Intro to PCOS

Question 1

What are polycystic ovaries (PCO) characterised by?

Answer 1

The ovary containing increased numbers (>12) of small antral follicles (2-9mm) visible on ultrasound (u/s)

Question 2

How does PCOS cause disorder of follicle growth at every stage?

Answer 2

o Possibly increased proportion of primordial follicles & increased number of activated (primary) follicles
o Arrested antral follicle growth before they mature – accumulation of antral follicles
o Lower rates of atresia » antral follicles persist (visible on u/s)
o In some cases there is a failure of dominant follicle selection and therefore anovulation

Question 3

What does PCO look like on ultrasound?

Answer 3

Normally ovary: only a few antral follicles

Polycystic ovary: a LOT of antral follicles and there’s a thickened stroma

Question 4

How is polycystic ovary syndrome (PCOS) diagnosed?

Answer 4

• diagnosed by ultrasound
• presence of bilaterally enlarged sclerocystic (hardened) ovaries – thought they were cysts but were just antral follicles
• patients will not have symptoms of cyst

Question 5

What disorders mimic PCOS/used in the diagnosis of exclusion?

Answer 5

• Non-classical adrenal hyperplasia (most common is deficiency of 21-hydroxylase → ↑17-hydroxyprogesterone & androgens) – increases hirsutism
• Hyperprolactinemia, thyroid disease, Cushing’s syndrome
• Ovarian hyperthecosis (very rare) - nests of luteinized theca cells

Question 6

What is the Rotterdam criteria?

Answer 6

Diagnosis for PCOS - need 2 out of 3 criteria
• Polycystic ovaries (seen using ultrasound)
• Hyperandrogenism (clinical evidence)
• Ovulatory Dysfunction (anovulation/oligomenorrhea)

This is so PCOS can be diagnosed accurately

Question 7

What does ultrasound show for normal ovaries, PCO and PCOS?

Answer 7

• Normal: no more than 5 follicles in an ovary with a small amount of stroma in a woman with regular cycles
• PCO: In at least one ovary ≥ 12 follicles of 2-9mm diameter arranged peripherally around an enlarged core of dense stroma - ovarian volume >10mls, without a dominant follicle
• PCOS: PCO on scan plus one or more symptoms

Question 8

What happens to the follicles in the menstrual cycle during anovulatory and ovulatory PCO?

Answer 8

Anovulatory PCO: all the antral follicles look the same but there are many

Ovulatory PCO: many antral follicles, one dominant follicle is chosen and matured but the rest of the follicles don’t die off

Question 9

Difference between PCO and PCOS?

Answer 9

PCO: when it looks like there’s polycystic ovaries but there’s no other symptoms – may develop PCOS later

PCOS: When there’s polycystic ovaries AND other symptoms also present

Question 10

What decides if a woman has PCO or PCOS?

Answer 10

Anovulation

Question 11

How does anovulation differentiate between PCO and PCOS?

Answer 11

• PCO - probably have regular or almost regular cycles
• PCOS - cycle problems/oligomenorrhoea

• Main difference between ov and anov is also the level of insulin resistance

Question 12

Reasons for follicle arrest?

Answer 12

• There are a number of candidates for follicle arrest
o androgens,
o intra-follicular inhibitors eg AMH
o defect in apoptosis
o dysregulated gonadotrophin secretion (both FSH and LH)

Question 13

Aetiology of PCOS?

Answer 13

• Familial aggregation:
o Sisters more likely to be affected
o first-degree relatives have higher rates of metabolic abnormalities
o Male relatives of women with PCOS increased prevalence of metabolic syndrome & obesity

• caused by an inherited disorder - most likely in the steroid biosynthetic pathway
• Complex polygenic disease – involves interaction with environmental factors

Question 14

What gene is important in PCOS?

Answer 14

• DENND1A

- Forced expression of DENND1A in normal theca cells results in increased androgen and progesterone production.

Question 15

What is a consistent feature of PCOS?

Answer 15

• disordered gonadotrophin secretion leading to downstream ovarian consequences

Question 16

How is gonadotrophin disorder seen in PCOS?

Answer 16

• Elevated/upper-normal mean LH - impairs downstream ovarian folliculogenesis and alters steroid hormone production
• Low/low-normal FSH - FSH threshold required for follicle maturation is not reached (due to dysregulated gonadotrophins and increased AMH, which alters FSH sensitivity) causing follicles to arrest in antral stages.
• The ratio of LH:FSH is altered – LH is favoured being higher
• Rapid GnRH frequency → favouring rapid LH pulse secretion

Question 17

Why does dysregulated gonadotrophin secretion occur?

Answer 17

High Testosterone (intrinsic in the polycystic ovaries) impairs negative feedback by Progesterone in presence of oestradiol – leads to increased LH levels

Question 18

What does high LH do in PCOS?

Answer 18

Drive thecal cell hyperplasia (as LH also drives thecal growth)

hyper-androgenemia, but HA is also intrinsic and can be independent of LH.

Question 19

What is a consistent biochemical abnormality in women with PCOS?

Answer 19

• hypersecretion of androgens
• ideal to measure free (T) i.e. SHBG (sex hormone binding globulin) and total testosterone to work out free T
• anov> ov>normal – anov women have higher testosterone than other women
• increased androgen production by the ovary, even in ovPCO

Question 20

Why is there increased androgen production in PCOS?

Answer 20

Increased LH leads to increased androgen production

Question 21

Effects of increased androgen production?

Answer 21

May lead to hirsutism and acne

Question 22

How do testosterone levels correlate with PCOS symptoms?

Answer 22

The higher the testosterone, the worse the symptoms

Women that are anovulatory AND have hirsutism have the highest T

But they will never have the same level of T as men – if T levels go above 7, need to check for a hormone/androgen producing tumour

Question 23

Why do some PCOS patients have hirsutism

Answer 23

• Testosterone converted to DHT at the hair follicle
• DHT is a more potent androgen
• 5a-reductase may be higher in PCOS

Question 24

Source of androgens in PCOS?

Answer 24

The ovaries

Question 25

How is the steroids produced by the theca cells affected in PCOS

Answer 25

Women with PCOS have high levels of androstenedione and progesterone levels

whole pathway is dysregulated

there’s an intrinsic dysregulation

Question 26

What does CYP-17 encode

Answer 26

17α-hydroxylase and C17-20-lyase reside on a single protein and are encoded

Question 27

Does oestradiol increase in PCOS and why?

Answer 27

Oestradiol is only slightly high due to increase in antral follicles (NOT because of anything else)

levels of androgen receptor and aromatase have not increased despite increase in androgen so E2 isnt as affected

Question 28

How is CYP-17 affected by PCOS?

Answer 28

• CYP17 promoter is more active
• CYP17 mRNA degrades more slowly

Therefore

The enzymes involved in androgen production are higher with increased promoter activity and decreased degradation of mRNA

Question 29

What does insulin do in PCOS?

Answer 29

• Insulin is co-gonadotrophin with LH
• hyperinsulinemia will augment hyper-androgenemia
• Insulin binds to its own receptor but stimulates similar pathways to LH

Question 30

In PCOS, what increases follicle numbers early in folliculogenesis?

Answer 30

• Androgens
• Androgens involved in stimulating primordial follicle initiation and increasing number of small antral follicles
• LH hypersecretion amplifies androgen production by theca
• AR (androgen receptor) expression found in GC at all follicle stages

Question 31

What is the reason for increased follicles at the primary compared to the antral stage

Answer 31

• Low/normal FSH:LH ratio reduce normal maturation – FSH needed for maturation
• Lower rate of atresia

Question 32

What factors may affect follicular recruitment & growth ?

Answer 32

• AMH & others TGF-β superfamily members

* AMH production high from granulosa cells of PCO

Question 33

What may be the causes of PCOS?

Answer 33

Not sure but these are suggested

• Androgens
• AMH

Question 34

How can androgens cause PCOS?

Answer 34

• Excess foetal T (exposure of female animals to elevated androgens in utero) induces PCOS-like traits that manifest in offspring during adulthood
• Exposure of developing hypothalamus to excess androgen before final programming of steroid feedback and other regulatory mechanisms alters GnRH pulsatility and feedback

Question 35

How can AMH cause PCOS

Answer 35

• Excess AMH in utero may affect development of female foetus - arises from mother and not the foetus
• In women with normal fertility AMH levels would drop during pregnancy
• In pregnant women with PCOS AMH levels are elevated
• altered neuroendocrine phenotype (GnRH pulses) of female offspring and induced PCOS-like phenotype