PCOS

Question 1

POLYCYSTIC OVARIES are

Answer 1

Ovaries containing increased numbers (>12) of small antral follicles (2-9mm) visible on ultrasound

Question 2

PCOS: There is a disorder of follicle growth at all stages

Answer 2

• Possibly increased proportion of primordial follicles & increased number of activated (primary) follicles
• Arrested antral follicle growth before they mature
• Lower rates of atresia » antral follicles persist (visible on u/s)

In some cases there is a failure of dominant follicle selection and therefore anovulation

Question 3

Before confirming/diagnosing PCOS -> Diagnosis of exclusion i.e. disorders that mimic PCOS:

Answer 3

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

Question 4

Rotterdam Criteria
Diagnosis - need 2 out of 3 criteria

THE STANDARD

Answer 4

Question 5

Definitions of PCO by ultrasound

Answer 5

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 6

The polycystic ovary morphology

Answer 6

Question 7

Anovulation

There are a number of candidates for follicle arrest

Answer 7

• androgens,
• intra-follicular inhibitors eg AMH
• defect in apoptosis
  -dysregulated gonadotrophin secretion (both FSH and LH)

Question 8

Main difference between ovulation and anovulation is

Answer 8

also the level of insulin resistance

Question 9

PCOS prevalence

Answer 9

PCO present in
32% of patients with amenorrhoea
87% with oligomenorrhoea
87% with hirsutism and regular cycles
75% of bulimics?
22% of ‘normal’ population

most common cause of anovulatory infertility-73%

Question 10

Aetiology of PCOS

Answer 10

• Familial aggregation
• Monozygotic twins twice as likely to both have PCOS than dizygotic.
• Common finding of raised androgen led to belief that PCOS is caused by an inherited disorder -most likely in the steroid biosynthetic pathway
• Many candidate genes were investigated: all ‘obvious’ ones ruled out
• Complex polygenic disease

– involves subtle interaction with environmental factors (intra- & extra-uterine)

Question 11

A study:
Researchers focused on understanding how a specific version of a gene, DENND1A.V2, affects hormone production in ovarian theca cells:

Answer 11

Question 12

Consistent feature of PCOS is

Answer 12

disordered gonadotrophin secretion leading to downstream ovarian consequences

ALTERED RATIO OF LH:FSH

Question 13

Why does dysregulated gonadotrophin secretion occur?

Answer 13

Impaired negative regulation of GnRH pulse generator

What we think is happening see pic

Question 14

Interestingly if use flutamide (which blocks the Androgen Receptors), this can reverse

Answer 14

this can reverse this insensitivity to progesterone

Question 15

LH in PCOS:
The higher LH will drive..

Answer 15

thecal cell hyperplasia and the hyper-androgenemia, but HA (Hyperandrogenemia) is also intrinsic and can be independent of LH.

Question 16

What is the most consistent biochemical abnormality in women with PCOS is hypersecretion of androgens?

This can lead to:

Answer 16

Increased androgen

can lead to hirsutism and acne

Question 17

Androgens and hirsutism (PCOS)

Answer 17

• Testosterone converted to DHT at hair follicle
• DHT more potent androgen
• 5a-reductase may be higher in PCOS
• Not just absolute levels of testosterone per se but the sensitivity to AR – see this with acne

Question 18

Where is all of this excess androgen coming from? (PCOS)

How would we find out?

Answer 18

Excess androgens coming from either the ovary and/or cells of adrenal cortex.

Dexamethasone test

Question 19

Androgen Production in Women

Answer 19

Question 20

In women with PCOS – main source of androgens is from..

Answer 20

..the ovary

Question 21

Due to ↑in number of arrested follicles will see a slight ↑E2 but not DF levels in spite of ↑T. This is because:

Answer 21

• Levels of AR may not be increased in GC, hence cannot bind excess T
• No massive increase in aromatase levels

Question 22

Both 17α-hydroxylase and C17-20-lyase reside on a single protein and are encoded by a single gene, namely,

Answer 22

CYP17

Question 23

The enzymes involved in androgen production are higher with..

Answer 23

increased promoter activity and decreased degradation of mRNA (i.e. increased mRNA stability).

Question 24

Insulin is co-gonadotrophin with LH and so
hyperinsulinemia will..

Answer 24

hyperinsulinemia (too much insulin in blood) will augment hyper-androgenemia

Question 25

What Androgens seems the likely candidate for increasing follicle numbers early in folliculogenesis

Answer 25

Androgens

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

Question 26

Foetal Androgen Exposure and PCOS

Answer 26

Exposure to high levels of testosterone (T) during fetal development can lead to PCOS-like symptoms in adulthood.

Question 27

Animal Models and LH Dynamics

Answer 27

Sheep models showed that elevated fetal T increases LH pulsatility and disrupts estrogen/progesterone (E2/P) feedback after birth.

Question 28

Ovarian Changes in Androgen-Exposed Offspring

Answer 28

50% of these offspring exhibit physical changes like enlarged ovaries and a higher count of follicles.

Question 29

Adolescents and LH Pulsatility

Answer 29

Adolescent girls with hyperandrogenism (HA) show rapid LH pulse secretion before their first menstrual cycle (menarche), similar to PCOS patterns.

Question 30

PCOS in Pregnancy and Foetal Exposure

Answer 30

In pregnant PCOS patients, while maternal T levels are high, the placenta’s SHBG and aromatase prevent T transfer to the fetus.

Question 31

Exposure of developing hypothalamus to excess androgen before final programming of steroid feedback and other regulatory mechanisms alters..

Answer 31

GnRH pulsatility and feedback

Question 32

High Anti-Müllerian Hormone (AMH) levels in the womb could negatively impact the..

Answer 32

development of the female fetus.

Question 33

The increased AMH implicated in fetal development issues originates from (the mother or fetus)

Answer 33

the mother, not the fetus.

Question 34

AMH Levels During Pregnancy in PCOS vs. Normal Fertility

Answer 34

During a typical pregnancy, AMH levels decrease in women with normal fertility; however, in women with PCOS, these levels stay elevated, suggesting a potential role in the condition’s pathogenesis and effects on fetal development.

Question 35

PCOS: Genetic and Follicular Origins

PCOS has genetic roots, possibly starting in fetal development, and is characterized by abnormal follicle growth due to inherent defects in steroid metabolism.

Answer 35

PCOS: Clinical Consequences

The condition manifests in reproductive complications like miscarriage, anovulation, infertility, and hyper-androgenism, with ongoing research identifying specific causative genes.