Polycystic Ovarian Syndrome Dr Louise Knowles 12/12/16

PCOS; points to cover today Diagnosis Clinical Features; presentation and long term consequences Hormonal Disturbances Subtypes PCOS Investigations Management.

PCOS Originally described 1935 by Stein and Leventhal. Redefined 2003 by American and European Societies reproductive medicine Patient likely to present with menstrual disturbance, acne, hirsutism, infertility.

PCOS; genetics Heterogenous; familial clustering. Autosomal dominant inheritance, variable penetrance in females; 50% chance of offspring being affected Phenotype manifests itself via raised androgen levels secreted by ovarian theca cells. Severity seems to be determined by factors such as obesity

PCOS Statistics Incidence: 15-25% UK Women 50% UK Asian Women South Asian women present at younger age and often have more severe symptoms

USS assessment 20-30% Caucasian women have PCO 5-15% Caucasian women have PCOS Polycystic ovaries not necessary to make diagnosis of PCOS

Ultrasound assessment of the polycystic ovary: international consensus 12 or more follicle measuring 2-9mm and/or Increased ovarian volume (>10cm3) ASRM Consensus 2003

Diagnostic Criteria Two out of three criteria required 1.Anovulation or oligo-anovulation 2.Hyperandrogenism Clinical (hitsuitism, acne) Biochemical (raised testosterone) 3.Polycystic ovaries(12 or more follicles,2-9mm diameter) Clinical signs hyperandrogenism; excess facial and body hair, midline hair growth.

Diagnostic criteria Other causes of menstrual disturbance and hyperandrogenism must be excluded. Conditions such as thyroid dysfunction, hyperprolactinaemia may present with cycle disturbance.

Hyperandrogenism Alopecia Hirsuitism Acne

Differential Diagnoses Cushings Adrenal/Ovarian tumours ( virilisation) Congenital adrenal hyperplasia Menopause/Ovarian failure Exogenous- anabolic steroid, testosterone medication Hypothalamic/pituitary disorders Cushings; proximal muscle weakness, plethoric round face, sriae, bruising, supraclavicular fat pad Virilisation; deep voice, smaller breasts, bulky muscles,clitromegaly. High total testosterone levels (>5nmol/l)may indicate a differnet diagnosis

Long Term Consequences Metabolic syndrome, with increased risk type 2 diabetes, hyperlipidaemia Fertility problems Psychological distress Endometrial cancer Increase risk sleep apnoea CVD is one of the leading casues of death in women with PCOS. Assess CVD risk; measure BP, lipids, HBa1c. Conventional CVD risk tables have not however been validated in these women. Increased visceral fat; check waist circumference.

Endocrinology Normal function of the pituitary and ovary Hormonal abnormalities underlying PCOS

PCOS; the hormones In women with PCOS, the theca cells of the ovary produce excess androgens, which may be due to hyperinsulinaemia or increased serum levels of luteinizing hormone (LH)

Insulin Resistance Androgenic Effects Weight gain Insulin  Fat storage Inhibits SHBG Testosterone  Insulin in hibits production SHBG by the liver. Testosterone is bound to SHBG; total testosterone may be normal but free testosterone is typicaly high. Even women with normal BMI have insulin resistance. South Asian women with PCOS should have OGTT even if BMI normal (RCOG) Androgenic Effects Acne Hirsuitism Irreg periods Infertility

PCOS; the hormones Insulin resistancehyperinsulinaemia as a key factor in PCOS for many women  Insulin and LH lead to  androgen production from theca cells.  androgen leads to follicular arrest and anovulation

Subtypes of PCOS LH Driven Insulin Driven

LH Driven Slim High LH High Impaired GTT (10%) Responds to ovarian diathermy

Insulin Driven XS Centripetal fat Acanthosis Nigricans Longer inter-menstrual interval

Investigations; PCOS LH;  or normal FSH often normal. Total testosterone; normal or slightly raised ( if >5 nmol/l exclude androgen secreting tumours) Free testosterone may be  SHBG normal or  Free androgen index normal or

Investigations Free androgen index FAI  FAI =Total testosteronex100/SHBG Or;  Free Testosterone.

Investigations for diff. diagnosis TSH Prolactin 17-hydroxyprogesterone ( CAH) DHEA-S and FAI ( androgen secreting tumours) 24 hr urinary cortisol ( Cushings)

Investigations PCOS In addition to hormone profile; need to check Lipid profile LFT’s if high BMI HBa1C/GTT ( fasting glucose not sensitive enough)

Other Menstrual Irregularities FSH + LH + E 

Other Menstrual Iregularities FSH + LH + E  Ovarian failure/ menopause

Other Menstrual Iregularities FSH + LH + E  Ovarian failure/ menopause FSH + LH + E

Other Menstrual Iregularities FSH + LH + E  Ovarian failure/ menopause FSH + LH + E Hypothalamic/pituitary Underweight Overexercise Chronic Illness

Management Aims: Managing symptoms Reducing long term consequences

Management Weight management/ psychological support Hair removal. Oligo/amenorrhoea Infertility

Weight Management Aim: 5-10% wt loss (can achieve 30% loss of visceral fat) Empower the patient Be kind Discuss long term health Depression in 70%

Oligo/amenorrhoea Need to bleed every 3-4m to avoid unopposed oestrogen, increased risk endometrial cancer. Endometrial protection will be provided by desogestrel/implant/ Mirena. Consider COCP If not having a bleed every 3 months consider inducing bleed with progesterone; eg medroxyprogesterone 10 mg bd for 10 days per cycle If amenorrhoea consider USS to check endometrial thickness. If >7mm consider referral for ? Endometrial biopsy. For every 1mm increase in endometrial thickness the risk of endomethrial hyperplasia increases by odds ratio of 1.5

COCP Oestrogens increase SHBG Dianette Yasmin Any cocp will help prevent androgenic effects and give regular bleed enabling endometrial protection Dianette licensed for hirsutism/acne of any cause; not just for PCOS.Because it is being used for licensed use other than contraception the rules about BMI are more flexible than COCP UKMEC rules. It is advised to stop 3-4m after the problem has improved. Its VTE risk is comparable to coc’s containing gestodene, drosperinone and desogestrel. Nice guidance suggest treating for 12m , having 6m break then treating another 12m.( due to life cycle of hair follicle a minimum ofr 6m treatment needed to make discernible difference)

Fertility, when BMI>30 Clomiphene citrate Ovarian drilling( useful in LH driven PCOS) Ovulation induction IVF Weight loss alone may be enough. Clomiphene can by used up to 6 months; but there is an increased risk multiple pregnancy; need scans; secondary care. Gonadatrophins may be used if failed clomiphene. Drilling/electrocautery should be considered for selected anovulatory patients specially with normal BMI

Goal weight 5-10% weight loss reduces visceral fat by 30%..... Beware of pregnancy Impact on insulin levels Give realistic goals; eg 1kg per week. Orlistat Bariatric surgery. Consider bariatric surgery if BMI.40 and failed other weight loss measures or if BMI>35 with co-existent T2D/ hypertension This will improve daibetes, hypertension and dyslipidaemia, reducing mortality from CVD and cancer.

What about metformin? Ineffective for hyperandrogenism Ineffective for anovulation Use for IGT( & continue if conceives?) May be used to reduce risk of ovarian hyperstimulation in IVF May be used in sec care in treatment infertility (Nice 2013)? Metformin is not licensed for treatment of PCOS so if used women need careful counselling to make informed choice. There is some evidence that it can modestly reduce androgen levels by 11% in women with PCOS compared to placebo and some studies show reduction in body weight but variable evidence.

Hirsutism Eflornithine ( Vaniqua); 4m trial.....£55 per tube!! Can be prescribed as NHS drug in PCOS/hirsutism (Spironolactone) Laser treatment

Pregnancy and PCOS Gestational diabetes( OR 3.6)Do GTT at 24-28w Increased risk hypertension, preclampsia. Increased risk preterm birth/ small for dates infants. Increased risk PCOS in offspring 14% will have a major pregnancy related complication

West Yorkshire! South Asian women resident in Yorkshire with anovular PCOS; Present younger Develop oligomenorrhoea younger Have more T2DM in families Have more acanthosis nigricans & hirsutism Have higher insulin resistance.

PCO and the future Increasing incidence Needs holistic approach Primary care pivotal role with support specialists; gynaecology, dietician, counsellors, beauticians.

Patient support groups www.verity-pcos.org.uk www.soulcysters.com American

Useful references Polycstic Ovary Syndrome; Nice CKS Feb 2013 RCOG Green Top guideline No 33; Long Term Consequences of PCOS (2014) Hirsutism; Nice CKS Dec 2014 https://www.womens-health-concern.org have an excellent fact sheet for patients.