POLYCYSTIC OVARIAN SYNDROME (PCOS) TL KHUMALO 30 AUGUST 2018

Dr TL Khumalo hails from Durban, KwaZulu-Natal, currently practicing as a Specialist Obstetrician and Gynaecologist in Edendale Regional Hospital (Pietermaritzburg) She obtained her undergraduate degree at the Nelson R. Mandela School of Medicine and obtained her Fellowship in Obstetrics and Gynaecology via the University of KwaZulu-Natal in 2016 She has keen interests in seeing both Maternal health and the stigmatized Disorders of Sex development improve She has research interests in Infertility management in low resource settings Her research interests are in the field of Sexual Reproductive Health

DISCLOSURES NIL DISCLOSURES

OUTLINE BACKGROUND DEFINITION / PREVALENCE ISSUES RELATED TO PCOS APPROACH TO MANAGEMENT

SYNDROME Greek Etymology Sun ~ TOGETHER DRAMEIN ~ TO RUN SYNDROME SunDRAMEIN ~ TO RUN TOGETHER

BACKGROUND 1935 : Stein IF and Leventhal ML designated PCO as a syndrome ’80s/’90s : Addition of ultrasound criteria 2003 : Rotterdam Consensus Conference 2018 : International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018

BACKGROUND : International evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018 Over 3 000 delegates SUPPORT OPTIMAL PATIENT CARE AIMS PROVIDE CLEAR INFORMATION ASSIST CLINICAL DECISION MAKING

BACKGROUND Ovarian Theca Cells >> Under the control of LH/IGF-1 >> Produces Testosterone >> Granulosa cells convert (Aromatase enzyme) to active Oestradiol Increased androgen production Increased free androgens

PCOS

CONTROVERSIES Rotterdam criteria is over 10yrs old Serum AMH is under intense debate Misnomer of the term poly“cystic” which is referring to aarested follicles not cysts COCP and the WHO MEC (2015) Ethics of Distributive Justice

PATHOPHYSIOLOGY

Polycystic Ovarian Morphology PCOS OA ~ Oligo-Anovulation HA ~ Hyper-androgenism PCOM ~ Polycystic Ovarian Morphology

OA:Oligo-Anovulation Primary / Secondary Amenorrhoea Oligomenorrhoea Less than 8 episodes of menses a year Cycle length exceeding 35 days (n:21-35) Complications PCOM diagnosis on US > No longer recommended in the presence OA

OA:Oligo-Anovulation Mx AIM Balance the steroid hormones (ER/PR) Compete with Oestrogen at receptor level /Hypothalamic level Block conversion to active hormone – Inhibit Aromatase enzyme Reduce Androgen excess Anti-oestrogenic action Anti-androgenic / Anti-oestrogenic action

OA:Oligo-Anovulation Mx Increase SHBG Suppress of FSH/LH > Negative Feedback on the axis Reduction in free circulating Androgens Regulation of menses > Risk reduction of endometrial hyperplasia / EC Reduce Androgen excess Low dose COCP

OA:Oligo-Anovulation Mx 35mcg Ethinyloestradiol + Cyproterone Acetate not for 1st line in PCOS Consider combining with Metformin in Adolescents or BMI ≥ 25kg/m² Regulation of menses > Risk reduction of endometrial hyperplasia / EC Low dose COCP Reduce Androgen excess

HA: Hyperandrogenism

HA: Hyperandrogenism Biochemical FSH:LH Ratio Testosterone DHEAS AMH Clinical Hirsutism Acne Alopecia Virilisation Grade the Hirsutism > modified Ferriman-Gallwey score Mx: Block the peripheral action of hair follicle 5α Reductase > Testosterone to Di-hydrotestosterone therefore blocked

HA: Hyperandrogenism Mx Grade the Hirsutism > modified Ferriman-Gallwey score (1961) Rx: Block the peripheral action of hair follicle 5α Reductase > Testosterone to Di-hydrotestosterone therefore blocked Lifestyle modification COCP + Drosperinone / Desogestrel / Norgestimate Anti-androgens : Spironolactone 50-200mg / day Cyproterone Acetate 50-100mg (5-15days Induction / Maintenance) *Ensure adequate contraception / Prevent under virilisation of the male foetus* S/E: GI distress, Breast tenderness, Headache, Increased weight, Emotional lability

HA: Hyperandrogenism Mx Insulin Lowering / Increase Insulin Sensitisation Generally off-label / EBM practice Under the control of LH/IGF-1 : Ovarian Theca Cells produce Testosterone Adjunctive BMI ≥ 25kg/m² for Ovulation induction Metformin 500mg tds > Slow release preferred Reduces Hepatic Glucose production / Lowering Insulin levels Possible improvement in Ovarian Steroidogenesis Ovulation induction / Androgen symptoms /Menstrual irregularity S/E: GI distress, Breast tenderness, Headache, Increased weight, Emotional lability

HA: Hyperandrogenism Mx GnRHa Blockade of GnRH > Blockade of FSH / LH Zoladex 3.6mg s/c (3-6 months) Leuprolide 3.75mg imi (3-6 months) Add-back therapy if intolerable side-effects 25-30mcg transdermal Oestradiol Tibolone is great for oestrogen withdrawal S/E: Hot flashes, Reduce Bone mineral density, Atrophic vaginitis, FSD Ovulation induction / Androgen symptoms /Menstrual irregularity S/E: GI distress, Breast tenderness, Headache, Increased weight, Emotional lability

HA: Hyperandrogenism Mx Anti-androgens + COCPs if no control of HA > 6mo

PCOM: Polycystic Morphology

PCOM: Polycystic Morphology Challenge is not so much the size or volume US has poor sensitivity in the background of OA /HA Arrest of Pre-antral follicles Failure of LH surge Leading to failure of Ovulation

MULTI-DISCIPLINARY TEAM Gynaecologist Dietician Physician/Endocrinologist Fertility Specialist Support Groups

Mx of PCOS Dietician Lifestyle modification Moderate exercise (30 minutes /week) Target to normalize BMI Reduction of adipose tissue > Reduces peripheral sites for Androgen production Higher spontaneous pregnancy rates with lifestyle adjustments

Physician/Endocrinologist Mx of PCOS Physician/Endocrinologist Metabolic control IGT / Insulin Resistance Risk of Metabolic syndrome secondary to Obesity Higher incidence of Depressive / Anxiety Disorders

PCOM: Infertility

Mx of PCOS Gynaecologist Fertility Specialist OVULATION INDUCTION AGENTS Letrozole Clomiphene Citrate (CC) 50mg / 100mg /150mg CC + Metformin

OVULATION INDUCTION AGENTS Letrozole Clomiphene Citrate CC + Metformin LETROZOLE Aromatase inhibition Anti-oestrogenic > Reduction up to 98% in Oestrogen levels FDA approved for HR+ Breast cancer Competitively blocks production by binding to the haeme of its CP450 unit Does not reduce production of mineralo-corticosteroids 2.5mg/d usual dosage Doses exceeding 2.5mg/d may cause reduced libido Competitively blocks production by binding to the haeme of its CP450 unit: Action specific to Letrozole Long-term use not advised >> S/S of hypo-oestrogenism, esp Osteoporosis >> Usually prescribed with Fosamax (Bisphosphonate)

OVULATION INDUCTION AGENTS Letrozole Clomiphene Citrate CC + Metformin Clomiphene Citrate Mechanism of stimulating ovulation remains elusive Anti-oestrogenic properties Competes with Oestrogen binding sites Increase in FSH / LH Pre-ovulatory LH surge / Corpus luteum maturation 50mg / 100mg / 150mg Half-life: 5 – 7 days Time to peak: 4 – 10 days Average 7 days Rare cases ovulation may occur late (14 days from last day of treatment)

OVULATION INDUCTION AGENTS Clomiphene Citrate Rare cases ovulation may occur late (14 days from last day of treatment)

Mx of PCOS Support Groups www.pcosaa.org #PCOSsupport

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