T2 L6 Disorders of Ovulation Flashcards
What initiates the first step of ovulation?
(in the hypothalmus the) Supra chiasmic nuclei (SCN) is the master circadian clock
Interacts with the Kisspeptin neurones and the KNDy neurones ( neurokinin B and dynorphin )
Where are the Kisspeptin neurons located?
Arcuate Nucleus (ARN)
Anteroventral peri ventricular area (AVPV).
What is the function of the Kisspeptin and KNDy neurons?
Potent stimulators of the GnRH neurons which drives LH production
What is stimulates the Kisspeptin and KNDy neurons?
High oestrogen levels
When oestrogen levels are critically 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)
Recap the function of GnRH, FSH and LH.
GnRH stimulates the release of LH and FSH
FSH acts on the follicles causing them to mature. It also increases the LH receptors on granulosa cells
LH is involved in ovulation. It’s also involved in the resumption of oocyte meiosis and changes the granulosa cells into luteal cells (corpus luteum)
How can ovulation be diagnosed?
History taking from the woman
- Regular menstruation lasts 28 days (but first check that the woman is not on hormonal contraception)
- Pain is felt mid cycle at ovulation
- Increased mucus release post ovulation
How is ovulation diagnosed?
Biochemistry:
- Day 21 progesterone blood test
(7 days before start of next menstrual period)
- LH detection kits : urinary kits which can be bought over the counter
NOTE: If cycle longer then take blood 7 days before expected usual period e.g. day 28 if cycle is 35 days long.
Transvaginal pelvic ultrasound
- Done from Day 10, on alternate days to demonstrate the developing follicle size and Corpus Luteum. Once the LH surge is detected ovulation occurs 24-36 hours later.
What are the various 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 (which could be non-functional))
- post pituitary surgery /radiotherapy
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
What is the most common cause of ovulation problems?
Polycystic Ovarian Syndrome (PCOS)
Define the following menstrual patterns terminology
- Amenorrhoea (primary and secondary)
- 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 (on a female)
IT IS NOT:
Androgen-independent hair growth ( a.k. a hypertrichosis)
Familial / racial hair growth
What the clinical features of PCOS?
Hyperandrogenism
-hirsutism, acne
Chronic oligomenorrhoea / amenorrhoea
- 9 (or less) periods / year - subfertility
Obesity (but 25% of women with PCOS are “lean”). In these patients the way to prevent it from getting worse is by avoiding weight gain.
How does PCOS relate to the metabolic syndrome?
Insulin resistance with increased insulin
- increased androgen production by ovarian theca cells (due to increased LH)
- granulosa cells become less functional ( = less oestrogen) and the follicles arrest
- reduced SHBG production by the liver
Impaired glucose tolerance
-increased risk of gestational DM and T2 DM
Dyslipidaemia
Vascular dysfunction
Increased risk cardiovascular disease (scientists are still unsure as to whether this is the case)
What appearance do polycystic ovaries have when examined using ultrasound?
10 (or more) subcapsular follicules 2-8 mm in diameter,
-arranged around a thickened ovarian stroma
NOTE: not all women with PCOS will have USS appearance
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
What is SHBG?
A glycoprotein that binds to androgens and oestrogens
It is produced by the liver
What happens if testosterone is bound to SHBG?
If testosterone bound it is not converted to active component dihydrotestosterone
i.e. it is not “free”
Which hormones increases/reduces SHBG levels?
Increased by oestrogens
Decreased by testosterone thus releasing more free testosterone
What 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 association of PCOS with endometrial cancer?
Increased endometrial hyperplasia and cancer due to lack of progesterone on the endometrium
Endometrial cancer associated with type 2 diabetes & obesity
NOTE: There has to be at least 4 periods per year to prevent endometrial hyperplasia
What lifestyle modifications are used to treat PCOS?
Diet & exercise
Stop smoking
What are the results of these lifestyle modifications?
Reduced insulin resistance
Increased [SHBG]
Reduced [free testo]
Improved fertility / pregnancy outcomes
Improve metabolic syndrome risk factors
NOTE: Lean women with PCOS should NOT try to get fat.
How do combine oral contraceptives pills help to treat PCOS?
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
What are the anti-androgens used to treat PCOS and how do they work?
Cyproterone Acetate (oral tablet) -inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors
Spironolactone (oral tablet)
-anti mineralocorticoid and anti androgen properties
NOTE: These drugs are used with COCP / other form of secure contraception
What drug is used to target insulin resistance in PCOS? How does it work?
Metformin (biguanide)
FUNCTION
- Decreases insulin resistance, decreases insulin levels, –Decreases ovarian androgen production
- May help with weight loss / diabetes prevention
- May increase ovulation (with clomifene), safe in pregnancy
NOTE: It is less helpful for hirsutism & oligomenorrhoea, but may be an option for obese PCOS women
How is hirsutism treated?
Via hair removal methods:
Photoepilation (laser) / electrolysis etc
Eflornithine cream (non-NHS) Inhibits ornithine decarboxylase enzyme in hair follicles
Name the differential diagnosis for hirsutism and their %
- 95% PCOS or ‘idiopathic hirsutism’
- 1% Non-classical congenital adrenal hyperplasia (CAH)
- <1% Cushing’s syndrome
- <1% Adrenal / ovarian tumour
What % of women have PCOS?
5 - 10 %
What is the aetiology of Primary Ovarian Insufficiency (POI) ?
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 is the presentation of Primary Ovarian Insufficiency (POI)?
- Primary or secondary amenorrhoea
- Secondary amenorrhoea may be associated with hot flushes & sweats
NOTE: Other terms used for POI are “Premature ovarian failure” or “Premature menopause”
What investigations are used to diagnose Primary Ovarian Insufficiency (POI)?
History / examination
Increased LH and FSH
Karyotype
Consider pelvic USS
Consider screening for other autoimmune endocrine disease (thyroid function tests, glucose, cortisol)
How is Primary Ovarian Insufficiency (POI) managed?
Psychological support
HRT = continue till approx 52 years of age
Monitor bone density = use DEXA scan
Fertility treatment via IVF with donor egg
What is Turner syndrome?
Complete / partial X monosomy in some / all cells
- 50% of cases will be XO - 50% due partial absence of X or mosaicism
What proportion of live born girls have this condition?
1:2000 – 1:2500
What are the presentations of Turner syndrome?
Diagnosed in the neonate
Short stature in childhood
Primary / secondary amenorrhoea
What problems are associated with Turner syndrome (according to systems)?
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)
When should you be worried about POI?
Sudden onset of severe symptoms
Virilisation
Frontal balding
Deepening of voice
Male-type muscle mass
Clitoromegaly (abnormal enlargement of the clitoris)
NOTE: This could be due to Cushing’s syndrome
What is Congenital Adrenal Hyperplasia (CAH)?
Disorders of cortisol biosynthesis
Carrier frequency 1 : 60
Most patients are compound heterozygotes (they have different mutations on two alleles)
What causes 95% of CAH cases? What does it result in?
21-hydroxylase deficiency
LEADS TO
- Defect in cortisol biosynthesis => raised CRH / ACTH (lack of negative feedback) => drives excess adrenal androgen production
- May have aldosterone deficiency
NOTE: This depends on degree of enzyme deficiency
How is CAH diagnosed?
- High concentrations of 17-hydroxyprogesterone
- Can confirm with Synacthen test
How does CAH present in childhood?
‘Classic’ / ‘severe’
Salt wasting
-hypovolaemia, shock
Virilisation
- ambiguous genitalia in girls - early virilisation in boys
Precocious puberty (puberty occurs at an earlier age)
Abnormal growth
- accelerated early - premature fusion
NOTE: Salt-losing (2/3rd), Non-salt losing (1/3rd)
How does CAH present in adulthood?
‘Non-classic’ / ‘mild’, ‘late onset’
Hirsutism
Oligo / amenorrhoea
Acne
Subfertility
NOTE: Its presentation is similar to ‘PCOS’ presentation
How is CAH treated?
Glucorticoid & mineralocorticoid replacement
- hydrocortisone & fludrocortisone - additional salt in infancy
Glucocorticoids suppress CRH / ACTH
Supraphysiological glucocorticoid doses may be needed to suppress adrenal androgen production
-Monitor [17-OH-P] / androstenedione
-Monitor growth in childhood
NOTE: Excess glucocorticoid treatment may inhibit growth
Surgical management for ambiguous genitalia
Non-classical CAH in adult women (mild)
-Can treat as for PCOS with COCP with/without anti-androgen
