PCOS Flashcards
(39 cards)
Rotterdam criteria
- Irregular menstrual cycles
- PCO appearance to ovaries on USS
- Clinical or biochemical signs of hyperandrogenism
Need two of three for diagnosis + exclusion of other causes
Differentials for PCOS
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)
Definition of irregular cycles and ovulatory dysfunction
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
Diagnosing PCOS in adolescents
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.
Biochemical and clinical hyperandrogenism (HA)
- 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.
Ultrasound features of PCOM
- FNPO (follicle number per ovary) is the most effective USS marker to detect PCOM in adults
- > /= 20, 2-9mm follicles, in one ovary threshold for dx in adults on TVUSS.
- 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.
Factors that affect AMH result
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.
What is AMH
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.
AMH and PCOS
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.
Diagnosis of IGT in PCOS
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.
PCOS and endometrial hyperplasia.
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.
PCOS and associated health problems
T2DM and IGT (++–)
Cardiovascular disease and mortality (+—)
OSA (+++-)
Endometrial hyperplasia (+—-)
Moderate to severe depression (++++)
Moderate to severe anxiety symptoms and disorders (++++)
Eating disorders (++–)
Lifestyle, diet and exercise
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
What drives weight gain risk in PCOS
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
COCP and effect on diagnosis of PCOS
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
Pharmocological management (not fertility desiring)
COCP and PCOS
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 (+—)
Metformin and PCOS
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. (++–)
Anti-obesity pharmacological agents
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)
Research supporting anti-obesity agents in PCOS
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.
GLP-1 RA - MoA in weight loss
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
evidence to support
SS weight loss over placebo for both liraglutide and semaglutide.
Semaglutide better.
Seems weight regain occurs with discontinuation of the medication.
Other metabolic medications
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.
Myo-inositol in PCOS
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”
