kisspeptin & (KNDy neurones )
At critically high levels
what are the 2 potent stimulators of GnRH
Kisspeptin-( KNDy neurones )
what stimulates the kisspeptin and GnRH neurons
High oestrogen and LH production (via stim of GnRH)
what is the function of LH and FSH
FSH causes the follicle to produce oestrogen and inhibin both of which negatively feedback to the hypothalamus and pitutary to decrease FSH.
LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells
what is a key concept to understand with the regulation of LH and FSH
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 the production of GnRH which stimulates the production of LH, (due to increased frequency and amplitude of the pulse from GnRH)
.
Its release occurs in a pulsatile fashion and triggers ovulation, oocyte meiosis & changes the granulosa cells into luteal cells ( small rise in FSH at this time).
describe the first half of the ovulation cycle
First half of cycle: FSH falls as oestrogen and inhibin rises. At a critical level oestrogen positively feeds back to Kisspeptin and in turn causes an increas in freq and amplitude of GnRH which causes the LH surge.
Second half of cycle: 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.
when taking a history, what important features of the menstrual cycle must you take into account
Regular cycle is 28 days
Bleeding begins from day 1-5
fertility is from day 11-15
mid cycle pain at ovulation
vaginal discharge alters (increased mucus post ovulation)
what is ovulation pain
leakage of follicle fluid at the time of ovulation irritates the peritoneum and causes pain
how do you diagnose ovulation
Biochemistry :
- Day 21 progesterone blood test
LH detection kits:
-urinary kits bought over the counter
Transvaginal pelvic ultrasound (done from day 10)
what can’t you do to diagnose ovulation
not: Basal temperature, cervical mucus change, vaginal epithelium changes nor endometrial biopsies
what are the 2 groups and possible causes of ovulation problems
Hypothalamus (lack of GnRH)
- Kiss1 gene deficiency- rare
- GnRH gene deficiency - rare
- weight loss/stress related/excessive exercise
- anorexia/bulimia
Pituitary (lack of FSH and LH)
- pituitary tumours (prolactinoma/other tumours)
- post pituitary surgery /radiotherapy
Causes of ovulation problems
Ovary (lack of oestrogen/progesterone)
-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
Define :
Amenorrhoea
oligomenorrhoea
polymenorrhoea
Amenorrhoea - lack of a period for more than 6 months
- Primary Amenorrhoea - never had a period (never went through menarche)
- Secondary Amenorrhoea -has menstruated before
Oligomenorrhoea - irregular periods
-usually occurring more than 6 weeks apart
Polymenorrhoea - periods occurring less than 3 weeks apart
Define hirsutism
Androgen-dependent’ hirsutism
Excess body hair in a male distribution
-NOT
-Androgen-independent hair growth
Hypertrichosis
-Familial / racial hair growth
what are the clinical features of PCOS Polycystic Ovarian syndrome (PCOS)
- Hyperandrogenism
- –Hirsutism, acne
Chronic oligomenorrhoea / amenorrhoea
-9 periods / year
-Subfertility
Obesity (but 25% of women with PCOS are “lean”)
what are the 3 elements in the diagnosis of PCOS
Polycystic ovaries
Androgen excess
Oligo/anovulation
(need at least 2 of these to diagnose PCOS)
what is the relationship that PCOS has with the metabolic syndrome
Insulin resistance with + insulin
- androgen production by ovarian theca cells
- +SHBG production by the liver
Impaired glucose tolerance
-+ risk gestational DM and T2 DM
- Dyslipidaemia
- Vascular dysfunction
- ? +risk cardiovascular disease ?
what is the mechanism between insulin resistance and PCOS
Insulin resistance is the underlying problem ( genetic factors also important).
High levels of Insulin and androgens cause granulosa cells to become less functional ( less oestrogen) and the follicle to arrest=anovulation,
also causes increased LH levels which drives thecal cells to increase androgens. leading to hirsutism
what is the USS appearance of Polycystic Ovaries
10 subcapsular follicules 2-8 mm in diameter,
arranged around a thickened ovarian stroma
( not all women with PCOS will have USS appearance & technically Not cysts – definition of cyst is a mass > 3cms. Wrong name for the condition! Should be poly small follicles disease!
)
what are the hormonal abnormalities in PCOS
Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1
Raised androgens and free testosterone
Reduced Sex Hormone Binding Globin (SHBG)
Oestrogen usually low but can be normal
Describe the sex hormone binding globulin SHBG
- Produced by the liver
- Binds testosterone and oestradiol
- If testosterone bound - not converted to active component dihydrotestosterone ie not “free”
- SHBG increased by oestrogens
- SHBG decreased by testosterone thus releasing more free testosterone
what are the reproductive effects of PCOS
PCOS is maybe associated with varying degrees of infertility
- 15% of all causes of infertility is lack of ovulation
- 80% of lack of ovulation due to PCOS
- Associated with increased miscarriages
- Increased risk of Gestational Diabetes
what is the relationship between PCOS and endometrial cancer
- Increased endometrial hyperplasia and cancer
- Lack of progesterone on the endometrium
- Endometrial cancer associated with type 2 diabetes & obesity
How do you treat PCOS (1)
Lifestyle modifications :
-Diet & exercise
Stop smoking
what does treatment result in
- less insulin resistance
- increased SHBG
- decreased free testosterone
- improved fertility
- Improve metabolic syndrome risk factors
How do you treat PCOS (2)
Combined Oral Contraceptives:
- increases SHBG and thus decreases free testosterone
- decreases FSH & LH and therefore ovarian stimulation
- regulates cycle & decreases endometrial hyperplasia
(BUT may cause weight gain, venous thrombosis, adverse effects on metabolic risk factors )
how do you treat PCOS (3)
-With COCP / other form of secure contraception
- Cyproterone Acetate (oral tablet)
- -inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors
- Spironolactone (oral tablet)
- -anti mineralocorticoid and anti androgen properties
how do you treat PCOS (4)
Photoepilation (laser) / electrolysis etc
Eflornithine cream (non-NHS) Inhibits ornithine decarboxylase enzyme in hair follicles
How do you treat PCOS (5)
Metformin (biguanide)
-+ insulin resistance, insulin levels, ovarian androgen production
- May help with weight loss / diabetes prevention
- May + ovulation (with clomifene), safe in pregnancy
- Less helpful for hirsutism & oligomenorrhoea, but may be an option for obese PCOS women
what is primary ovarian insufficiency
Presentation:
- Primary or secondary amenorrhoea
- –Secondary amenorrhoea may be associated with hot flushes & sweats
Other terms used:
- Premature ovarian failure
- Premature menopause
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 chemotherapy
what can you investigate in premature ovarian failure
- history / examination
- LH and FSH
- ? Karyotype
-Consider pelvic USS
Consider screening for other autoimmune endocrine disease
—Thyroid function tests, glucose, cortisol
how do you manage ovarian failure
Management:
-Psychological support
HRT
–Continue till +-52
Monitor bone density
-DEXA scan
Fertility
-IVF with donor egg
what is 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
Presentation
- May be diagnosed in the neonate
- May present with short stature in childhood
- May present with primary / secondary amenorrhoea
what are the associated problems with turner syndrome
Short stature
-Consider GH treatment
CV system
- Coarctation of aorta
- Bicuspid aortic valve
- Aortic dissection
- Hypertension (adults)
Renal
-Congenital abnormalities
Metabolic syndrome
Hypothyroidism
Ears / hearing
problems
Osteoporosis (lack HRT)
look at slide 32
how is it
what are the differentials of hirsutism
95% PCOS or ‘idiopathic hirsutism’
1% Non-classical congenital adrenal hyperplasia (CAH)
<1% Cushing’s syndrome
<1% Adrenal / ovarian tumour
Prevalence of polycystic ovarian syndrome:
5-10% women!
what are the very worrying/serious symptoms of hirsutism
Sudden onset of severe symptoms
Virilisation
- Frontal balding
- Deepening of voice
- Male-type muscle mass
- Clitoromegaly
Possible Cushing’s syndrome
describe congenital adrenal hyperplasia
CAH
disorders of cortisol biosynthesis
-Carrier frequency 1 : 60
-Most patients are compound heterozygotes
Different mutations on two alleles
95% CAH cases caused by 21-hydroxylase deficiency
- Cortisol deficiency
- May have aldosterone deficiency
- Androgen excess
- Depends on degree of enzyme deficiency
what is the CAH- 21 hydroxylase deficiency
Defect in cortisol biosynthesis raised CRH / ACTH (lack of negative feedback) drives excess adrenal androgen production
Diagnosis: high concentrations of 17-hydroxyprogesterone
Can confirm with Synacthen test
how does CAH present itself (non-specific general )
childhood:
- classic/severe
- salt-losing -2/3rd
- non-salt losing -1/3rd
- simple virilising
Adulthood
- Non-classic
- Late onset
CAH presentation specifics
Childhood:
Salt wasting
-Hypovolaemia, shock
Virilisation
- Ambiguous genitalia in girls
- Early virilisation in boys
-Precocious puberty
Abnormal growth
- Accelerated early
- Premature fusion
Adulthood
- Hirsutism
- Oligo / amenorrhoea
- Acne
- Subfertility
-Similar to ‘PCOS’ presentation
CAH treatment
Glucorticoid & mineralocorticoid replacement
- Hydrocortisone & fludrocortisone
- Additional salt in infancy
Glucocorticoids suppress CRH / ACTH
Supraphysiological glucocorticoid doses may be needed to suppress adrenal androgen production
-Excess glucocorticoid treatment may inhibit growth
Surgical management for ambiguous genitalia
Do quiz
how did it go
