6. Disorders of ovulation

Question 1

What regulates GnRH release?

Answer 1

Kisspeptin and the KNDy neurones are potent stimulators of GnRH
They are stimulated by high oestrogen and they drive LH production through stimulation of GnRH
Note: Kisspeptin / GnRH/ LH all pulsatile (60-90 minutes)

Question 2

How does GnRH act?

Answer 2

GnRH stimulates FSH which 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)
HOWEVER 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)

Question 3

What does LH do?

Answer 3

LH triggers ovulation, resumption of oocyte meiosis and changes the granulosa cells into luteal cells

Question 4

Describe the first half of the cycle

Answer 4

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 increase in freq and amplitude of GnRH which causes the LH surge.

Question 5

Describe the second half of the cycle

Answer 5

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.

Question 6

Diagnosis of ovulation

Answer 6

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)
History: regular 28 days between the first day of every period. Ovulation pain (leakage of follicle fluid at the time of ovulation irritates the peritoneum and causes pain.

Biochemistry: Day 21 progesterone blood test
(7 days before start of next menstrual period)

LH detection kits:
urinary kits bought over the counter

Transvaginal pelvic ultrasound done from Day 10, alternate days
to demonstrate the developing follicle size and Corpus Luteum

not Basal Body Temperature, cervical mucus change, vaginal epithelium changes nor endometrial biopsies

Question 7

Causes of ovulation problems

Answer 7

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 

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

Question 8

Menstrual patterns (terminology)

Answer 8

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

Question 9

Hirsutism

Answer 9

‘Androgen-dependent’ hirsutism
Excess body hair in a male distribution

NOT:
Androgen-independent hair growth
Hypertrichosis
Familial / racial hair growth

Question 10

Clinical features of hirsutism

Answer 10

Hyperandrogenism
Hirsutism, acne
Chronic oligomenorrhoea / amenorrhoea
< 9 periods / year
Subfertility
Obesity (but 25% of women with PCOS are “lean”)

Question 11

Elements in diagnosis of PCOS

Answer 11

Polycystic ovaries
oligo/anovulation
androgen excess

Question 12

Insulin and PCOS

Answer 12

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, also causes increased LH levels which drives thecal cells to increase androgens.

Question 13

USS appearance of polycystic ovary syndrome

Answer 13

> 10 subcapsular follicules 2-8 mm in diameter,
arranged around a thickened ovarian stroma
not all women with PCOS will have USS appearance

Question 14

USS appearance of polycystic ovary syndrome

Answer 14

> 10 subcapsular follicules 2-8 mm in diameter,
arranged around a thickened ovarian stroma
not all women with PCOS will have USS appearance

Question 15

Hormonal abnormalities in PCOS

Answer 15

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

Question 16

Sex hormone binding globulin

Answer 16

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

Question 17

Reproductive effects of PCOS

Answer 17

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

Question 18

PCOS and endometrial cancer

Answer 18

Increased endometrial hyperplasia and cancer
Lack of progesterone on the endometrium
Endometrial cancer associated with type 2 diabetes & obesity

Question 19

Life-style modifications to treat PCOS

Answer 19

Diet & exercise
Stop smoking
RESULTS:
Decreased insulin resistance
Increased [SHBG]
Decreased [free testo]
Improved fertility / pregnancy outcomes
Improve metabolic syndrome risk factors
High frequency eating disorders
Bulimia associated with PCOS

Lean women with PCOS should try not to get fat!

Question 20

Combined oral contraceptives in PCOS

Answer 20

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

Question 21

Anti-androgens in PCOS treatment

Answer 21

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

Question 22

Hair removal in PCOS

Answer 22

Photoepilation (laser) / electrolysis etc

Eflornithine cream (non-NHS)
Inhibits ornithine decarboxylase enzyme in hair follicles

Question 23

Targeting insulin resistance in PCOS

Answer 23

Metformin (biguanide)
Decreasesinsulin resistance, decreases insulin levels, decreases 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

Question 24

Primary ovarian insufficiency

Answer 24

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

Question 25

premature ovarian failure

Answer 25

Investigations:
history / examination
Increase LH and FSH
? Karyotype
Consider pelvic USS
Consider screening for other autoimmune endocrine disease
Thyroid function tests, glucose, cortisol
Management:
Psychological support
HRT
Continue till +/- 52
Monitor bone density
DEXA scan
Fertility 
IVF with donor egg

Question 26

Turner syndrome

Answer 26

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

Question 27

Associated problems with Turner Syndrome

Answer 27

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)

Question 28

Differential diagnosis of hirsutism

Answer 28

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!

Question 29

When to worry

Answer 29

Sudden onset of severe symptoms
Virilisation
Frontal balding
Deepening of voice
Male-type muscle mass
Clitoromegaly
Possible Cushing’s syndrome

Question 30

Congenital adrenal hyperplasia (CAH)

Answer 30

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

Question 31

21-hydroxylase deficiency

Answer 31

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

Question 32

CAH presentation

Answer 32

CHILDHOOD
‘Classic’ / ‘severe’

Salt-losing (2/3rd)

Non-salt losing (1/3rd)
Simple virilising

Salt wasting
Hypovolaemia, shock
Virilisation
Ambiguous genitalia in girls
Early virilisation in boys
Precocious puberty
Abnormal growth
Accelerated early
Premature fusion

ADULTHOOD
‘Non-classic’ / ‘mild’
‘late-onset’

Adulthood (mild):
Hirsutism
Oligo / amenorrhoea
Acne
Subfertility

Similar to ‘PCOS’ presentation

Question 33

CAH treatment

Answer 33

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
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 +/- anti-androgen