Treatment of PCOS Flashcards
What is the metabolic defect associated with polycystic ovaries
There is a metabolic defect associated with PCO
The central feature is insulin resistance (IR)
What is insulin resistance? (aka pre-diabetes)
IR = body is producing insulin but not able to use it effectively (i.e. muscle, fat and liver), hence in order to keep blood glucose in normal range beta-pancreatic cells produce more and more insulin – hyperinsulinemia
Pre-diabetes and T2D = develop hyperglycemia because glucose levels can not be maintained.
Average weight gain in UK with age is 0.5kg/year
circulating insulin levels increase to compensate = hyper-insulinaemia, so glucose glucose goes down but cannot be maintained, developing hyperglycaemia
Relationship between weight and insulin resistance
Although everyone becomes more insulin resistant with increasing weight » insulin sensitivity declines at a faster rate in women with PCOS than in women with normal ovaries with increasing weight
Average weight gain in UK with age = 0.5kg/year
Plot of insulin sensitivity against weight – direct correlation i.e. as you get heavier your insulin sensitivity decrease but in women with PCO it’s a more rapid decline i.e. at the same weight the IS in women with PCO is half that of women with normal ovaries
PCOS and obesity link
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 increases visceral fat accumulation
Molecular mechanism causing insulin resistance in PCOS
insulin resistance is familial
No mutations in insulin receptor gene found in PCOS
Post-receptor binding defect somewhere in signalling pathway in granulosa cells
PCO link with insulin resistance, Type 2 diabetes mellitus and gestational diabetes
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 it present first in pregnancy?
Describe the OGT (oral glucose tolerance) test to determine IGT (impaired glucose tolerance)
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): <6 mM;
At 2 hours: <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
How does gestational diabetes occur
lacenta produces E, cortisol & human placental lactogen
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HPl interferes with insulin receptors
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Maternal Hyperglycemia
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Increased glucose in maternal circulation crosses to foetal circulation
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Increase in fetal insulin
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Excess fetal growth – large for gestational age
Human placental lactogen interferes with insulin receptors, resulting in hyperglycemia i.e. fetus makes mum IR, resulting in hyperglycemia in maternal circulation. HPL drops after delivery.
Glucose travels freely from the mother to the foetus, but maternal insulin does not. Thus, maternal gestational diabetes exposes the foetus to higher concentrations of glucose than normal, which force the foetus to increase its own insulin production. Unfortunately, excess insulin produced by the foetus in response to the mother’s gestational diabetes can cause the foetus to grow excessively, a condition known as large for gestational age. For foetus they are large for age and low blood sugar and increased risk of childhood obesity.
Even if glucose goes back to normal after pregnancy, have an increased risk of T2D
If already IR and then pregnant, it induces increase in GDM risk, pre-eclampsia and later T2D.
Unpublished data from SGH, showed that nearly all women with GDM had PCO.
The oral glucose challenge test (OGCT) is a short version of the OGTT, used to check pregnant women for signs of gestational diabetes.[3][13] It can be done at any time of day, not on an empty stomach.[3] The test involves 50g of glucose, with a reading after one hour
There is a direct inverse relationship between hyperinsulinemia and ovulation rate.
Also we know that high insulin levels can have a detrimental effect on follicles
Describe some other manifestations of metabolic defects in PCO
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 sarcopenia
Why do women with PCOS tend to gain weight
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.
WHY? Are women with PCOS more inclined to put on weight or is it parallel to growing obesity epidemic?
PCO is associated with reduced energy expenditure equivalent to over 17,000 kcal/pa
PCOS and PPT (post-prandial thermogenesis)
PCOS is associated with reduced energy expenditure
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
the difference in PPT between normal and PCO is small if lean, but half if obese.
SHBG (serum hormone binding globulin) in PCO
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)
Putting it all together, in the lifespan of a woman with PCOS, the insulin levels initially rise exponentially with increasing weight, resulting in increasing IR. The increased insulin drives increasing androgens and also decreases SHBG – make hyperandrogenism worse. All increase’s anovulation. As age, then insulin struggling to keep pace with IR, results in glucose intolerance. If you conceive then will get GDM and in 40-50s will get T2D and CVD.
Lifestyle changes as treatment for 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
First line management for menstrual abnormalities and hirsutism/acne in PCOS are hormonal contraceptives (HC)
First 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
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 (Kiddy et al, 1992, Clin. Endocrinol. (Oxf) 36:105-11)
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 (Harrison CL et al, 2011, Hum. Reprod. Update 17:171-83)
Serum lipids
Serum T and SHBG
Glucose tolerance and fasting insulin
Hirsutism
Ovulation and menstrual cycle regularity
Obesity and PCOS
Weight loss notoriously hard to achieve
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
Treatment of IR In PCOS
Diabetes drugs such as metformin
Metformin is a biguanide (insulin sensitiser)
Decreases hepatic glucose production therefore less in serum
Enhances glucose uptake into muscle
Increases oxidation by adipose tissue
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
Treating menstrual irregularity
irregular cycles i.e. oligo/amenorrhoea
unlike many women with amenorrhoea, women with PCO are well-oestrogenised ………..why?
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
