Disorders of ovulation

Question 1

Outline the negative feedback loop of ovulation

Answer 1

GnRH stimulates FSH which acts on primary follicle granulosa cells which start producing oestrogen + inhibin.
FSH increases LH receptors in granulosa cells.
These hormones inhibit FSH (negative feedback).
But when oestrogen levels get to critical high level they positively act on Kisspeptin + KNDy neurones which stimulate production of GnRH which produces LH (due to increased frequency + amplitude of pulse from GnRH).
LH triggers ovulation, resumption of oocyte meiosis + changes granulosa cells into luteal cells.

Question 2

How can a diagnosis of ovulation be established?

Answer 2

take a history.
regular menstruation usually 28 days (check not on hormonal contraception).
mid cycle pain at ovulation.
vaginal discharge alters (increased mucus post ovulation).
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 developing follicle size and Corpus Luteum.

Question 3

What are the causes of ovulation problems?

Answer 3

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 4

What are the clinical features/elements in the diagnosis of PCOS?

Answer 4

Hyperandrogenism - hirsutism, acne
Chronic oligomenorrhoea / amenorrhoea - incl/less than 9 periods / year, subfertility
Obesity (insulin resistance can worsen PCOS).

Question 5

How does PCOS affect hormones?

Answer 5

Raised baseline LH and normal FSH levels.
Raised androgens and free testosterone.
Reduced Sex Hormone Binding Globin (SHBG).
Oestrogen usually normal

Question 6

What is the function of sex hormone binding globulin (SHBG) and what is it increased and decreased by?

Answer 6

Binds testosterone and oestradiol.
If testosterone bound - not converted to active component.
increased by oestrogens.
decreased by testosterone, so releases more free testosterone.

Question 7

How is PCOS associated with metabolic syndrome?

Answer 7

Insulin resistance with high insulin: increased androgen production by ovarian theca cells, reduced SHBG production by liver.
Impaired glucose tolerance:
increased risk gestational DM and T2 DM.
Dyslipidaemia
Vascular dysfunction

Question 8

What are the reproductive effects of PCOS?

Answer 8

maybe associated with varying degrees of infertility, increased miscarriages and increased risk of gestational diabetes

Question 9

Why does PCOS increase the risk of endometrial cancer?

Answer 9

high oestrogen levels and highly infrequent periods can lead to Increased endometrial hyperplasia and cancer.
due to lack of progesterone on endometrium. can be prescribed progesterone.
endometrial cancer associated with type 2 diabetes and obesity.

Question 10

What are the lifestyle modifications for treating PCOS?

Answer 10

Diet and exercise, stop smoking - decreased insulin resistance,
increased [SHBG], decreased
[free testo], improved fertility / pregnancy outcomes,
improve metabolic syndrome risk factors.
High frequency eating disorders - bulimia.
Lean women with PCOS should try not to get fat.

Question 11

Why can combined oral contraceptives be used as treatment for PCOS?

Answer 11

increases SHBG and thus decreases free testosterone
decreases FSH and LH and therefore ovarian stimulation
regulates cycle and decreases endometrial hyperplasia.

Question 12

How are anti-androgens used as treatment for PCOS and give examples?

Answer 12

With COCP / other form of secure contraception.
Cyproterone acetate (oral tablet) -
inhibits binding of testosterone and 5 alpha dihydrotestosterone to androgen receptors.
Spironolactone (oral tablet)
anti mineralocorticoid and anti -androgen properties.

Question 13

Which drug can target insulin resistance in PCOS?

Answer 13

Metformin:
decreases insulin resistance, insulin levels and ovarian androgen production.
may help with weight loss / diabetes prevention.
May increase ovulation (with clomifene).
Less helpful for hirsutism and oligomenorrhoea, but may be an option for obese PCOS women.

Question 14

What are the treatment options for hirsutism?

Answer 14

Photoepilation (laser) / electrolysis etc.
Eflornithine cream (non-NHS)

Question 15

How is primary ovarian insufficiency presented?

Answer 15

Primary or secondary amenorrhoea - secondary amenorrhoea may be associated with hot flushes and sweats.

Question 16

What are the causes of primary ovarian insufficiency?

Answer 16

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 17

How is premature ovarian failure investigated?

Answer 17

history / examination
increased LH and FSH
karyotype?
consider pelvic USS
consider screening for other autoimmune endocrine disease - thyroid function tests, glucose, cortisol.

Question 18

How is premature ovarian failure managed?

Answer 18

Psychological support
HRT
Monitor bone density - DEXA scan
Fertility - IVF with donor egg

Question 19

What is the presentation of Turner syndrome?

Answer 19

may be diagnosed in the neonate, may present with short stature in childhood, may present with primary / secondary amenorrhoea

Question 20

Which problems are associated with Turner syndrome?

Answer 20

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 21

What is congenital adrenal hyperplasia (CAH) and what is it caused by?

Answer 21

disorders of cortisol biosynthesis.
95% CAH cases caused by 21-hydroxylase deficiency -
cortisol deficiency, may have aldosterone deficiency, androgen excess, depends on degree of enzyme deficiency.

Question 22

What is the presentation of CAH in childhood?

Answer 22

Salt wasting - hypovolaemia, shock.
Virilisation - ambiguous genitalia in girls, early virilisation in boys.
Precocious puberty
Abnormal growth - accelerated early, premature fusion.

Question 23

What is the presentation of CAH in adulthood?

Answer 23

Hirsutism, oligo / amenorrhoea,

acne, subfertility, similar to PCOS presentation

Question 24

What is the treatment for CAH?

Answer 24

Glucocorticoid and mineralocorticoid replacement -

hydrocortisone and fludrocortisone as cortisol and aldosterone levels are low, additional salt in infancy.

Question 25

What are the consequences of 21-hydroxylase deficiency in CAH?

Answer 25

Defect in cortisol biosynthesis > raised CRH / ACTH (lack of negative feedback) > drives excess adrenal androgen production