reproduction > PCOS > Flashcards

PCOS Flashcards

(55 cards)

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1
Q

What is PCOS?

A
  • the ovary contains increased numbers (>20) of small Antral follicles (2-9mm) visible in a necklace shape on high quality transvaginal transducers
  • there is a disorder of follicle growth at all stages
  • in some cases there is a failure of dominant follicle selection and therefore anovulation
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2
Q

What are the different stages of follicle growth where disorder can occur in PCOS?

A
  1. Possibly increased proportion of primordial follicles and increased number of activated primary follicles
  2. Arrested in antral follicle growth before they mature
  3. Lower rates of atresia > antral follicles persist (visible in US)
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3
Q

What are multiple symptomatology with PCOS

A
  • endocrine , gynaecological, diabetic, dermatological, earring disorders, psychiatry.
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4
Q

What are systematic metabolic manifestations with PCOS?

A

-Insulin resistance
-obesity has a bigger impact on PCOS population compared to normal, especially regarding IR
-Annual economic cost of diagnosis and treatment of PCOS in USA was calculate d$4.36 billion and 40% of this was IR/ T2D related

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5
Q

How is PCOS diagnosed?

A

darker regions which indicates fluid
NOT CYST but follicles that have stopped growing
> 20 follicles arranged in necklace like way around the ovary indicates PCOS
< 20 follicles isn’t diagnostic of PCOS

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6
Q

What are some disorders that mimic PCOS so must be excluded in diagnosis?

A

-non classical adrenal hyperplasia
-hyoerprolactinemia, thyroid disease , Cushing syndrome
-ovarian hyper the oasis - nests of luteinized theta cells

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7
Q

What is the diagnose criteria?

A

Rotterdam criteria
- 2/3 criteria’s met means PCOS positive
1. hyperandrogenism
2. Ovulatory dysfunction
3. PCO

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8
Q

What is the issue with identifying polycystic ovaries?

A

Techniques and equipment dependent
Transvaginal imaging not always appropriate (eg in adolescence girls)

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9
Q

What is Hyperandrogenism and limitations (criteria 1)

A

too much androgen levels
-Clinical and biochemical evidence
-assays not standardised across labs
-normative data not clearly defined
-clinical hyperandrogenism difficult to quantify
-ethnicity

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10
Q

What is ovulatory dysfunction and it’s limitations (criteria 2)

A

=>oligomenorrhea and anovulation
-frequent bleeding <21days or infrequent bleeding > 35days.
-to confirm ovulation serum progesterone level at mid luteal phase of cycle

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11
Q

What are 3 polycystic ovary morphology (PCOM) (criteria 3)?

A
  1. Normal = 5 or less follicles in an ovary with a small amount of stroma
  2. Anovulatory = 20 or more follicles, 2-9mm diameter arranged peripherally around an enlarged core dense stroma, ovarian volume >10ml with NO dominant follicle
  3. Ovulatory PCO = early follicular, mid follicular and ovulation, dominant follicle present, but instead of other ovaries dying small follicles persist.
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12
Q

What are the different phenotypes and their diagnostic criteria that match (alphabetical -H,O,P)?

A

Phenotype A = criteria 1/2/3
Phenotype B = criteria 1/2
Phenotype C = criteria 1/3
Phenotype D = criteria 2/3

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13
Q

What are features of phenotype A and B (classic PCOS)?

A

Phenotype A = HOP , phenotype B = HO
caused by:
- BMI syndrome
-metabolic syndrome
- Most common 2/3

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14
Q

What are the features of phenotype C (ovulatory PCOS)?

A

phenotype C = HP
BMI is often normal but BMI increases can alter phenotypic presentation

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15
Q

What are features of phenotype D (normandrogenic PCOS)?

A

-chronic anovulation and PCOM but normal serum androgens and no HA

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16
Q

How do you know a woman has ovulated at some point?

A

corpus luteum or albican present

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17
Q

Most PCOS women have …

A

oligomenorrhea

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18
Q

what are different factors that are involved in follicles arrest, which annovulatory PCOS women have?

A
  1. androgens
  2. intra- follicular inhibitors, eg. AMH
  3. Defect in apoptosis
  4. dysregulated gonadotrophin (both FSH and LH)
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19
Q

what is a key factor that distinguishes ovulatory and anovulatory women?

A
  • insulin resistance level
    study: adult rhesus monkey fed western style diet (high fat/sugars) and exposed to chronically elevated T from puberty to menopause => altered small AF numbers, morphology and transcriptome
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20
Q

oligomenorrhoea

A

infrequent periods, fewer than 6-8 periods per year

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21
Q

amenorrhea

A

absence of periods

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22
Q

What is the prevalence of PCO?

A
  • 32% patients have amenorrhea
  • 87% patients have oligomenorrhea
  • 87% patients have hirsutism and regular cycle
  • 22% of ‘ normal’ population - no signs
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23
Q

The most common cause of anovulatory infertility is …

Study These Flashcards
A

PCOS
73% of women with anovulatory infertiltiy have PCOS

24
Q

What is PCOS prevalence in the world

Study These Flashcards
A

PCOS presentation in European population differs
from US population
* Within US – variability seen between Hispanic ,
African-American and White populations
* East Asian population with PCOS have ↓ BMI and hirsutism compared to other population
* South Asian populations have greater insulin
resistance; metabolic sequelae and obesity cf to other populations

25
What is the aetiology of PCOS?
1. Familial aggregation– Sisters more likely to be affected – first-degree relatives have higher rates of metabolic abnormalities (including insulin resistance, decreased beta-cell function etc) – Male relatives of women with PCOS increased prevalence of metabolic syndrome & obesity compared to general US male population 2. Monozygotic twins twice as likely to both have PCOS than dizygotic. 3. common finding of raised androgen led to belief that PCOS is caused by an inherited disorder -most likely in the steroid biosynthetic pathway 4. Many candidate genes were investigated: all ‘obvious’ ones ruled out 5. Complex polygenic disease – involves subtle interaction with environmental factors (intra- & extra-uterine)
26
Chinese studies on PCOS
1st Genome-wide association study (GWAS) identified causative genes in Han Chinese women (2011) – 744 women with PCOS & 895 controls GWAS confirmed variants in DENND1A, THADA, FSHR & INSR => Confirming the biological relevance of PCOS-associated variants by molecular analysis.
27
What are 3 candidate genes seen in PCOS?
- LHCGR and FSHR genes = involved in making LH and FSH , so variation in these genes causes dysregulation of gonadotrophins – THADA = linked to Type 2 diabetes – DENND1A = linked with obesity
28
What is the link between expression of DENND1A.V2 in normal theca cells and PCOS?
- DENND1A. V2 transfected in normal theca cells results in augmented androgen and progestin production (high androgen levels are involved in follicle arrest seen in PCOS (anovulatory)) DENND1A is linked to obesity = obese woman have more DENND1A = more DENND1A = high levels of androgen bc of DENND1A
29
PCOS & Gonadotrophins I
- consistent feature of PCOS is disordered gonadotrophin, secretion leading to downstream ovarian consequences -high LH , low FSH or vice versa = basically LH: FSH ratio is altered Rapid GnRH frequency -> favoring rapid LH pulse secretion
30
Studies on PCOS and Gonadotrophins I
In PCOS women there is an increase in LH secretion regardless of body weight when lean and obese PCOS women were compared to lean and obese control women.
31
Why does dysregulated gonadotrophin secretion occur?
In normal ovaries - CL releases progesterone - negative feedback in HPG - decreased FSH and LH (regulated) In PCOS = high testosterone levels = impairs progesterone ability to provide negative feedback to decrease levels of gonadotrophins = increased LH /FSH
32
Evidence for increased testosterone impacting progesterone's ability to cause negative feedback comes from ..
1. Flutamide = an androgen antagonist = binds to androgen decreasing levels = progesterone negative feedback not impaired = less FSH and LH 2. oral contraceptive pills: normal ovaries OC pill = high levels of progesterone and oestrogen = negative feedback = decreased levels of FSH and LH PCO OC pill = high levels of progesterone = negative feedback impaired by androgen = high levels of LH and FSH
33
What does high levels of LH in PCOS lead to?
- thecal hyperplasia and the hyper-androgenemia, but high androgens (HA) is also intrinsic and can be independent of LH (so woman without high LH can still have HA)
34
hyperandrogenism
- increased/hypersecretion of androgen is the most consistent biochemical abnormality in women with PCOS
35
How do you measure increased androgen (testosterone)?
- measure free testosterone, measure sex hormone binding globulin (SHBG) which binds to testosterone and total testosterone, work out free T by total T - SHBG T -increased LH leads to increased androgen production >7 nmol/L then need to screen for androgen producing tumour
36
What are clinical signs of high androgen?
- androgenic alopecia -hirustism (excess terminal hair) - acne - distressed
37
Testosterone levels and symptoms in PCOS
- higher the T the more the symptoms - anovulatory with hirustism has the most severe symptoms - anov - h > anov> ov-h > PCO> normal
38
More than what level of androgen is indicative of tumour and need to screen for it?
>/= 7nmol/L
39
Androgen and hirsutism
T converted to DHT in hair follicle - hirtuism PCOS women - high T levels = more hirtusism -5 alpha-reductase may be higher = DHT conversion - sensitivity to androgen may be higher The excess testosterone comes from theca cell dysfunction in PCOS not from adrenals , increase in testosterone and progesterone is seen in PCOS
40
How can we test where the excess androgen is coming from?
Dexomathosone (cortisol)- suppresses the adrenals by negative feedback to HPA so if the levels are still high then androgen must be coming from ovary. - inhibitor can be used to reduce excess androgen from ovaries
41
Where are androgens produced in women?
- adrenal glands - ovaries - peripheral tissue - androgen target tissue : ie hair follicles,skin which explains hirsutism in PCOS
42
When there is intrinsic dysfunction in theca cells we look at androgen and progesterone production - why is progesterone also measured?
-same biosynthetic pathway for androgen and progesterone so shows inherent disorder -both 17 alpha- hydroxylase and C17-20 lyase reside on a single protein and are encoded by a single gene, CYP17
43
increased androgen doesnt always mean increased oestrogen
- oestrogen is not elevated in PCOS, increased androgens doesn't always mean its converted to oestrogen bc aromatase levels are still normal (not elevated) - due to increase in number of arrested follicles will see a slight increase E2 but not DF levels even when T increases. - levels of AR may not be increased in GC even if androgen levels increased
44
How is CYP17 involved in increased steroid production by theca which is common in PCOS?
- CYP17 promoter is more active - more steroids - CYP17 mRNA degrades more slowly - more steroids so we have more androgen and progesterone in the theca.
45
Biosynthetic pathway
- insulin is co - gonadotrophin with LH so hyperinsulinemia will lead to increased hyper andogenemia via cross talk on pathways -women with T1D have to take exogenous insulin - develop hyperinsulinemia - leads to hyperandrogenism - develop secondary PCOS
46
Morphometric studies
Hughesden 1982 : counted follicle numbers in sections from 17 PCOS and 17 normal ovaries -found 2x all of the growing stages in PCO, Webber et al(2003)...Lancet -counted follicles in biopsies -six times more primary follicles -no significant increase in primordials Maciel GA et al (2004), CEM -counted follicles in sections -'stockpiling' of primary follicles (PCOS increased follicles numbers in early stage of folliculogenesis)
47
Why do we see increased follicles in PCO?
Androgens seem likely candidate for increasing follicles number in early folliuculogenesis – 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
48
If we see increased follicles in PCOS then why anovulation common?
- increased follicle activation and recruitment but growth of follicles (at primary stage) arrested before they mature due to high levels of AMH in PCOS women
49
What causes arrest before the follicles at primary stage proceed to antral stage?
- altered ratio of FSH : LH , bc there is low FSH : LH (due to LH hypersecretion) ratio normal maturation is reduced, lower rates of atresia.
50
What are the intra-ovarian factors involved in follicular recruitment & growth that also contribute to arrest?
- AMH and other TGF- beta superfamily members - AMH production is higher from granulosa cells of PCO - Reflected in AMH serum levels which is 2-3x higher in PCO compared to normal.
51
Androgen in utero as a cause of PCOS
- excess foetal T (exposure of female animals to elevated androgens in the utero) induces PCOS like traits that manifest in offspring during adulthood: - sheep models had increased LH pulsatility and impaired E2/ P feedback - offspring of T exposed monkey mothers after puberty => LH hypersecretion, ovulatory dysfunction, hyper- androgenism and IR => 50% have enlarged ovaries and increased follicles counts - Adolescent girls with high androgen have similar pattern of rapid LH pulse secretion before menarche - obesity in pubertal girls also alters LH pulses
52
Pregnant women with PCOS? maternal T raised but is fetus exposed to HA?
High levels of SHBG and aromatase activity in placenta, prevent maternal T crossing over, so female foetus is not androgenised. => aromatase converts the high androgens to oestrogen so excess secretion may be coming from fetus itself?
53
Androgens and hypothesis of PCOS origin
Exposure of developing hypothalamus to excess androgen before final programming of steroids feedback and other regulatory mechanisms alters GnRH pulsatility and feedback.
54
AMH & hypothesis of PCOS origin
- Excess AMH in utero may affect development of female fetus - AMH arises from mother and not the fetus - in women with normal fertility AMH levels would drop during pregnancy - in pregnant women with PCOS AMH levels are elevated leading to follicle arrest. Treated pregnant mice with AMH → altered neuroendocrine phenotype (affects GnRH neurones) of female offspring and induced PCOS-like phenotype
55
Summary
Polycystic ovaries are genetically acquired and may have a foetal origin * There is a defect in the way follicles grow * There is a basic defect in steroid metabolism * The gene/s causing this are becoming known * Endocrine disturbances result in miscarriage, anovulation, infertility and hyper- androgenism
reproduction
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