Polycystic Ovary Syndrome: An overview Welcome Dr. Julie Tomlinson PhD MSc BSc(Hons) PgDipClinEd PgCert SCPHN RGN QN Consultant Nurse & Advanced Nurse Practitioner

Intended learning outcomes To understand how Polycystic Ovary Syndrome is diagnosed. To develop a greater understanding of the significance that Polycystic Ovary Syndrome has on individual women and society. To develop understanding of the clinical management of women with Polycystic Ovary Syndrome

Polycystic Ovary Syndrome Overview of Polycystic Ovary Syndrome

WHAT IS POLYCYSTIC OVARY SYNDROME (PCOS)? The most common female endocrine disorder, 15% prevalence rate1 Characterised by androgen excess during the reproductive years. Different diagnostic criteria in use: NIH 19902 versus Rotterdam consensus3 Treatment usually revolves around resolving acne, hirsutism or infertility4 Overview of polycystic ovary syndrome 1. Fauser et al. (2012) Consensus on women’s health aspects of polycystic ovary syndrome. Fertil Steril 97:28-38 2.Zawadski J, Dunaif A(1992) Diagnostic criteria for polycystic ovary syndrome. In: Dunaif, A et al (eds) Polycystic Ovary Syndrome. Blackwell Scientific Publications, Boston 3. Rotterdam/ESRE Workshop Group(2004) Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Human Reprod 19: 41-7 4. Tomlinson JA & Pinkney JH (2007) Diabetes and polycystic ovary syndrome. Practice Nurse. 34 (10): 43-7

WHAT IS POLYCYSTIC OVARY SYNDROME (PCOS)? PCOS is associated with increased metabolic risk (Type 2 diabetes [T2D] and cardiovascular disease)4 Increasing prevalence of childhood obesity is resulting in increased referral of teenage girls with PCOS related hirsutism, acne, oligomenorrhoea, IGT and T2D5 What is less well-known about PCOS.. 4. Gluek CJ et al (2003) Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome Metaboilsm; 52:908-15 5. Palmert MR, Gordon CM, Kartashov AI, Legro RS, Ermans SJ, Dunaif A. (2002) Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 87, 1017-1023

Polycystic Ovary Syndrome – historical aspects 400 BC – Hippocrates reportedly described 2 cases of hirsute women with amenorrhea 1921 –report of bearded woman with diabetes 1935 ‐ Stein & Leventhal described 7 women with amenorrhea, hirsutism, obesity, and enlarged polycystic ovaries

Polycystic ovary syndrome is a complex condition involving an interplay of various organs and hormonal regulation systems in the body. This results in a variety of chemical and physical changes including hyperandrogenism, insulin resistance, increased free fatty acids and hyperglycaemia.

The aetiological, hormonal and clinical features of PCOS Teede et al. 2011

Polycystic Ovary Syndrome Learning outcome 1: To understand how Polycystic Ovary Syndrome is diagnosed

Defining Polycystic Ovary Syndrome Prior to 1990, no agreed diagnostic criteria NIH 1990 diagnosis ( US and most literature) Rotterdam 2003 consensus ( Europe) Androgen Excess Society recommendations Endocrine Society 2014 (USA) recommends use of Rotterdam in USA.

A diagnosis of PCOS may be made if there is both: The NIH 1990 criteria for the diagnosis of PCOS A diagnosis of PCOS may be made if there is both: Presence of hyperandrogenism with either clinical signs (hirsutism, acne, or male pattern balding) or biochemical signs of hyperandrogenaemia (high serum androgen concentrations) and Presence of chronic menstrual irregularity due to oligomenorrhoea / amenorrhoea (authors comment: usually accepted to be 6 or fewer periods per year) after   Excluding other known disorders such as Cushing’s syndrome, Congenital Adrenal Hyperplasia, androgen-secreting tumours, and hyperprolactinaemia

The Rotterdam 2003 criteria for the diagnosis of PCOS A diagnosis of PCOS may be made if any TWO of the following features are present: The presence of menstrual irregularities - oligomenorrhoea and/or annovulation The presence of clinical and/or biochemical signs of hyperandrogenism The presence of polycystic ovaries After Excluding other potential causes of menstrual irregularity or hyperandrogenism

In essence, the Rotterdam 2003 expanded the NIH 1990 definition creating two new phenotypes: ovulatory women with polycystic ovaries and hyperandrogensm and oligo-anovulatory women with polycystic ovaries, but without hyperandrogenism

Prevalence rates vary according to diagnostic criteria Rotterdam Criteria PCOS prevalence 15% NIH Criteria PCOS prevalence 5-6% “The Rotterdam criteria are inclusive of National Institutes of Health (NIH) criteria in that a woman diagnosed with PCOS using the NIH criteria will also meet Rotterdam criteria; however, a woman diagnosed with PCOS using Rotterdam criteria may not meet NIH criteria.” Teede et. al, 2011

The Androgen Excess Society have suggested a further amendment… A diagnosis of PCOS may be made if the following features are present: The presence of hyperandrogenism (clinical and/or biochemical) and The presence of ovarian dysfunction (oligo-anovulation and/or polycystic ovaries) after Excluding other causes *Most of the U.S. uses 1990 criteria and Europe uses 2003 criteria

different diagnostic criteria different phenotype & genotype different health needs & prevalence rates urgent need to standardise diagnostic criteria!

FINALLY, WHEN DIAGNOSING PCOS IN YOUNG WOMEN… Caution should be applied if diagnosing PCOS in young women. Multiple ovarian follicles, acne and irregular periods are common in teenagers, so avoid diagnosis in under 18’s or within first two years of menarche.

Diagnostic features of PCOS

Clinical features of PCOS Clinical hyperandrogenism: hirsutism

Ferriman Gallwey score – a clinical aid?

Clinical features of PCOS Clinical hyperandrogenism: androgenic alopecia (AA) Gradual onset Hair loss on vertex (top of head) & angles of the front-line (‘triangular thinning”) AA is less commonly used for diagnostic criteria Reproduced with permission: Futterweit at http://www.doctorsinfoweb.com/women/pcos-hair-loss-dr-futterweit.htm

Clinical features of PCOS Clinical hyperandrogenism: acne Acne is common in the young and difficult to measure Image reproduced from: http://www.fightyourinfertility.com/wp-content/uploads/2015/04/PCOS-cystic-acne.jpg

Biochemical hyperandrogenism Ideally use a calculated measure to investigate biochemical hyperandrogenism, i.e. a raised Free Androgen Index (FAI) FAI derived through a calculation between total testosterone and Sex Hormone Binding Globulin (SHBG) Remember if SHBG is raised, ie with combined pill use, this will lower the bioavailable serum testosterone. Therefore a raised total-testosterone might not produce hirsutism etc. Obesity lowers SHBG, therefore more testosterone is bioavailable and women become more hirsute/oligomenorrhoeic etc.

Serum Testosterone/SHBG Bound (inactive) Testosterone SHBG Unbound (active) Testosterone

Beware the polycystic ovaries! Women don’t need polycystic ovaries to diagnose PCOS Women can have multiple cysts but not have PCOS (i.e. teenagers,OCP)

ultrasound to diagnose: IF you use ultrasound to diagnose: >12 follicles 2-9 mm in at least one of the ovaries Increased volume (>10cc) Excluded are those on OCPs and those with follicle >10mm) – can be reason for misdiagnosis! “Chain of Pearls sign” is not required

Common phenotypical features of PCOS Obesity

phenotypical features of PCOS Common phenotypical features of PCOS Acanthosis nigricans Axillary skin tags

Differential diagnoses of PCOS Cushing’s syndrome Diabetes Thyroid disease- hypo or hyper Hyperprolactinaemia Hypothalamic dysfunction Pituitary gland dysfunction Adrenal gland dysfunction or tumour Congenital Adrenal Hyperplasia Acromegaly Ovarian failure or tumour Medication effects Pregnancy

Learning outcome 2: To develop a greater understanding of the significance that Polycystic Ovary Syndrome has on individual women and society.

Individual concerns may include: Reproductive - fertility issues Psychosocial -self esteem issues (poor body image or feminine identity issues through acne, excess weight), lower quality of life, anxiety and depression, psychosexual dysfunction, eating disorders Metabolic – increased cardiovascular risk factors and type 2 diabetes

PCOS – a public health priority What is the extent of the problem? Prevalence rate currently ± 15% Likely to increase prevalence with rising levels of obesity PCOS is associated with increasing cardiometabolic risk and type 2 diabetes

The PCOS iceberg Cardiometabolic risk Infertility and hirsutism Glucose intolerance Dyslipidaemia Inflammation Copyright © Tomlinson & Pinkney

Evidence that PCOS is associated with T2D and impaired glucose tolerance Insulin resistance found in lean and obese women with PCOS1 7.5 – 10% PCOS have T2D and 31-35% IGT2 Lean PCOS have higher prevalence T2D than weight matched controls, but obesity increases their risk further3 1Dunaif et al., 1989 2Ehrmann et al. 1999; Legro et al., 1999 3Tomlinson et al. In press

Learning outcome 3: To develop understanding of the clinical management of women with Polycystic Ovary Syndrome

Recommended treatment guidelines for PCOS (Australia) Ref: Teede et al, 2011

Hirsutism Choice of options depends on patient preferences; impact on wellbeing; access and affordability: First line: Self-administered and professional cosmetic therapy (laser therapy recommended) Eflornithine (Vaniqa) cream can be added and may induce a more rapid response If cosmetic therapy is not adequate, pharmacological therapy can be considered Second line: pharmacological therapy if patient is concerned and cosmetic therapy is ineffective/inaccessible/unaffordable Primary therapy is the OCP (monitor glucose tolerance in those at risk of diabetes) Anti-androgen monotherapy (eg, spironolactone or cyproterone acetate) *not be used without adequate contraception Trial therapies for ≥ 6 months before changing dose or medication Combination therapy — if ≥ 6 months of OCP is ineffective, add anti-androgen to OCP (twice daily spironolactone > 50 mg or cyproterone acetate 25 mg/day, days 1–10 of OCP)  

Oligomenorrhoea/amenorrhoea Lifestyle change (5%–10% weight loss + structured exercise) Oral contraceptive pill (OCP) (low oestrogen doses [eg, 20 μg] may have less impact on insulin resistance) Cyclic progestins (eg, 10 mg medroxyprogesterone acetate 10–14 days every 2–3 months) Unlicensed metformin (improves ovulation and menstrual cyclicity)-but works better if clomiphene is added in secondary care.

Infertility Lifestyle intervention (to optimise preconception health and fertility and reduce pregnancy and long-term complications). LOSE WEIGHT! Advise on folate, smoking cessation and optimal weight and exercise before conception Given age-related infertility, advise women to optimise family initiation Infertility therapies may include clomiphene citrate, (?) unlicensed metformin, gonadotrophins, surgery and in-vitro fertilisation.

Cardiometabolic risk Lifestyle change: WEIGHTLOSS! >5%weight loss in those who are overweight reduces diabetes risk by approximately 50%–60% in high-risk groups Assess for and optimise cardiovascular risk factors – OGTT for diabetes (?best test for PCOS), lipids, BP, smoking cessation, age, BMI, waist circumference, Consider unlicensed metformin (reduces the risk of diabetes by ~50% in adherent high-risk groups)

Psychosocial and emotional wellbeing Assess and offer help for psychosexual problems including anxiety, depression, psychosexual dysfunction, poor body image, eating disorders

In Conclusion, PCOS… Is a very common condition but poorly identified and managed Is prevalent in 15% women and likely to rise with obesity Is often complicated to diagnose; urgent need for standardisation Has can have dramatic consequences on the individual and on society Is a risk factor for T2D and increased cardiovascular risk Can have a negative impact on emotional as well as physical wellbeing

Recommended Reading 1. Fauser BC et al. (2012) Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM- Sponsored 3rd PCOS consensus workshop group. Fertility and Sterility, 97,28-38 e25 2. Teede, H et al. (2011) Evidence-based guideline for the assessment and management of polycystic ovary syndrome.[online pdf] 3.Teede, H et al (2011) Assessment and management of polycystic ovary syndrome: summary of an evidence based guideline [online]

Thank you for listening contact: julie.tomlinson5@nhs.net