PCOS Flashcards
POLYCYSTIC OVARIES are
Ovaries containing increased numbers (>12) of small antral follicles (2-9mm) visible on ultrasound
PCOS: There is a disorder of follicle growth at all stages
- 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
Before confirming/diagnosing PCOS -> Diagnosis of exclusion i.e. disorders that mimic PCOS:
-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
Rotterdam Criteria
Diagnosis - need 2 out of 3 criteria
THE STANDARD
Definitions of PCO by ultrasound
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
The polycystic ovary morphology
Anovulation
There are a number of candidates for follicle arrest
- androgens,
- intra-follicular inhibitors eg AMH
- defect in apoptosis
-dysregulated gonadotrophin secretion (both FSH and LH)
Main difference between ovulation and anovulation is
also the level of insulin resistance
PCOS prevalence
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%
Aetiology of PCOS
- 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)
A study:
Researchers focused on understanding how a specific version of a gene, DENND1A.V2, affects hormone production in ovarian theca cells:
Consistent feature of PCOS is
disordered gonadotrophin secretion leading to downstream ovarian consequences
ALTERED RATIO OF LH:FSH
Why does dysregulated gonadotrophin secretion occur?
Impaired negative regulation of GnRH pulse generator
What we think is happening see pic
Interestingly if use flutamide (which blocks the Androgen Receptors), this can reverse
this can reverse this insensitivity to progesterone
LH in PCOS:
The higher LH will drive..
thecal cell hyperplasia and the hyper-androgenemia, but HA (Hyperandrogenemia) is also intrinsic and can be independent of LH.
What is the most consistent biochemical abnormality in women with PCOS is hypersecretion of androgens?
This can lead to:
Increased androgen
can lead to hirsutism and acne
Androgens and hirsutism (PCOS)
- 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
Where is all of this excess androgen coming from? (PCOS)
How would we find out?
Excess androgens coming from either the ovary and/or cells of adrenal cortex.
Dexamethasone test
Androgen Production in Women
In women with PCOS – main source of androgens is from..
..the ovary
Due to ↑in number of arrested follicles will see a slight ↑E2 but not DF levels in spite of ↑T. This is because:
- Levels of AR may not be increased in GC, hence cannot bind excess T
- No massive increase in aromatase levels
Both 17α-hydroxylase and C17-20-lyase reside on a single protein and are encoded by a single gene, namely,
CYP17
The enzymes involved in androgen production are higher with..
increased promoter activity and decreased degradation of mRNA (i.e. increased mRNA stability).
Insulin is co-gonadotrophin with LH and so
hyperinsulinemia will..
hyperinsulinemia (too much insulin in blood) will augment hyper-androgenemia
What Androgens seems the likely candidate for increasing follicle numbers early in folliculogenesis
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
Foetal Androgen Exposure and PCOS
Exposure to high levels of testosterone (T) during fetal development can lead to PCOS-like symptoms in adulthood.
Animal Models and LH Dynamics
Sheep models showed that elevated fetal T increases LH pulsatility and disrupts estrogen/progesterone (E2/P) feedback after birth.
Ovarian Changes in Androgen-Exposed Offspring
50% of these offspring exhibit physical changes like enlarged ovaries and a higher count of follicles.
Adolescents and LH Pulsatility
Adolescent girls with hyperandrogenism (HA) show rapid LH pulse secretion before their first menstrual cycle (menarche), similar to PCOS patterns.
PCOS in Pregnancy and Foetal Exposure
In pregnant PCOS patients, while maternal T levels are high, the placenta’s SHBG and aromatase prevent T transfer to the fetus.
Exposure of developing hypothalamus to excess androgen before final programming of steroid feedback and other regulatory mechanisms alters..
GnRH pulsatility and feedback
High Anti-Müllerian Hormone (AMH) levels in the womb could negatively impact the..
development of the female fetus.
The increased AMH implicated in fetal development issues originates from (the mother or fetus)
the mother, not the fetus.
AMH Levels During Pregnancy in PCOS vs. Normal Fertility
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.
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.
PCOS: Clinical Consequences
The condition manifests in reproductive complications like miscarriage, anovulation, infertility, and hyper-androgenism, with ongoing research identifying specific causative genes.
