PCOS

Question 1

Rotterdam criteria

Answer 1

1. Irregular menstrual cycles
2. PCO appearance to ovaries on USS
3. Clinical or biochemical signs of hyperandrogenism

Need two of three for diagnosis + exclusion of other causes

Question 2

Differentials for PCOS

Answer 2

Hyperandrogenism:
1. Non-classical CAH
2. Cushing’s disease (midnight cortisol level)
3. Androgen secreting tumour (adrenal or ovarian in origin) - vey high androgen/rapid symptoms onset
Also need to consider exogenous steroids.

Irregular menstrual cycles:
1. Hypo/hyperthyroidism (TSH)
2. Elevated prolactin (PRL)
3. Hypo hypog (FSH, LH and E2)
4. Hyper hypog - POI (FSH, AMH, then additional testing as needed)

Question 3

Definition of irregular cycles and ovulatory dysfunction

Answer 3

Irregular menstrual cycles are defined as:
Normal in the first year post menarche as part of the pubertal transition
> 1 to < 3 years post menarche: < 21 or > 45 days
> 3 years post menarche to perimenopause: < 21 or > 35 days or < 8 cycles per year or if > 1 year post menarche > 90 days for any one cycle
Primary amenorrhea by age 15 or > 3 years post thelarche (breast development)
When irregular menstrual cycles are present a diagnosis of PCOS should be considered and assessed according to these PCOS Guidelines

Question 4

Diagnosing PCOS in adolescents

Answer 4

For adolescents who have features of PCOS, but do not meet diagnostic criteria,
an ‘increased risk’ could be considered and reassessment advised at or before full
reproductive maturity, 8 years post menarche.
- PCOM on USS normal in adolescents.
- Irregular cycles normal in adolescents -Normal in the first year post menarche as part of the pubertal transition > 1 to < 3 years post menarche: < 21 or > 45 days
- Acne common in teenagers so can make HA assessment challenging.

Question 5

Biochemical and clinical hyperandrogenism (HA)

Answer 5

• should use total and free testosterone to assess biochem HA.
• T measured with highly accurate tandem mass spectometry. FAI can be used for free testosterone (need total T and SHBG)
• If total and free T are normal could test DHEAS and androstenedione.
• biochemical best utilised with no clinical symptoms of HA.
• Hirsuitism alone considered diagnostic of HA (modified Ferriman Gallwey score of 4-6)
• Female pattern hairloss and acne are relatively weak predictors of biochem HA
• issue with biochem assays is that they aren’t sensitive enough to detect HA in females, better at male range testosterone measurement.

Question 6

Ultrasound features of PCOM

Answer 6

1. FNPO (follicle number per ovary) is the most effective USS marker to detect PCOM in adults
2. > /= 20, 2-9mm follicles, in one ovary threshold for dx in adults on TVUSS.
3. FNPS (follicle number per section) >/= 10 and ovarian volume (OV) >/= 10mls also accurate markers in adults and these should be used for diagnosis over FNPO if TAUSS.

Question 7

Factors that affect AMH result

Answer 7

age: Serum AMH generally peaks between the ages of 20-25 years in the general population
body mass index (BMI): Serum AMH is lower in those with higher BMI in the general population
hormonal contraception and ovarian surgery: Serum AMH may be suppressed by current or recent COCP use
menstrual cycle day: Serum AMH may vary across the menstrual cycle.

Question 8

What is AMH

Answer 8

Anti-Mullerian hormone
Polypeptide of the transforming growth factor beta (TGF-B) family.
Solely secreted by the granulosa cells of preantral and small antral follicles.

Question 9

AMH and PCOS

Answer 9

Higher in those with PCOS.
Strong correlation between circulating AMH levels and antral follicle count on USS in PCOS.
Recommendations in Monash guideline:
Could be used for defining PCOM in adults, but only in accordance with the diagnostic algorithm.
Shouldn’t be used as a single test to define PCOS.
Shouldn’t yet be used as a diagnostic test in adolescents.

Probelm is that there is no agreed upon cut-off.

Question 10

Diagnosis of IGT in PCOS

Answer 10

Gold standard is OGTT 75g.
Second line - fasting plasma glucose or HbA1c (noting significantly reduced accuracy)
Above are very low quality evidence recommendations
In pregnancy OGTT offered at booking if not done pre-pregnancy and then at 24-28 weeks.
Insulin resistence pathophysiological factor however insulin assays are of limited clinical relevance and not recommended in routine care.

Question 11

PCOS and endometrial hyperplasia.

Answer 11

Premenopausal women with PCOS have markedly higher risk of developing endometrial hyperplasia and endometrial cancer.
Overall chance of developing endometrial cancer is low, therefore routine screening is not recommended.
Long-standing untreated amenorrhea, higher weight, type 2 diabetes and persistent thickened endometrium are additional to PCOS as risk factors for endometrial hyperplasia and endometrial cancer.

Question 12

PCOS and associated health problems

Answer 12

T2DM and IGT (++–)
Cardiovascular disease and mortality (+—)
OSA (+++-)
Endometrial hyperplasia (+—-)
Moderate to severe depression (++++)
Moderate to severe anxiety symptoms and disorders (++++)
Eating disorders (++–)

Question 13

Lifestyle, diet and exercise

Answer 13

Lifestyle intervention (exercise alone or multicomponent diet combined with exercise and behavioural strategies) should be recommended for all women with PCOS, for improving metabolic health including central adiposity and lipid profile. (+—)
Lack of evidence to support one type of diet over another (+—)
Lack of evidence to support one type and intensity of exercise over another (+—)
- adolescents 60mins per day
- 250min/week of moderate-intensity of 150min/week of vigorous intensity exercise

Question 14

What drives weight gain risk in PCOS

Answer 14

There is very low quality evidence that women with PCOS may have some differences in lifestyle behaviours (higher total dietary fat intake and lower physical activity on self-report) and may have some differences in appetite related hormones after a mixed meal tolerance test (MMTT). There is no evidence of certainty for other outcomes including energy
intake (on pooled analysis), other macronutrients (carbohydrate, protein), glycaemic index, glycaemic load, subjective hunger or satiety, meal induced thermogenesis or resting energy expenditure. Most outcomes are selfreported and prone to recall bias and misreporting.
It is acknowledged that women with PCOS have higher rates of weight gain and excess weight; however, the mechanisms contributing to this are not well understood

Question 15

COCP and effect on diagnosis of PCOS

Answer 15

Should be off COCP for 3/12 for accurate diagnosis of PCOS.
Obviously will mask irregular menstrual cycles.
Suppresses HA (reduces acne and hirsuitism).
COCP increases liver synthesis of SHBG and reduces gonadotrophin dependent androgen production

Question 16

Pharmocological management (not fertility desiring)

Answer 16

Question 17

COCP and PCOS

Answer 17

COCP first line for management of hirsutism and irregular cycles (+—)
COCP first line in adolescents at risk or with a confirmed diagnosis (+—)
No clinical advantage in 30mcg vs 20mcg ethinylestradiol for hirsutism (+—)
35mcg ethinylestradiol with cyproterone acetate 2nd line balancing benefits and risks (increased VTE risk) (+—)
POP considered for endometrial protection (+—)

Question 18

Metformin and PCOS

Answer 18

Low cost, oral medication. Insulin sensitiser.
Insulin resistence present in 75% of lean PCOS and 95% of higher BMI PCOS.

Metformin alone should be considered in adults with PCOS and a BMI ≥ 25 kg/m2
for anthropometric, and metabolic outcomes including insulin resistance, glucose,
and lipid profiles.(+—)
Could be considered for cycle regulation in adolescents acknowledging limited evidence (+—)
COCP better agent than metformin for menstrual regularity and hirsuitism (+—)
Metformin better agent than COCP for metabolic indications (+—)
Combo of both offers little additional benefit over agents on their own in those with BMI <30 (+—)

Metformin in pregnancy has not been shown to prevent: (++–)
gestational diabetes
late miscarriage (12 weeks +1 day to 21 weeks +6 days gestational age)
hypertension in pregnancy
pre-eclampsia
macrosomia or birthweight ≥ 4000 g.

Metformin for infertility - can be used as an ovulation agent alone or in combination with clomiphene. If women are using as an ovulation agent should be aware that there are better options available. (++–)

Adjunct metformin therapy could be used before and/or during FSH ovarian
stimulation in women with PCOS undergoing IVF/ICSI treatment with GnRH agonist
long protocol, to reduce the risk of developing ovarian hyperstimulation syndrome
and miscarriage. (++–)

Question 19

Anti-obesity pharmacological agents

Answer 19

Anti-obesity medications including liraglutide, semaglutide, both glucagon-like peptide-1 receptor agonists (GLP-1 RA) and orlistat, could be considered, in addition to active lifestyle intervention, for the management of higher weight in adults with PCOS as per general population guidelines. (consensus recommendation rather than EBR)

Agents:
GLP-1 RA - semaglutide, liragultide - significant weight loss
Metformin – increased BMI and PCOS – may prevent further weight gain, not clearly associated with weight loss.
Orlistat – decreases the digestion and absorption of fats (FDA approved for weight management)
Phentermine-topiramate and Naltrexone-Bupropion work by suppressing appetite (FDA approved for weight management)

Question 20

Research supporting anti-obesity agents in PCOS

Answer 20

Anti-obesity pharmacological agents for PCOS: A systematic reivew and meta-analysis to inform the 2023 international evidence-based guideline. Obesity reviews. 2024

• Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included.
• On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes.
• Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone).
• no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02–0.17, I2 = 18%, 2 trials).
• Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: −8.65 pmol/L, −33.55 to 16.26, I2 = 67%, 2 trials).
• Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research.

MUST NOT USE IN PREGNANCY. IDEALLY STOP 1-3 MONTHS BEFORE FALLING PREGNANT.

Question 21

GLP-1 RA - MoA in weight loss

Answer 21

Incretin hormone produced by the L cells in the intestine in response to food intake.
50-70% of insulin secretion is in response to the release of incretins from the GI tract.
Incretin hormone – increases insulin secretion and decreases glucagon production (there-by lowering blood glucose levels)
Also – regulates appetite, lower glucose, increases satiety, slows GI transit.
GLP-1 receptors found throughout body, mainly in brain, GI tract and pancreas but in a lot of organs throughout the body.
GLP-1 receptor agonists include Liraglutide (Victoza/Saxenda) and Semaglutide (Ozempic)
Initially approved as glucose lowering medication in T2DM
Both found to induce weight loss T2DM
For those without T2DM also been proven to cause weight loss

Question 22

evidence to support

Answer 22

SS weight loss over placebo for both liraglutide and semaglutide.
Semaglutide better.
Seems weight regain occurs with discontinuation of the medication.

Question 23

Other metabolic medications

Answer 23

Gliptins (Dipeptidyl peptidase-4 DPP-4 inhibitors) - prevent breakdown into inactive form of GLP-1. More limited scope in those with PCOS.
Sodium-glucose co-transporter-2 inhibitors (SGLT-2) - found in kidney and reduces glucose reabsorption and increases urinary glucose excretion and reduction in plasma levels. Risk of hypos low. Role in PCOS is not well established those is well established in diabetes.

Question 24

Myo-inositol in PCOS

Answer 24

Inositol
Carbocylic sugar present in abundance in human and plant cells.
Different isomeric forms - myo (MI) and D-chiro (DCI) most common
Second messenger in insulin and FSH signalling.
Promotes glucose uptake and is also involved in FSH mediated pathways which regulate the proliferation and maturation of granulosa cells.
In the ovary - MI supports FSH signalling, and DCI is responsible for insulin-mediated testosterone synthesis.
Synthesised in liver and kidney and naturally present in legumes, cereal, corn and meat.

Inositol in any form alone, or in combination with other therapies, should be considered experimental therapy in women with PCOS with infertility, with benefits and risks currently too uncertain to recommend the use of these agents as fertility therapies. (+—)

Cochrane review on myo-inositol 2018 -
Evidence very low quality
Uncertain whether improves LBR, clinical pregnancy or reduces pregnancy loss
Used as adjuvant in both OI and IVF.

“There was a strong consumer voice on the need to inform women on the limited efficacy, poor quality evidence and concerns were raised around misinformation surrounding these products which was supported by GDG members, as well as consideration of costs. Conflicts of interest were also raised in this field of research,
alongside the need for high quality research in this area”

Question 25

Anti-androgens and PCOS

Answer 25

In combination with effective contraception, anti-androgens could be considered
to treat hirsutism in women with PCOS, if there is a suboptimal response after a
minimum of six months of COCP and/or cosmetic therapy. (+—)
Options:
- spironolactone at 25-100 mg/day appears to have lower risks of adverse effects
- cyproterone acetate at doses ≥ 10 mg is not advised due to an increased risk
including for meningioma
- finesteride has an increased risk of liver toxicity
- flutamide and bicalutamide have an increased risk of severe liver toxicity

If pregnancy occurs on this can cause male fetal amigious genitalia/undervirilisation due to androgen/testosterone essential role in internal and external genitalia embryogenesis.

Question 26

Bariatric surgery and PCOS

Answer 26

General population data is clear on the role of bariatric/metabolic surgery. In PCOS evidence is more limited.
A recent large single centre prospective cohort study was published in 993 women with PCOS showing dramatic improvement in hirsutism, menstrual irregularity and associated comorbidities [T2D (79.7%), hypertension (78.7%), sleep apnea (98.5%)] and symptoms of PCOS were statistically (p < 0.0001) reduced at follow-up.
Also showed decreased total and free T, increased SHBG, decreased toward normal AMH levels.
There was a high risk of bias and low certainty or evidence, but it was supported by existing literature in the general population and in PCOS. (2022 Obesity Surgery, study done in India)
Consensus Recommendations only in guideline.

Need stabilisation of weight loss before attempt at pregnancy, at least 12 months.

Question 27

Pregnancy outcomes and PCOS

Answer 27

Increased risk of:
Miscarriage
Preterm birth
SGA/IUGR
GDM
higher gestational weight gain
Hypertensive disorders of pregnancy and pre-eclampsia
caesarean section

PCOS on it’s own does not cause increased risk of macrosomia, LGA or instrumental deliveries.

Question 28

PCOS and fertility treatment flow chart

Answer 28

Question 29

Letrozole OI

Answer 29

EBR - Letrozole should be the first-line pharmacological treatment for ovulation induction in infertile anovulatory women with PCOS, with no other infertility factors. (++++) - cochrane review 11 trials 2060 participants.
PP - The use of letrozole is still off-label in many countries. Where it is not allowed, clinicians could use other ovulation induction agents.
PP - Letrozole should not be given where there is any possibility of a pre-existing
pregnancy, though there is no evidence for increased teratogenicity compared
to other ovulation induction agents.

Question 30

Clomiphene

Answer 30

Selective oestrogen receptor modulator with both oestrogenic and anti-oestrogenic effects. Has lower live birth rates than letrozole ?anti-oestrogenic effects on endometrium + cervical mucus.
If used as an OI agent metformin in conjuction can be recommended (++–)

Question 31

Gonadotrophins for OI

Answer 31

GT increases LBR compared to clomiphene (++–)
Either GT or Laparoscopic ovarian drilling could be used for those with clomiphene resistent anovulation. Higher LBR and higher MPR with GT (++–)
Where gonadotrophins are to be prescribed, the following should be considered:
-Cost of the intervention for ovulation induction.
-Expertise required for the use of the intervention for ovulation induction.
-The degree of intensive ultrasound monitoring that is required.
- A low dose step-up gonadotrophin protocol should be used to optimise the chance of monofollicular development.
- Implications of potential multiple pregnancy.

Question 32

Laparoscopic ovarian drilling (LOD) (evidence/recommendations)

Answer 32

LOD could be considered as a second line therapy for women with PCOS who are anovulatory and infertile, with CC resistence and no other infertility factors. (++–)
The justification for these recommendations considered all relevant comparisons, relative efficacy, single procedure, no monitoring, costs, side-effects and potential long-term considerations.
FSH was superior to LOD for live birth rates, yet higher rate of multiple pregnancies per patient were significant. Informed shared decision making can allow choice of second-line therapy based on patient preferences and priorities.

Ovarian drilling -
primary intervention - increased ovulation, reduced male hormones, doesn’t change metabolic parameters
CR PCOS - can be considered - LBR cf to gonadotrophin but also lower MPR.
Could consider prior to IVF to reduce OHSS rate

Question 33

Laparoscopic ovarian drilling (LOD) how it’s performed.

Answer 33

Consent - risks and benefits, alternative options - risks and benefits discussed
systematic assessement of pelvis
Isolate ovary
Ovary held with toothed grasper - one hold and lower risk of tearing and damage
Unipolar diathermy through central port
non touch, pure cut technique to penetrate cortex
Insertion of full length probe to medulla
4 seconds of pure cut full contact, deep energy delivery
Irrigation
Repeated 4-6 times dependent on the size of ovary
Some evidence that unilateral may be as beneficial as bilateral - less time, reduced complications

Complications:
Normal surgical complications
Adnexal adhesions

Question 34

IVF and PCOS

Answer 34

No RCTs comparing stimulated IVF/ICSI therapy with alternative
therapies including aromatase inhibitors, metformin, clomiphene citrate, gonadotrophins, ovarian surgery, IUI or no intervention, in women with PCOS.

CR - In the absence of an absolute indication for in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI), IVF could be offered in women with PCOS and anovulatory infertility, if first- or second-line ovulation induction therapies have failed.

Question 35

IVM maturation versus IVF for PCOS

Answer 35

The use of in vitro maturation (IVM) and ICSI could be considered in women with
PCOS, as an alternative to a stimulated IVF/ICSI cycle, where an embryo is frozen
and replaced in a subsequent embryo transfer cycle, acknowledging there is no
risk of ovarian hyperstimulation syndrome, but a lower cumulative live birth rate. (++–)

Answer 36

Question 37

Clomid/letrozole resistence
Clomid/letrozole failure

Answer 37

up to 150mg/7,5mg and unable to ovulate
Ovulating but not pregnant

Question 38

Network meta-analysis of OI in terms of best to worse for LBR in women with PCOS.

Answer 38

letrozole
FSH
Clomid + metformin
Clomid
Metformin
Placebo

Question 39

Pathophysiology of hyperandrogenism in PCOS

Answer 39

Hyperinsulinaemia important endocrine feature of PCOS causes:
Inc pit secretion of LH with inc Hx and amplitdue of LH pulses
Inc thecal cell production of androgens and dysregulation of thecal cells
Insulin bind to IGF-1 preventing occyte maturation
Insulin decreases SHBG and increases FAI

Adrenal production of androgens often increased with DHEAS and Androstenedione often elevated.

Peripheral aromitisation of androgens to oestrogens causes oestrogenic negative feedback on HPO axis resulting in decreased FSH sectreion and produce enough FSH to grow many antral follicles but not to cause recruitment and growth of one dominant follicle.