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Science of Repro > Intro To PCOS > Flashcards

Intro To PCOS Flashcards

1
Q

WHY PCOS?

A

arguable most prev. medical condition in women

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2
Q

What systemic metabolic manifestations are associated with multiple symptomatology? (9)

A

endocrine, gynaecological, diabetic, dermatological, eating
disorder, psychiatry - complex

  • life long impact from IR
    -Obesity has bigger impact on PCOS compared to normal esp IR
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3
Q

Polycystic Ovaries (5)

A

-increased numbers (>20) of small antral follicles (2-9mm)
= dependent on quality : visible on high quality transvaginal u/s transducers (arranged as necklace of pearls)

There is a disorder of follicle growth at all stages:
– Possibly inc. proportion of primordial follicles & inc. no. of activated (primary) follicles
– Arrested antral follicle growth before they mature
– Lower rates of atresia » antral follicles persist (visible on u/s)

-some cases there is a failure of df selection and therefore anovulation infertility

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4
Q

why are they called cysts?

A

They are arrested follicles not cysts - just named due to their initial discovery but these differ from ovarian cysts.

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5
Q

PCOS discovery (2)

A

Described as obesity, hirsutism and anovulation in the presence of bilaterally enlarged sclerocystic (hardened) ovaries

(1935) - Stein + Leventhal

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6
Q

Diagnosis then and now (2)

A

Then: visuall - biopsies, surgeries, deaths (post mortem)
now: ultrasounds +(transvaginal probe)

spectrum of presentation =Lack of consensus for definition
- now measured using rotterdam criteria POST-EXCLUSION of other disorders

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7
Q

disorders that mimic PCOS/ diagnosis of exclusion: (3)

A

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

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8
Q

Rotterdam Criteria : Diagnosis - need 2 out of 3 criteria (6)

A

-polycystic ovaries
-Hyper-androgenism
-Ovulatory dysfunction

Polycystic Ovaries: (20 or more follicles measuring 2-9mm diameter and/or increased ovarian volume >10ml in either ovary & no DF >10mm)
-Technique and equipment dependent. T/V imaging not always appropriate

Hyper-androgenism: (clinical (acne/ hair)/biochemical evidence) Assays not
standardized across labs; normative data not clearly defined; clinical hyperandrogenism difficult to quantify; ethnicity

Ovulatory Dysfunction: (Oligomenorrhea/anovulation): Frequent bleeding
<21d or infrequent bleeding >35d.
-To confirm ovulation serum progesterone level at mid-luteal phase (d21-22) of cycle (values ≥7ng/ml needed for regular luteal function)

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9
Q

Polycystic ovary morphology (PCOM) (3)

A

NORMAL: ≤5 follicles in an ovary with a small amount of stroma early follicular mid-follicular ovulation - then DF emerging + shrunk other follciles

ANOVULATORY PCO: ≥ 20 follicles, 2-9mm diameter arranged necklace follicles around enlarged core of dense stroma - ovarian volume >10mls, with NO df

OVULATORY PCO: scan early = anov. , continue scanning during cycle = emergence of DF but instead of others shrinking + dying - they persist

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10
Q

Refinement of Rotterdam criteria - phenotypes (7)

A

(table)
A: hyperandro., OD, PCOM
B: hyperandro., OD,
C:hyperandro., PCOM
D: OD, PCOM

  • Phenotypes A&B are considered classic PCOS → (2/3 of cases) + also common in these phenotypes is BMI and metabolic syndrome
  • Phenotype C (ovulatory PCOS) → BMI is often normal, but if BMI increases can alter phenotypic presentation
  • Phenotype D (normoandrogenic PCOS) includes chronic anovulation + PCOM but normal serum androgens and no HA
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11
Q

Anovulation (4)

A
  • Most women with PCOM probably have regular/almost regular cycles
  • Most women with PCOS and cycle problems have oligomenorrhoea
  • Main difference between ov and anov is also the level of IR - IR tps them into Anov
  • Adult rhesus macaques fed western style diet (high fat/sugar) & exposed to chronically elevated T from pre-puberty to menopause altered small AF no.’s, morphology and transcriptome
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12
Q

What are the candidates for follicle arrest? (4)

A

– androgens
– intra-follicular inhibitors eg AMH
– defect in apoptosis (follicles that don’t shrink + die)
– dysregulated gonadotrophin secretion (both FSH and LH)

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13
Q

Prevalence of PCO (9)

A

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%

Numerous studies since on prevalence:
– PCOM approx. 20%
– PCOS 5-10% depending on definition

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14
Q

PCOS prevalence across populations (4)

A
  • PCOS presentation in European pop differs from US pop
  • US: variability seen between Hispanic , African-American + White pop.’s
  • East Asian population w/ PCOS have ↓ BMI + hirsutism compared to other population
  • South Asian populations have greater IR ; metabolic sequelae and obesity cf to other populations
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15
Q

Aetiology- genetics (8)

A
  • 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
  • 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)
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16
Q

The Chinese Studies (4)

A
  • 1st Genome-wide association study (GWAS) identified causative
    genes in Han Chinese women (2011)
    – 744 women with PCOS & 895 controls
  • 3 loci linked and candidate genes within these loci are: (Important in aetiology of PCOS regardless of ethnicity)
    – LHCGR
    – FSHR
    – THADA…linked to T2D
    – DENND1A …linked with obesity
  • (October 2014) GWAS confirmed variants in DENND1A, THADA, FSHR &
    INSR were associated w/ PCOS in Europeans
  • Confirming the biological relevance of PCOS-associated variants by molecular analysis (e.g. expression analysis, targeted genetic disruption in cell culture or organism) is critical to confirming findings from GWAS – rarely done.
17
Q

Forced expression of DENND1A.V2 in normal theca cells results in
augmented androgen and progestin production (3)

A
  • Theca cells were transfected with DENND1A isoform and treated
    with/without forskolin (to stimulate cAMP)
  • Measured production of various androgens and progestegins

= DENND1A.V2 overexpression recreated(recapitulated) hyperandrogenic theca cell function (that women w/xs androgen gene have)

18
Q

PCOS & Gonadotrophins I - LH:FSH(6)

A

Consistent feature of PCOS is disordered gonadotrophin sec. = downstream ovarian consequences:
– Elevated/upper-normal mean LH
– Low/low-normal FSH
(basically generally see an altered ration of LH:FSH)
– Rapid GnRH frequency → favouring rapid LH pulse secretion

study: 24h LH pulse profiles from control lean and obese women (blue) and lean and obese PCOS women (red).

= Clearly showing increased LH measurements that reflect an increase in LH pulse frequency & amplitude irrespective of body weight (=inherent)

19
Q

Why does dysregulated gonadotrophin secretion occur? (4)

A

Impaired negative regulation of GnRH pulse generator because: High T impairs -ve feedback by Proges. in presence of E2

– Proof: block Ar with flutamide → proges. then able to↓ LH & FSH (reinstate function)

– Also see that in late puberty girls without HA respond to proges. w/↓LH pulse frequency overnight, which did not occur in HA girls at same pubertal stage

20
Q

LH levels in PCOS- graph result

A

The higher LH will drive thecal cell hyperplasia and the hyper-androgenemia, but HA is also intrinsic and can be independent of LH.

21
Q

Increased androgens in PCOS (5)

A

– Most consistent biochemical abnormality w/PCOS: hypersecretion of androgens
– ideal to measure free (T) i.e. SHBG and total testosterone to work out free T
– anov> ov>normal
– increased androgen production by the ovary, even in ovPCO
– Increased LH leads to increased androgen production

22
Q

Clinical HA signs (2)

A

– Androgenic alopecia, hirsutism (excess terminal hair) & acne
– consistently reported as most distressing symptoms in
women

23
Q

testosterone levels & symptoms (6)

A

normal: 0.5-2.0nmol/L
PCO: higher
Anov: even higher
Anov H: even higher than higher
= increasing T w/ increasing severity of symptoms

≥ 7nmol/L then need to screen for androgen-producing tumour

24
Q

Explain the MoA of Androgens + hirsutism (4)

A
  • Testosterone converted to DHT at hair follicle
  • DHT more potent androgen
  • 5a-reductase may be higher in PCOS
  • Not just absolute levels of testosterone but the sensitivity to AR – see this with acne
25
Q

Where is all of this excess androgen coming from? - and how do you test it? (3)

A

In women with PCOS – main source of androgens is from the ovary(theca cells) + adrenal gland

Test w/ Dexamethasone: suppress adrenal gland ,still high androgens = coming from ovary, if reduced = adrenal gland

in women w/ PCOS: main source = OVARY

diagram

26
Q

steroid production by theca (6)

A

Measuring Adione + proges. levels - normal vs PCOS: both had higher levels w/PCOS

look at these because its the same pathway (all levels of androgens are higher in theca) = Intrinsic dysfunction in theca cells (CYP17):
* Stable phenotype of PCOS theca
* CYP17 promoter is more active
* CYP17 mRNA degrades more slowly

27
Q

Oestradiol in PCOS?

A

There is not a big increase, assumed because there is no increase in aromatase + levels of androgen r’s are not upreg. = no binding.

28
Q

Due to ↑in number of arrested follicles will see a slight ↑E2 but not DF levels
in spite of ↑T – why? (2)

A
  • Levels of AR may not be increased in GC, hence cannot bind excess T
  • No massive increase in aromatase levels
29
Q

what is Insulin is co-gonadotrophin with and what is the triple whammy? Also explain secondary PCOS due to T1D. (5)

A

LH

1) women w/ PCOS have hyper-androgenemia because of inherent problem of making xs androgens

2) also have xs androgen because of high LH

3)Hyperinsulinemia will also augement hyper-androgenemia via cross talk on pathways

Women with T1D have to take exogenous insulin → often develop HI → leads to HA → develop secondary PCOS

30
Q

What causes the change in morphology in PCOS?

A

Increased follicle activation and recruitment but growth of follicles arrested before they mature

31
Q

Morphology Studies explained - 3 studies (11)

A
  • 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
    – 6X more primary follicles in PCOS
    – no significant increase in primordials
  • Maciel GA et al, (2004)…JCEM
    – Counted follicles in sections
    – ‘stockpiling’ of primary follicles in PCOS

Increased follicle activation and recruitment but growth of follicles arrested before they mature

32
Q

What might cause increased numbers of follicles? (9)

A
  • Androgens seem likely candidate for increasing follicle numbers early in folliculogenesis:
    – 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
  • Increased numbers at the primary stage persist to antral stages?
    — Low/normal FSH:LH ratio reduce normal maturation
    — Lower rate of atresia
  • Intra-ovarian factors involving follicular recruitment & growth also contribute
    ― AMH & others TGF-β superfamily members
    ― AMH production high from granulosa cells of PCO(Pellat et al (2009) JCEM)
    ― Reflected in AMH serum levels which 2-3x higher in PCO cf normal
33
Q

Excess foetal T (exposure of female animals to elevated
androgens in utero studies): (4)

A

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 HA have similar pattern of rapid LH pulse secretion before menarche
– Obesity in pubertal girls also alters LH pulses
– Pregnant women with PCOS? Maternal T is raised but is foetus
exposed?

» High levels of SHBG & aromatase activity in placenta, prevent maternal T crossing over, so a female foetus is not androgenised

» Maybe excess secretion coming from foetus itself?

34
Q

Androgens & Hypothesis of PCOS origin - AMH in-utero (7)

A

Exposure of developing hypo. to XS androgen before final programming of steroid feedback + other regulatory mechanisms alters GnRH pulsatility + feedback

  • XS AMH in utero may affect development of female foetus
  • This AMH 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

Proof: Treated pregnant mice with AMH → altered neuroendocrine phenotype (affects GnRH neurones) of female offspring and induced PCOS-like phenotype

35
Q

PCO - summary (5)

A
  • Polycystic ovaries are genetically acquired + 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

Science of Repro (32 decks)

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