Treatment of PCOS Flashcards
1
Q
What is the metabolic defect associated with PCO?
A
- The central feature is insulin resistance (IR) (aka pre-diabetes).
- Progresses from normal to impaired glucose tolerance to diabetes and then progression of diabetes.
- Average weight gain in UK with age is 0.5kg/year
- Insulin resistance does not form part of the Rotterdam criteria, but it is very much prevalent. Some of it could be in parallel just with increasing levels of obesity in worldwide populations, but some of it is intrinsic to PCO itself.
- After a meal, food enters the stomach and is digested so blood glucose increases. Insulin is released from the pancreas. It regulates blood glucose; taken up by muscles and organs (some is converted into glycogen). Blood glucose is very tightly controlled by insulin.
- During insulin resistance, insulin is released but body can’t use it effectively (resistant to the effects) to get rid of the blood glucose, so body produces more. Someone with insulin resistance requires more insulin to get rid of the blood glucose compared to someone without. Initially, they will have hyperinsulinaemia and glucose levels will be normal because the body is trying to maintain homeostasis (trying to keep its normal levels of glucose but needs more insulin to do so). Eventually, things will change.
- With IR, body is producing insulin but not able to use it effectively (i.e. muscle, fat and liver). To keep blood glucose in normal range, beta-pancreatic cells produce more and more insulin = hyperinsulinemia. Blood glucose is initially normal and insulin levels are high. In Pre-diabetes and T2D, patients develop hyperglycemia because glucose levels can not be maintained.
- Circulating levels of insulin initially increase to try and maintain euglycaemia (steady glucose levels). Then, it doesn’t work so well; the action is decreasing, and the glucose levels increase. Eventually, there is disruption, or the beta cells get fatigued and don’t produce more insulin (system is broken). This is when the patient converts and becomes diabetic.
2
Q
How does insulin insensitivity correlate to weight?
A
- 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 shows direct correlation, i.e. as weight increases, insulin sensitivity decreases, but it is a more rapid decline in women with PCO, i.e. at the same weight, the IS in women with PCO is half that of women with normal ovaries
- Women with PCO will have a lower insulin sensitivity than women with normal ovaries. Even though weight gain predisposes people to become insulin resistant, PCOS speeds up the whole process and makes it worse quickly.
3
Q
What is the link between PCOS and adiposity?
A
- In the USA, obesity affects 80% of women with PCOS & in rest of world 50% (Endocrine Reviews (2015) 36)
- Women with PCOS have central adiposity, which is linked to IR). Used to think it was more visceral fat (around the organs; more dangerous, produces inflammatory cytokines and inflammatory mediators). This was contradicted by some studies that used good scanning techniques to be able to measure this; literature is very contradicting. May NOT be due to higher relative percentage of visceral fat!
- In animals, exposure to androgens is associated with increased fat accumulation (Maliqueo et al (2013) Endocrinology 154:434-45). E.g. seen in macaque monkeys and sheep model.
- In transsexuals, when they have to be treated with androgens to induce masculinity in the female to male transsexual, it increases fat accumulation around the organs, so androgens are a contributing element. Treatment with high androgens in female-to-male transsexuals increases visceral fat accumulation.
4
Q
Outline the molecular mechanism of IR in PCOS.
A
- Insulin resistance is familial (within families = familial traits), but no mutations in insulin receptor gene has ever been found in PCOS.
- Therefore, it is likely to be a post-receptor binding defect somewhere in signalling pathway of granulosa cells.
- In general, systemic insulin resistance in the body, it is a defect in the signalling in the muscles, fat and in other tissues. This is why glucose is not taken up effectively. Even though insulin binds to its receptor on these tissues, it does not do the downstream signalling events properly to allow glucose to be taken up into the cell. For a long time, people thought the ovary was exempt from this because steroid output was normal. However, research suggests it is a post receptor binding defect; it maintains a steroid pathway, but it affects glucose metabolism.
- Thought to be a situation whereby insulin could bind to its receptor but in insulin resistance, this signalling pathway which allows for GLUT4, a vesicle that must be inserted into the membrane to allow glucose entry, has a defect somewhere along it.
- From a lot of other tissues, adipocytes and skeletal muscles, we know that in insulin resistance, as well as having a defect in this pathway which eventually results in glucose entering, macrophages and cytokines will contribute to it. Insulin resistance leads to a lot of inflammation, because the fat is associated with inflammation. A lot of those inflammatory markers also contribute to this dysregulation in the pathway (double whammy of effects).
5
Q
What are the effects if obesity on PCOS?
A
- Obesity exacerbates many aspects of PCOS (clinical, hormonal and metabolic features in women). This becomes part of the problem. Often, girls will have PCOS-like traits/be prone to it from adolescence, but they are not followed up or taken seriously (especially irregular periods). A lot of girls stop doing any form of exercise after entering puberty (due to becoming more body conscious); with traits of PCOS, the girls are more prone to putting on weight. Exponential increased risk.
- If patient has oligomenorrhea & hyper-androgenism in adolescence then increased risk of developing obesity & MetS by 24y
- These women are prone to problems by 24/25 years old, all related to obesity, insulin resistance and metabolic syndromes.
- 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. T2DM is very prevalent in Indian sub-continent Asians, as is PCOS, and having a family history increases the risk.
- While the clinical consequences are not about death, they are still significant and awareness is important.
- Obesity & insulin resistance results in increased incidence of gestational diabetes (GDM) if pregnant with PCOS. It presents first in pregnancy due to how the foetus behaves and it is the foetus who can make the mum insulin resistant.
- Unpublished data shown that nearly all women with GDM had PCO
6
Q
What is the gold standard test used to measure impaired glucose tolerance?
A
- Oral glucose tolerance test to determine IGT = Begin by fasting 8-12h before test (usually overnight) → glucose given as a solution → blood samples taken at regular time points over the next two hours to determine how quickly glucose is 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 - It is not always easy to administer and it is time consuming, so not always carried out in routine clinical practice.
- If someone did not have insulin resistance (normal insulin sensitivity), their fasting glucose levels should be around less 5.6mM before their test. By two hours, it should be less than 7.8mM. Normally, by two hours, it is back to below 5.6mM but this is the limit.
- If someone was starting to get insulin resistance, so glucose tolerance is impaired, then their fasting glucose value is a bit higher than normal even before the test. After two hours, it still would not come back down to normal. This shows that the body is not able to clear the glucose, so glucose tolerance is impaired because the body is resistant to the effect of insulin (insulin resistance).
- If diabetic, glucose values are very high before the test and they remain over 11 or 12 mM even after the test.
- These are the principles of the oral glucose tolerance test used to assess impaired glucose tolerance and insulin resistance.
7
Q
How does the foetus make the mother insulin resistant in gestational diabetes mellitus?
A
- Hormones produced by foetus can induce insulin resistance in mother.
- The placenta will produce oestradiol, cortisol, human placental lactogen → HPl interferes with insulin receptors → Maternal Hyperglycemia (fetus makes mum IR, resulting in hyperglycemia in maternal circulation) → Increased glucose in maternal circulation crosses to foetal circulation → Increase in fetal insulin → Excess fetal growth – large for gestational age.
- If the mom already had insulin resistance or impaired glucose tolerance, it will be made worse, and the mother will become diabetic during pregnancy. Increased glucose occurs in the maternal circulation and this crosses into the foetal circulation, causing other problems for the foetus eventually. . 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.
- It is a two-way thing; the placenta produces all these hormones which then interfere with the maternal glucose clearance. There is high glucose in circulation, and this feeds back to the foetus. This affects the foetus and can cause things like increasing foetal insulin, which can cause excess foetal growth and result in big babies.
- Normally, once the baby has been delivered, HPL levels will fall, and normal insulin sensitivity resumes in most cases. Often, if a mom has had gestational diabetes in one pregnancy, she is prone to getting it in the next pregnancy. Also, it can long-term postnatally cause problems for the foetus itself then.
- There are issues with big babies and various complications associated with GDM.
8
Q
What are the complications of GDM for mother & foetus?
A
- 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 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. It can be done at any time of day, but not on an empty stomach. The test involves 50g of glucose, with a reading after one hour.
- If the birth weight is very big, it’s not very healthy for the baby; baby can get trapped in the birth canal during delivery, Can trigger pre-eclampsia and premature delivery. All very serious complications.
- Percentage increase in odds of complications with GDM:
1) Birth weight >90th percentile = 38%
2) Shoulder dystocia (birth injury) = 22%
3) Premature delivery = 16%
4) Preeclampsia = 28%
9
Q
What is the correlation between IR and anovulation?
A
- There is a direct inverse relationship between hyperinsulinemia and ovulation rate.
- Also known that high insulin levels can have a detrimental effect on follicles.
- Insulin resistance is also linked to anovulation. Inverse correlation graph; as serum insulin levels increase, the number of cycles decrease.
- More severely insulin resistant = less menstrual cycles (increased chances of becoming anovulatory)
10
Q
What are the other manifestations of metabolic defect in PCO?
A
- tendency to obesity with increase in truncal-abdominal fat
- increased hypertension (variable)
- 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
1) Increased coronary artery calcification (independent of age & BMI)
2) Increased carotid artery intima-media thickness (predictor of stroke & MI) compared to age-matched controls
3) Limited longitudinal studies → PCOS diagnosed during reproductive lifespan (20-30 years old) but CVD manifests 30 to 40 years later.
4) 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 (Kazemi M et al (2020) JCEM 105:e3400-e3414)
- Limited longitudinal studies re. CV risk factors, but indications are there. Osteosarcopenia is a newly described syndrome that describes the co-existence of osteoporosis and sarcopenia, two chronic musculoskeletal conditions associated with ageing. Osteoporosis, a condition of low bone mass and micro-architectural deterioration of bone, and sarcopenia, the loss of muscle mass, strength and function, often co-exist in a frail subset of the elderly population, leading to significantly worsened outcomes than seen in either condition alone.
- Increased tendency to obesity with the deposition of fat around the truncal-abdominal area (apple-shaped)
- All of the associations of metabolic syndrome, e.g. increased hypertension, altered lipid profiles
- Lots of controversy about whether there was an increased risk for atherosclerotic disease (cardiac disease). It was debateable because it could not be diagnosed. Does not present in woman until their 60’s/70’s (quite a while after menopause because oestrogen is thought to be protective of CVD). It is difficult to look at women in their 60’s/70’s, because there was no diagnostic method for PCOS when they were in their 30’s. Longitudinal studies to follow them up have been difficult; just started to come out now and there are indicators of increased risk of CVD.
- Osteosarcopenia = combination of osteoporosis and muscle degeneration
- This is not something that just ends when reproductive life finishes; the effects have consequences post menopause for a lot of women.
11
Q
Why do women with PCOS gain weight? Are women with PCOS more inclined to put on weight or is it parallel to growing obesity epidemic?
A
- 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. HRQoL = health related quality of life.
- PCO is associated with reduced energy expenditure equivalent to over 17,000 kcal/pa. Can live on less calories with PCO than normal.
- When putting two groups on matching low-calorie diets, where one group has PCOS and the other doesn’t, women who have PCOS will lose weight slower than women with normal ovaries. This shows that there is something intrinsic about having PCOS which predisposes women to gaining weight. One of the important factors is reduced energy expenditure. It also relates to the food available nowadays, e.g. processed food, additives. This alters the environment in the body and how calories are handled, but women also have this intrinsically reduced energy expenditure. This is due to reduced post-prandial thermogenesis.
12
Q
How does post-prandial thermogenesis differ in PCOS?
A
- 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 diff in PPT between normal and PCO is small if lean, but half if obese.
- PPT = following a meal (after eaten)
Thermogenesis = body’s normal ability to burn off the calories from a meal. This is in the normal processes of the body’s functions. - Reduced energy expenditure predisposes them to gain weight.
- The graph shows that in women who are weight matched, women with PCOS have slightly decreased PPT. This means that they must work harder to maintain that same weight. Looking at obese women, can see that woman with PCO have half the postprandial thermogenesis. Even women who are lean have slightly reduced PPT, meaning they have to work harder than their normal counterparts to maintain their weight, but this gets worse (even harder to lose weight) if weight is put on.
- Insulin sensitivity is decreased; one thing feeds in to the other.
13
Q
How does reduced PPT result in weight gain?
A
- As there is a deficit in how calories are burned, a small amount of weight is put on from the age of 15. Because you are prone to it (since it coincides with girls stopping exercise at school), then weight gain is quite a lot by the time they think about conceiving. This will then have a negative effect on the menstrual cycle, on ovulation. This feeds into that. Therefore. it is important to start interventions with adolescent girls. Often, the focus may be on the external presentation (hirsutism or acne), but the woman/girl needs to be treated as a whole, looking at all of the parameters; the problem with PCOS is that everyone treats each symptom as it presents individually.
- If PCOS is associated with so many negative things, why does it persist in the population (especially if it is a polygenic disease; there are many genes that predispose us to PCOS)?
- If you go and see your GP in your teens, they usually tell you to go away and come back when you want a baby, or your cycles will settle down in a bit. By the time the patient is in their 20s they’ve put 1.9kg/year (17,200 calories p.a.) which complicates the situation and make it very hard to lose weight, get regular cycles etc.
14
Q
How are SHBG levels affected in PCO?
A
- SHBG, sex hormone binding globulin, binds androgens and that determines free androgens. 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 is dependent on BMI. If BMI increases, it decreases as SHBG production from the liver and increases testosterone. The graph shows that in woman with BMI over 25 who have PCO, their SHBG is almost half of the normal (even though the normal population includes all of the weights). This proves that if SHBG is low, free testosterone is high. The effects and symptoms of testosterone are then known. - SHBG production by liver is also inhibited by insulin (not just linked with high BMI)
- Insulin also stimulates ovarian androgen production (synergises with LH)
- Hyperinsulinemia will also reduce SHBG. Insulin is also a cogonadotrophin with LH, stimulating it to increase testosterone. Hyperinsulinaemia makes the androgen problem worse by driving the ovary to make more A but also by increasing free androgens.
- In normals, the androgens are low anyway so even if reduce SHBG the increase in androgens is not very much. In PCO and with higher BMI, have half the amount of SHBG and so increases the androgens even further.
- Overall, increase in testosterone!
15
Q
Summarise long-term outcomes for women with PCOS.
A
- 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.
- The long-term outcome for women with PCOS = they gain weight because they have reduced PPT, their bodies are geared up with the insulin resistance to also increase their weight etc. With increasing weight, the women are more prone to insulin resistance, which just gets worse with weight increase. Insulin resistance presents as high insulin initially and will then convert to type 2 diabetes before insulin levels drop off. High insulin will augment androgen secretion, which increases the total androgen secretion. High insulin decreases SHBG, which then again increases free androgens, increasing hirsutism and acne. It is also linked with anovulation. As weight gain increases and insulin increases, all those effects can cause problems ovulating. Pregnant with PCOS means the woman is more prone to getting gestational diabetes. Later in life, they can get type 2 diabetes. It also seems that there is a risk of CVD. The long term outcome for women with PCOS are not great with all of the complications.
