Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Year 3- Repro > Introduction to PCOS > Flashcards

Introduction to PCOS Flashcards

1
Q

Why is it important to learn about PCOS?

A

Arguably the most prevalent medical condition in women

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Patients with PCOS have systemic metabolic manifestations with multiple symptomatology, some of these are:

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q
A

Insulin resistance (IR) likely to have a life-long impact on patient.
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 recently calculated to be $4.36 billion and 40% of this was IR/T2D-related

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the physical signs of polycystic ovaries?

A

The ovary contains increased numbers (>20) of small antral follicles (2-9mm) visible on high quality transvaginal u/s transducers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Disorder of follicle growth at all stages

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

The main problem with PCOS is that there is a …

A

Disorder of follicle growth occurs across all stages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is displayed on an ultrasound in PCO?

A

Not cysts but follicles that have stopped growing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What was PCOS originally described as?

A

First described in 1935 by Stein and Leventhal -
syndrome described as obesity, hirsutism and anovulation in the presence of bilaterally enlarged sclerocystic ovaries.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How might have PCOS been originally found?

A

Through biopsies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Changes in diagnosing PCOS now

A

Discovered that many women have the change in the ovaries and do not necessarily have the symptoms
Spectrum of presentation has led to lack of consensus regarding the definition

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Diagnosis of exclusion i.e. disorders that mimic PCOS include:

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

sclero-cystic=

A

Sclero-cystic = hardened or stiff

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Inital PCOS diagnosis (extra)

A

Initially diagnosis by laparotomy and visually examination – no ultrasound or laparascopes, now diagnosed routinely by U/S (since 1980s).
Ovarian hyperthecosis – excess androgen production due to nests of luteinized theca cells scattered throughout ovarian stroma. Ovary slightly enlarged but devoid of antral follicles – hence distinct from PCOS. Serum testo levels>women with PCOS but <from androgen-secreting tumours.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the Rotterdam Criteria?

A

According to the Rotterdam consensus, polycystic ovarian syndrome (PCOS) is defined by the presence of two of three of the criteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the 3 possible criteria for diagnosing PCOS according to the Rotterdam criteria?

A

1) Polycystic ovaries (20 or more follicles measuring 2-9mm diameter and/or increased ovarian volume >10ml in either ovary & no DF >10mm)

2) Ovulatory Dysfunction (Oligomenorrhea/anovulation)

3) Hyper-androgenism (clinical/biochemical evidence)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How are polycystic ovaries diagnosed?

A

Technique and equipment dependent. T/V imaging not always appropriate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How is an ovulatory dysfunction diagnosed?

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How is hyper-androgenism diagnosed?

A

Assays not standardized across labs; normative data not clearly defined; clinical hyperandrogenism difficult to quantify; ethnicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What does Clinical hyperandrogenism include?

A

hirsutism, acne, or male pattern alopecia or biochemical signs of hyperandrogenism i.e. elevated levels of total or free testosterone.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is anovulation?

A

Anovulation is either frequent bleeding at intervals <21d or infrequent bleeding at intervals of >35d.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q
A

Normal ovulation is hard to define – mid-luteal Progesterone <3-4ng/ml indicates oligo-anovulatory. Chang et al reported that 16% of 316 women with PCOS had normal-appearing cycles, despite having oligo-anovulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What does a normal ovary look like?

A

≤5 follicles in an ovary with a small amount of stroma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What does an anovulatory PCO look like?

A

≥ 20 follicles, 2-9mm diameter arranged peripherally around an enlarged core of dense stroma - ovarian volume >10mls, with NO dominant follicle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What does an ovulatory PCO look like?

A

Dominant follicle persists

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Describe the refinement of PCOS diagnostic criteria and phenotypes
Still have 3 diagnostic criteria but with 4 phenotypes (A, B, C and D): Phenotype A: Hyperandrogenism, Ovulatory Dysfunction and PCOM Phenotype B: Hyperandrogenism and Ovulatory Dysfunction Phenotype C: Hyperandrogenism and PCOM Phenotype D: Ovulatory Dusfunction and PCOM
26
Significance of Phenotypes
Phenotypes A&B are considered classic PCOS → (2/3 of cases) and 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 and PCOM but normal serum androgens and no HA
27
Characteristic of anovulatory PCO?
No period for 6 months but you can see a CL and CA – so she had ovulated at some stage. Also see the ring of follicles and dense stroma and white thick tunica – so laparascopically would appear like a shiny ovary.
28
Characteristic of ovulatory PCO?
Dissected the stroma to show the DF, which is so large it pushes everything out of the way.
29
Most women with PCOM probably have regular or almost regular cycles Most women with PCOS and cycle problems have oligomenorrhoea
30
There are a number of candidates for follicle arrest, they include:
androgens, intra-follicular inhibitors eg AMH defect in apoptosis dysregulated gonadotrophin secretion (both FSH and LH)
31
What is the main difference between ovulatory and anovulatory PCO?
Main difference between ov and anov is also the level of insulin resistance. Adult rhesus macaques fed a western style diet (high fat/sugar) & exposed to chronically elevated T from pre-puberty to menopause altered small AF numbers, morphology and transcriptome (Bishop CV et al, 2015, Fertil.Steril.)
32
Prevalence of PCOS
32% of patients with amenorrhoea 87% with oligomenorrhoea 87% with hirsutism and regular cycles 75% of bulimics? [secretly binge — eating large amounts of food with a loss of control over the eating — and then purge, trying to get rid of the extra calories in an unhealthy way] 22% of ‘normal’ population
32
Prevalence of PCOS
32% of patients with amenorrhoea 87% with oligomenorrhoea 87% with hirsutism and regular cycles 75% of bulimics? [secretly binge — eating large amounts of food with a loss of control over the eating — and then purge, trying to get rid of the extra calories in an unhealthy way] 22% of ‘normal’ population
33
Most common cause of anovulatory infertility
PCOS (735)
34
Numerous studies since on prevalence:
PCOM approx. 20% PCOS 5-10% depending on definition
35
Does PCOS presentation in European population differ from the US population?
Yes
36
Prevalence within the US
Within US – variability seen between Hispanic , African-American and White populations
37
Prevalence in East Asian Population
East Asian population with PCOS have ↓ BMI and hirsutism compared to other population
38
Prevalence in South Asian populations
South Asian populations have greater insulin resistance; metabolic sequelae and obesity cf to other populations
39
Familial aggregation (aetiology of PCOS)
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
40
Aetiology in twins
Monozygotic twins twice as likely to both have PCOS than dizygotic.
41
common finding of raised androgen led to belief that PCOS is caused by an inherited disorder -most likely in the steroid biosynthetic pathway
42
Many candidate genes were investigated: all ‘obvious’ ones ruled out Complex polygenic disease – involves subtle interaction with environmental factors (intra- & extra-uterine)
43
Why does PCOS definitely run in families?
Because of hyperandrogenimia thought that gene in biosynthetic pathway for androgens was responsible.
44
What are monozygotic twins?
Identical twins coming form the same embryo
45
What did the 1st GWAS identify in the chinese studies?
1st Genome-wide association study (GWAS) identified causative genes in Han Chinese women (2011) 744 women with PCOS & 895 controls
46
What were the genes and loci found in chinese studies?
3 loci linked and candidate genes within these loci were: LHCGR FSHR THADA….linked to T2D DENND1A ...linked with obesity
47
Genes important in aetiology of PCOS regardless of ethnicity were:
THADA.... linked to T2D DENND1A... linked with obesity
48
(October 2014) GWAS confirmed variants in DENND1A, THADA, FSHR & INSR were associated with PCOS in Europeans (Brower et al (2014) JCEM) 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.
49
Forced expression of DENND1A.V2 in normal theca cells results in augmented androgen and progestin production.
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 recapitulated hyperandrogenic theca cell function (women with variations of the gene produced increased androgens related to PCOS?)
50
Significance of cAMP in the study
secondary messenger for LH and FSH
51
Consistent feature of PCOS is
disordered gonadotrophin secretion leading to downstream ovarian consequences
52
(Elevated/upper-normal mean LH Low/low-normal FSH)- (ALTERED RATION LH: FSH) Rapid GnRH frequency → favouring rapid LH pulse secretion
53
(Refer to Graph on Intro to PCOS lecture- slide 20)
Example of 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
54
Why does dysregulated gonadotrophin secretion occur?
Impaired negative regulation of GnRH pulse generator
55
Describe the Impaired negative regulation of GnRH pulse generator
High Testosterone impairs negative feedback by Progesterone in presence of oestradiol Proof: block AR with flutamide → progesterone then able to↓ LH & FSH Also see that in late puberty girls without HA respond to progesterone with ↓LH pulse frequency o/n, which did not occur in HA girls at same pubertal stage
56
LH levels in PCOS
The higher LH will drive thecal cell hyperplasia and the hyper-androgenemia, but HA is also intrinsic and can be independent of LH.
57
What does a high LH level in PCO+OC Pill women indicate?
GnRH does not respond to negative fedback from oral contraceptive
58
What happens to androgens in PCOS
Increased androgen
59
Androgens in PCOS
Most consistent biochemical abnormality in women with PCOS is 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
60
Clinical HA signs include:
Androgenic alopecia, hirsutism (excess terminal hair) & acne consistently reported as most distressing symptoms in women
61
Testosterone levels in response to increased severity of symptoms
Increases (≥ 7nmol/L then need to screen for androgen-producing tumour)
62
How is Hirsutism caused in 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
63
Where is all of this excess androgens coming from?
Either ovaries or adrenals
64
How do we test if excess androgens are coming from the adrenals rather than the ?
- Dexamethasone- supresses ACTH Suppress ovary with GnRH analogues and measure adrenal androgens. Then stimulate adrenals with synacthen and measure cortical and 17-OHP. If >33 then has CAH.
65
In normal women the adrenal glands and ovaries secrete androgens in response to ACTH and LH respectively. Approximately half the androgen production stems from direct secretion and half from peripheral conversion by enzymes in skin, liver and adipose tissue. In women with PCOS the ovary is main source of androgen, though adrenals do contribute in about 30-50% of women
66
Theca grown in vitro and steroids measured. Be aware that it’s a log scale. Androstenedione is the main androgen from ovary and not testo. Comparing the androgen output/1000 theca cells from normal nad PCOS. Remember it’s not just androgens that are higher but also progesterone – why are we measuring prog in relation to androgens?
Steroid conversion (progesterones are converted to androgens)
67
Due to ↑in number of arrested follicles will see a slight ↑E2 but not DF levels in spite of ↑T – why?
Levels of AR may not be increased in GC, hence cannot bind excess T No massive increase in aromatase levels
68
Reason for more androgens and progesterones
Stable phenotype of PCOS theca CYP17 promoter is more active CYP17 mRNA degrades more slowly
69
Insulin is co-gonadotrophin with LH » hyperinsulinemia will augment hyper-androgenemia via cross talk on pathways
70
T1D and PCOS
Women with T1D have to take exogenous insulin → often develop HI → leads to HyperAndrogenism → develop secondary PCOS
71
What causes the change in morphology?
72
At what stage do the follicles increase in number?
73
Hughesden 1982 findings:
Increased follicle activation and recruitment but growth of follicles arrested before they mature counted follicle numbers in sections from 17 PCOs and 17 normal ovaries found 2x all of the growing stages in PCO
74
Webber et al (2003)..Lancet findings:
counted follicles in biopsies six times more primary follicles no significant increase in primordials
75
Maciel GA et al, (2004)…JCEM findings:
Counted follicles in sections ‘stockpiling’ of primary follicles
76
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
77
Increased numbers at the primary stage persist to antral stages?
Low/normal FSH:LH ratio reduce normal maturation Lower rate of atresia
78
Intra-ovarian factors involving follicular recruitment & growth also contribute
AMH & others TGF-β superfamily members AMH production high from granulosa cells of PCO Reflected in AMH serum levels which 2-3x higher in PCO cf normal
79
Excess foetal T (exposure of female animals to elevated androgens in 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 HyperAndrogenism 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 fetus 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?
80
Androgens & Hypothesis of PCOS origin
Exposure of developing hypothalamus to excess androgen before final programming of steroid feedback and other regulatory mechanisms alters GnRH pulsatility and feedback
81
AMH & Hypothesis of PCOS origin
Excess 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 Treated pregnant mice with AMH → altered neuroendocrine phenotype (affects GnRH neurones) of female offspring and induced PCOS-like phenotype
82
Where does AMH come from?
Granulosa cells of large pre-antral follicles
83
Give a brief summary of PCO
Excess 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 Treated pregnant mice with AMH → altered neuroendocrine phenotype (affects GnRH neurones) of female offspring and induced PCOS-like phenotype

Year 3- Repro (34 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions