PCOS Treatment Flashcards
How is IR different to Type 2 diabetes (aka pre-diabetes)? (2)
circulating insulin levels increase to compensate = hyper-insulinaemia for IR (basically tolerance for IR) - so glucose levels low at first but as IR inc. so does glucose (hyperglycaemia)
T2D has prog. so no response to insulin or no insulin made
IR in PCOS driven by adiposity-facts (5)
- USA – obesity affects 80% of women with PCOS & in rest of world
50% - Women with PCOS have central adiposity, which is linked to IR
- May NOT due to higher relative percentage of visceral fat
- In animals exposure to androgens is associated with increased fat
accumulation - Treatment with high androgens in female-to-male transsexuals inc. visceral fat accumulation
Insulin sensitivity in relation to weight compared to normal (2)
Although everyone becomes more IR w/ increasing weight »
insulin sensitivity declines at a faster rate in women with PCOS than in
women with normal ovaries with increasing weight
However, in some PCOS women IR is inherent and not driven by obesity
Molecular mechanism of IR in PCOS (5)
- insulin resistance is familial
– No mutations in insulin receptor gene found in PCOS
– Post-receptor binding defect somewhere in downstream signalling pathway/cascade
i.e. insulin binds to receptor = phosph. + triggers GLUT4 to send transporters vesicle = bind and allow entry of glucose into cell out of blood (something messed up in this pathway)
-inflammation + markers as result of obesity can interact + inhib. thsi pathway
Using OGTT to determine IGT (4)
- Oral glucose tolerance test to determine IGT
– Fasting 8-12h before test → glucose given as a solution → blood samples taken (0-2h) to determine how quickly cleared from blood
Normal: Fasting value (before test): <5.6 mM;
At 2 hours: between 6-7.8 mM
Impaired: Fasting value (before test): 6.0 -7.0 mM;
At 2 hours: 7.9-11.0 mM
Diabetic: Fasting value (before test): >7.0 mM;
At 2 hours: >11.0 mM
PCOS, IR, T2DM & GDM (5)
- Obesity exacerbates many aspects of PCOS clinical, hormonal and metabolic features in women
– If patient has oligomenorrhea & hyper-androgenism in adolescence then increased risk of developing obesity & MetS by 24y - 30-40% women with PCOS have impaired glucose tolerance (IGT) and 10% develop T2DM by age 40yrs
- Higher incidence of T2DM in women with family history i.e. Indian sub-continent Asians
- Obesity & insulin resistance results in – increased incidence of GDM
Why would Gestational Diabetes Mellitus (GDM) present first in pregnancy? (6)
1)Placenta produces E, cortisol & human placental lactogen
↓
2)HPl interferes with insulin receptors
↓
3)Maternal Hyperglycemia
↓
4)Increased glucose in maternal circulation crosses to foetal circulation
↓
5)Increase in fetal insulin
↓
6)Excess fetal growth – large for gestational age
Complications of GDM for mother & fetus (4)
- probelms in labour + delivery: shoulders get stuck
-premature delivery
-preeclampsia
-birth weight > 90 percentile
IR also linked to anovulation - graph
increase in Insulin = decrease in no. of menstrual cycles
not obese women get IR - so despite IR + weight being linked, it is not causal
Other manifestations of metabolic defect in PCO - outcomes of longterm studies (risks) (5)
- tendency to obesity with increase in truncal-abdominal fat
- increased hypertension
- Altered lipid profile
– higher levels of LDL cholesterol – regardless of BMI
– low levels of HDL cholesterol and elevated triglycerides - apparent increased risk for atherosclerotic disease
– Increased coronary artery calcification (independent of age & BMI)
– Increased carotid artery intima-media thickness (predictor of stroke & MI)
compared to age-matched controls
– Limited longitudinal studies → PCOS diagnosed during reproductive lifespan
(20-30 years old) but CVD manifests 30 to 40 years later.
– Also majority of conducted research on CVD on male →concept that women
present differently - Recent study showed that women with PCOS at ↑risk of osteosarcopenia
Why do women with PCOS gain weight? (5)
-increased food production + availability
- androgens
- Constant tendency to gain weight:
– Normal-weight women with PCOS consistently maintain a lower-calorie diet than their over-weight counterparts
– HRQoL study in women with PCOS → normal-weight women experienced as many problems with their weight as obese women.
Are women with PCOS more inclined to put on weight or is it parallel to growing obesity epidemic? (2)
PCO is associated with reduced energy expenditure equivalent to over 17,000 kcal/pa - extra storing compared to others
+ due to Post- Prandial Thermogenesis (PPT)
PCOS and PPT (3)
PCOS is associated with reduced energy expenditure - by 1700 calories
* this is due to reduced post -prandial thermogenesis (PPT)
* it is amplified by obesity in PCOS
* Insulin sensitivity is reduced in both obese & lean women with PCOS compared to normal
PCOS and weight (3)
constant increase
1) young: look at skin
2) mid 20’s put on a lot of weight
3) want children - cannot and struggle to conceive
Sex Hormone Binding Globulin (SHBG) levels in PCO (6)
- Vast majority of testosterone is bound to SHBG.
- Small change in SHBG causes large change in free testosterone
- SHBG dependent on BMI ie obesity ↓SHBG & ↑free T
- SHBG production by liver is also inhibited by insulin
- # Insulin also stimulates ovarian androgen production (synergises with LH)Increase T
Summary - Long-term outcomes for women with PCOS
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Endocrine Society Clinical Guidelines for Treatment of PCOS
No “cure” – treatment is symptomatic
- Lifestyle intervention and weight loss improves overall PCOS status in overweight/obese patients along with other health benefits eg insulin resistance, CVD
- 1st line management for menstrual abnormalities and hirsutism/acne in PCOS are hormonal contraceptives (HC)
- 1st line therapy for infertility is Clomiphene
- Metformin is beneficial for metabolic/glycaemic abnormalities & for improving menstrual irregularities, but of limited benefit in treating hirsutism, acne or infertility
Lifestyle Interventions & Weight Loss
- First line treatment to improve insulin resistance
– diet and exercise - Kiddy: 24 women on very calorie-restricted diet (1000 calories)
- Target was to loose 5% of body weight
– Of the 13 who succeeded → 5/7 conceived
– 11 who didn’t → 1/8 conceived - Subsequent trials shown that if overweight/obese women with PCOS have 5-15% weight loss then significant improvement in following parameters
– Serum lipids
– Serum T and SHBG
– Glucose tolerance and fasting insulin
– Hirsutism
– Ovulation and menstrual cycle regularity
How would diet and exercise help?
Studies from Australia show diet is as successful as medical intervention
(Anne Clarke) but drop-out rate high » requires support system and frequent
attendance and exercise programme
Use weight loss drugs?
Orlistat (lipase inhibitors)…reduces uptake of fat from bowel and
increases it in stools – side effects of anal leakage
For morbidly obese (BMI>40) bariatric surgery (4)
Meta-analysis of 2130 women who had bariatric surgery:
» 46% identified as having PCOS pre-op → dropped to 7% one year post-op (p<0.001)
» Incidence of hirsutism pre-op was 67% & dropped to 39% one year post-op (p=0.03)
» Menstrual irregularity was 56% pre-op and dropped to 8% one year post-op
» Pre-op fertility was 18% and post-op was 43%
metformin MoA- Good for PCOS? (5)
Diabetes drugs
* Metformin is a biguanide (insulin sensitiser)
* Decreases hepatic glucose production therefore less in serum
* Enhances glucose uptake into muscle
* Increases oxidation by adipose tissue
for IR not PCOS - so need PCOS w/IR
Treatment of PCO…metformin (6)
Recent recommendations for use of metformin in women with
PCOS who have T2DM or IGT who fail lifestyle interventions
* Improvement in ovulation rates on metformin (Tang et al, Cochrane
Review (2012); Endocrine Society Clinical Practise Guideline for PCOS)
* Metformin is 2nd-line treatment for women with PCOS who have
menstrual irregularities and cannot tolerate HC
* Adjust dose for different body weights
* Metformin maybe of use to treat gestational diabetes
* Recommended for use in adolescents with PCOS
HC Treatment – Menstrual Irregularity- to limit endometrial hyperplasia (+cancers) (8)
irregular cycles i.e. oligo/amenorrhoea
– unlike many women with amenorrhoea, women with PCO are well-oestrogenised
– Aim for minimum of 4 ovulations per year to avoid
endometrial hyperplasia
– HC pill first line treatment for menstrual abnormalities:
* Important to limit endometrial hyperplasia and menorrhagia
* Increased risk of endometrial CA with prolonged amenorrhoea in
PCOS as well-oestrogenised
* Progestins in HCs suppress LH levels and hence ovarian androgen
production
* Avoid androgenic progestogens
* Risk…appetite stimulant so need advice regarding weight gain
