Treatment of PCOS

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

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

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

insulin resistance is familial No mutations in insulin receptor gene found in PCOS Post-receptor binding defect somewhere in signalling pathway in granulosa cells

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?

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

lacenta produces E, cortisol & human placental lactogen ↓ HPl interferes with insulin receptors ↓ Maternal Hyperglycemia ↓ Increased glucose in maternal circulation crosses to foetal circulation ↓ Increase in fetal insulin ↓ 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

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

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 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.

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.

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

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

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

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

Even when amenorrhoeic, women with PCOS are well-oestrogenised Unopposed oestrogen on endometrium → risk factor for hyperplasia Probably exacerbated by obesity Recent meta-analysis showed 3 fold increased risk of endometrial CA…even under 50 (Chittenden et al, (2009) Rep.Biomed.Online) Another study found an increase only in obese women with PCOS (Fuberg & Thune (2003) Int. J. Cancer) Recommendation to have bleed at least every 3 months, more often if very heavy

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 to just improve the appearance includes tretinoin (derivative of Vitamin A), 20% urea, alpha hydroxyacids and lactic or salicylic acid. Acanthosis nigricans is a disorder that may begin at any age. It causes velvety, light-brown-to-black, markings usually on the neck, under the arms or in the groin. Acanthosis nigricans is most often associated with obesity. Most patients with acanthosis nigricans have a higher insulin level than those of the same weight without acanthosis nigricans. Elevated levels of insulin in most cases probably cause acanthosis nigricans. The elevated insulin levels in the body activates insulin receptors in the skin, forcing it to grow abnormally. Treatment to just improve the appearance includes tretinoin, 20% urea, alpha hydroxyacids, and lactic or salicylic acid prescriptions. Acanthosis nigricans is a disorder that may begin at any age. It causes velvety, light-brown-to-black, markings usually on the neck, under the arms or in the groin. Acanthosis nigricans is most often associated with obesity. Most patients with acanthosis nigricans have a higher insulin level than those of the same weight without acanthosis nigricans. Elevated levels of insulin in most cases probably cause acanthosis nigricans. The elevated insulin levels in the body activates insulin receptors in the skin, forcing it to grow abnormally. Treatment to just improve the appearance includes tretinoin, 20% urea, alpha hydroxyacids, and lactic or salicylic acid prescriptions.

COCP with non-androgenic progesterone eg deogestrel* Weight reduction COCP with androgen blocking diuretic effect eg drospirenone* Physical therapies – electrolysis, laser hair removal, waxing, shaving, plucking Anti-androgens eg cyproterone acetate, ethinyloestradiol, spironolactone (monitor renal function), finasteride (post-menopausal), flutamide Topical treatments: eg eflornithine 11% for facial hair** Isotretinoin (popular drug used to treat acne) but not recommended in PCOS GnRH therapy – very severe acne only Psychological intervention BSO – bilateral saplingo-oophorectomy (after had children) Androgenetic alopecia – 2% solution minoxidil used 2x/day for 6 months

Electrolysis 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 Laser 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 opical cream inhibits enzyme - Ornithin Decarboxylase – that is needed for hair shaft growth.

Weight reduction is primary goal in the overweight 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 Which diets are best? Hard to say……but low calorie of any kind seems to work

Clomiphene Citrate i.e. anti-oestrogen (1st line) raised acyclical oestrogen results in disordered pituitary LH and more importantly FSH given for 5 days to mimic inter-cycle rise in FSH CC is a SERM (selective oestrogen receptor modulator) and binds to ER in hypoth/pit & removes negative feedback, allowing for GnRH & FSH release 70-90% responders in the best hands Multiple pregnancy around 10% high miscarriage rate……up to 40% risk of multiple follicles/ovulation & OHSS…ultrasound monitoring 1st cycle Metformin + CC Improves clinical pregnancy rates but not live birth rates Aromatase inhibitors (eg Letrozole) Same effects as the anti-oestrogen but inhibits production of oestrogen (Legro et al, NEJM (2014) 371:119-129) FSH treatment Daily injections of FSH: aim for single follicle

748 women with PCOS and anovulation (18-40 years) AMH measured at baseline Treated with clomiphene citrate or letrozole for 5 days per cycle & for 5 cycles AMH levels significantly lower in women who achieved ovulation vs women who did not overall and also within each treatment group High serum AMH associated with a reduced response to ovulation induction among women with PCOS

ovary “drilled” laparoscopically with laser 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…..although recent study suggested better outcome than those not receiving it Reduced response rate to subsequent IVF IVF Recommended use of metformin as adjuvant to prevent OHSS which is very common in women with PCOS

Some publications on acupuncture Cochrane review (2011) found no randomized trials to investigate effect of acupuncture treatment for PCOS Herbal preps also suggested Agnus castus Saw palmetto etc No known micronutrient deficiency has been identified as relevant to PCOS