Treatment of PCOS Flashcards
What metabolic defect is associated with PCO/PCOS?
Insulin resistance - it’s not part of the diagnostic criteria but its prevalent
How is it different to Type 2 diabetes?
- initially glucose levels are low
- circulating insulin levels increase to compensate = hyper-insulinaemia
- Insulin levels increase to try and maintain steady glucose but the insulin doesn’t work well
- so the insulin and glucose levels increase eventually
- beta cells get fatigued, no more insulin made, the whole system breaks and the person is known as diabetic
What is insulin sensitivity like in PCOS?
- insulin sensitivity declines at a faster rate in women with PCOS than in women with normal ovaries with increasing weight
- Insulin sensitivity is reduced in both obese & lean women with PCOS compared to normal
What do women with PCOS have that is linked with insulin resistance?
- Women with PCOS have central adiposity, which is linked to IR
- May NOT be due to higher relative percentage of visceral fat – visceral fat is more dangerous
What is the molecular mechanism of IR 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
- Steroid pathway is maintained but signalling pathway that allows glucose to be stored and taken in from the blood stream is affected
What can IR lead to?
IR leads to inflammation and inflammatory markers also play a role in dysregulating the glucose pathway
What can exacerbate symptoms of obesity?
Obesity
What is IGT?
impaired glucose tolerance - seen in may patients with PCOS
What can obesity and IR result in?
o increased incidence of GDM (gestational diabetes)
What relation does type 2 diabetes have with PCOS?
some PCOS patients develop it by age 40
What is OGTT?
Oral glucose tolerance test
What is OGTT used for?
to determine IGT
How is an OGTT carried out?
→ Fasting 8-12h before test
→ glucose given as a solution
→ blood samples taken (0-2h) to determine how quickly cleared from blood
OGTT results for normal glucose tolerance, impaired glucose tolerance and diabetics?
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 Mellitus (GDM) happen?
Placenta 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– if mother was already IR, this makes it worse, insulin will be even higher
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Increase in fetal insulin
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Excess fetal growth – large for gestational age
What issues can GDM cause?
- Pre-eclampsia
- shoulder birth injury
- premature birth
- very high birth weight
What is IR linked to and why?
Anovulation
- There is a direct inverse relationship between hyperinsulinemia and ovulation rate.
- Also high insulin levels can have a detrimental effect on follicles
What are other manifestations of metabolic defect in PCO:
- tendency to obesity with an increase in truncal-abdominal fat
- increased hypertension
• Altered lipid profile:
o higher levels of LDL cholesterol – regardless of BMI
o low levels of HDL cholesterol and elevated triglycerides
• apparent increased risk for atherosclerotic disease
o Increased coronary artery calcification (independent of age & BMI)
o Increased carotid artery intima-media thickness (predictor of stroke & MI) compared to age-matched controls
Why are women with PCOS more inclined to put on weight?
PCOS is associated with reduced energy expenditure equivalent to over 17,000 kcal/pa
- this is due to reduced post-prandial thermogenesis (PPT): the loss of energy after eating a meal
- it is amplified by obesity in PCOS
What is SHBG?
sex hormone binding globulin
What does SHBG do?
- Vast majority of testosterone is bound to SHBG.
- Small change in SHBG causes large change in free testosterone
- Increases testosterone
What does SHBG depend on?
• SHBG dependent on BMI ie obesity ↓SHBG from liver & ↑free T
Where is SHBG produced and what inhibits it?
- SHBG production by liver is also inhibited by insulin
* Insulin also stimulates ovarian androgen production (synergises with LH)
Do lean women have more SHBG or obese women?
• Lean women have more SHBG
What is the cure for PCOS?
No “cure” – treatment is symptomatic
What treatment improves PCOS?
• Lifestyle intervention and weight loss improves overall PCOS status in overweight/obese patients along with other health benefits eg insulin resistance, CVD
What is used to treat menstrual abnormalities and hirsutism/acme?
First line management for menstrual abnormalities and hirsutism/acne in PCOS are hormonal contraceptives (HC
Treatment for infertility?
First line therapy for infertility is Clomiphene
Treatment for metabolic/glycaemic abnormalities + menstrual irregularities
Metformin is beneficial for metabolic/glycaemic abnormalities & for improving menstrual irregularities, but of limited benefit in treating hirsutism, acne or infertility
What improves insulin resistance?
diet and exercise
what are the drugs for weight loss?
Orlistat (lipase inhibitors) reduces uptake of fat from bowel and increases it in stools – side effects of anal leakage
Treatment for morbidly obese PCOS patients?
bariatric surgery – very effective, post op:
- hirsutism decreases
- menstrual irregularities decrease
- PCOS phenotype decreases
- fertility increases
What drug may be used to treat IR?
• Metformin (insulin sensitiser)
o Decreases hepatic glucose production therefore less in serum
o Enhances glucose uptake into muscle
o Increases oxidation by adipose tissue
o Helps with getting a regular cycle
o However wont work if body weight is too high
How many ovulations per year a patient should have to avoid endometrial hyperplasia
• minimum of 4 ovulations per year to avoid endometrial hyperplasia
Difference between women with amenorrhoea and women with PCOS?
• Unlike women with amenorrhoea, women with PCOS are well-oestrogenised due to antral follicles in arrest – lining of the endometrium grows really thick
How can PCOS increase the risk of Endometrial Cancer:
- Even when amenorrhoeic, women with PCOS are well-oestrogenised
- Unopposed oestrogen on endometrium → risk factor for hyperplasia
- Probably exacerbated by obesity
- increased risk of endometrial CA (CR) - even under 50
- Recommendation to have bleed at least every 3 months, more often if very heavy
How can PCOS cause cutaneous manifestations
Hyperinsulinemia from IR acts at dermis to induce acanthosis nigricans (velvety, light-brown-to-black markings) on neck, under arms, in groin & skin tags
Treatment for cutaneous manifestations in PCOS
Treatment to just improve the appearance includes tretinoin (derivative of Vitamin A), 20% urea, alpha hydroxyacids and lactic or salicylic acid.
Mechanical treatments for hirsutism
- Electrolysis
- Laser
- Vaniqa. Eflornithine HCl
How does electrolysis treat hirsutism
- Electrical current causes high temperature in hair shaft
- Must destroy dermal papillae to prevent regrowth
- Not really practical for large areas
- Often worth removing hair by another means a short while before, then growing hairs can be focussed on.
- May be best combined with medical treatment
How does laser treat hirsutism
- heat destroys the hair follicle. Need dark pigment to absorb the heat of the light/laser
- Needs dark hair on light skin
- Not often available on NHS
- Hair follicle cycle is long → many sessions
How does Vaniqa. Eflornithine HCl treat hirsutism
- Topical cream inhibits enzyme - Ornithin Decarboxylase – that is needed for hair shaft growth.
- Must be applied 2x day every day
- Grows back as soon as stop use
How can weight reduction help with fertility in PCOS?
- Increased chance of spontaneous ovulation
- Reduced chance of miscarriage
- Need less drugs for induction of ovulation
- Reduction in GDM
- Improved outcome for baby
- Improved long term outcome for patient
Different drug/hormone treatments for fertility in PCOS?
- Clomiphene Citrate (CC)
- Metformin + CC
- Aromatase inhibitors
- FSH treatment
How does CC improve fertility in PCOS
o raised acyclical oestrogen results in disordered pituitary LH and more importantly FSH
o given for 5 days to mimic inter-cycle rise in FSH
o CC is a SERM (selective oestrogen receptor modulator) and binds to ER in hypoth/pit & removes negative feedback, allowing for GnRH & FSH release
o high miscarriage rate - up to 40%
o risk of multiple follicles/ovulations & OHSS ultrasound monitoring 1st cycle
How does Metformin + CC improve fertility in PCOS
Improves clinical pregnancy rates but not live birth rates
How does aromatase inhibitors improve fertility in PCOS
Same effects as the anti-oestrogen but inhibits production of oestrogen
How does FSH treatment improve fertility in PCOS
Daily injections of FSH: aim for single follicle
What is high serum AMH associated with in PCOS women?
High serum AMH is associated with a reduced response to ovulation induction among women with PCOS
What procedures are for infertility in PCOS?
- Ovarian laser diathermy/ovarian puncture or wedge resection
- IVF
How does Ovarian laser diathermy/ovarian puncture or wedge resection work?
- ovary “drilled” laparoscopically with laser – women started to ovulate
- mechanism of action unknown → may act by destroying stroma, reducing size of matrix and lowering endogenous androgen production
- Return of cycles for up to 6 months in high percentage of women
- no risk of hyper-stimulation
- should be used only as a last resort as long term damage unknown
- Reduced response rate to subsequent IVF
