PCOS PHENOTYPES LEARNING OBJECTIVES PCOS Phenotypes At the - PowerPoint PPT Presentation

Management of Menstrual Disclosure Irregularities and Hirsutism Nothing to disclose Heather Huddleston, MD Associate Professor University of California San Francisco PCOS PHENOTYPES LEARNING OBJECTIVES PCOS Phenotypes At the conclusion of this presentation, participants should be able to: ● Describe strategies for menstrual cycle management. Oligo-ovulation ● Discuss controversies around use of oral contraceptives in the Hyperandrogenism population. ● Describe strategies for management of the cutaneous manifestations of hyperandrogenism. Polycystic Ovaries Insulin BMI Resistance

PCOS is a multi-system disorder Clinical Features of Importance to Women with PCOS Hyperglycemia Diabetes Depression Obesity Cardiovascular disease Hyperinsulinemia Insulin Resistance Non-Alcoholic Fatty Liver Disease Decreased SHBG Increased Free ovary IGF Androgen Infertility RECEPTO R anovulation Clinical Hyperandrogenism Androgen Gibson-Helm M., Dokras et al. Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary production Syndrome. J Clin Endocrinol Metab. 2016;102(2):604-612. 2017 Feb 01. Distress • Secondary analysis of data collected from 17,015 young, Australian women • Cross sectional study using online questionnaire participating in a national longitudinal cohort study. • Recruitment via support group web sites in 2015 and 2016 • 60% of women reporting a diagnosis of PCOS had moderate to severe levels of psychological distress. • 1385 women with PCOS • Compared to women without PCOS, the odds of moderate to severe psych distress at Survey 2 were significantly higher for women recently diagnosed with • 1/3 reported 2 years and >3 health professionals before a PCOS (AOR 1.52 1.21-2.18). diagnosis was established. • Women recently diagnosed with PCOS also had a greater likelihood of moderate • Satisfied with diagnosis experience: 35.2% to severe distress in the year prior to their diagnosis. • Hormonal contraceptive use did not attenuate the risk of distress among women • Satisfied with information received: 15.6% with PCOS . Rowlands, I.J. et al. Young Women's Psychological Distress After a Diagnosis of Polycystic Ovary Syndrome or Endometriosis. Gibson-Helm M., Dokras et al. Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Hum Reprod 31 (9), 2072-2081. 2016 Jul 13. Syndrome. J Clin Endocrinol Metab. 2016;102(2):604-612. 2017 Feb 01.

PCOS Diagnostic Treatment Plan Perceptions of the PCOS Diagnosis Experience Rotterdam Criteria: • Oligomenorrhea: • Hyperandrogenism: • Polycystic Ovaries: Control of Hyperandrogenism Menstrual Cycle Control Psychology Fertility Long Term Health and Lifestyle Modification Gibson-Helm et al Clin Endocrinol Metab 2017 Feb 1;102(2):604-612. Menstrual Regulation and Endometrial Cancer Menstrual Regulation: Why? ● Irregular cycles indicate Meta-analysis indicates a roughly 3x increased risk of endometrial cancer anovulation, which leads to lack in PCOS, including in pre- of progesterone menopausal women ● Progesterone is needed to Women with PCOS have several antagonize the stimulatory effects risk factors, including of estrogen on endometrium oligomenorrhea, infertility, diabetes, obesity ● Unimpeded estrogen stimulation can lead to hyperplasia or It is likely, but not known, that the risk is primarily linked to lack of endometrial cancer progesterone exposure Degree of risk reduction with OCP is not known, but can be extrapolated Barry, J.A. et al Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014; 20(5):748-758.

Meta-analysis of ever versus never oral contraceptive use Oral contraceptives and cancer risk reduction and endometrial cancer incidence 46,022 women recruited to UK Roual College Oral Contraception study in 1969 and observed for up to 44 years Ever use of oral contraceptives was associated with reduction in endometrial cancer (incidence rate ratio, 0.66 [0.48-0.89]) OCPs result in reduction of endometrial cancer risk of about 50% Iverson L. et al; Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. Institute of Applied Health Jennifer M. Gierisch et al.Cancer Epidemiol Biomarkers Prev 2013;22:1931-1943. Sciences, University of Aberdeen, Aberdeen, UK. Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK. Obstet Gynecol. 2017 Jun;2016(6):580. Oral Contraceptives Strategies for Menstrual Cycle Regulation ● Oral contraceptives ● Cycle progesterone ● Levonorgestrel-releasing intrauterine device Oral contraceptives are first-line management for menstrual abnormalities and hirsutism in PCOS. Legro, R.S. et al. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2013) 98 (12): 4565-4592.

Levonorgestrel IUD in PCOS Levonorgestrel IUD (LNG-IUS) ● 30 patients with PCOS with poor tolerance of Mirena: 20 mcg LNG per day Kyleena: 19.5 mcg LNG per day OCP versus 30 ovulatory Skyla: 14 mcg LNG per day patients, followed for 6 months Often associated with spotting or irregular bleeding LNG-IUS saw decreases in ovarian volume 10%, LDL 5.2%, and total cholesterol for 6 months, followed by amenorrhea 6.7% (p<.05) Fasting glucose increased in LNG-IUS, but decreased 2.6% in controls. Da Silva, A.V., Levonorgestrel-Releasing Intrauterine System for Women With Polycystic Ovary Syndrome: Metabolic and Clinical Effects. Reprod Sci. 2016 Jul;23(7):877-84. Androgens and the Pilosebaceous Unit Management: Hyperandrogenism • Pilosebaceous Unit (PSU) is sensitive to androgens Androgenic • 5 alpha reductase activity Alopecia Acne Hirsutism converts T to DHT binds to PSU with androgen insensitivity with high affinity • Not all patients with hirsutism/acne have elevated androgens and vice versa Escobar-Moreale, H.F et al., Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2011;18(2):146-170.

Hirsutism: Objective Evaluation Symptoms of Androgen Excess: Prevalence ● The modified Ferriman-Gallwey Score is gold standard 40 MFG Score Distribution: UCSF PCOS Cohort ● Cutoff score of 6-8 vs. “patient important hirsutism” 35 (N=409) 30 25 Count MFG Cutoff of > 8 20 Hirsutism: 55% 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 25 27 28 29 30 31 MFG score Huddleston, unpublished data Hirsutism and Quality of Life Hirsutism and the Patient Experience ● 229 women with PCOS completed the Skindex and underwent UCSF PCOS Cohort: 229 Women with Rotterdam PCOS, Ages 14-52 a complete dermatologic exam ● Validated quality of life index for all skin disorders ● Assess impact on three domains: skin symptoms, emotions, social and physical functioning ● Findings: – High degree of effect on emotions and functioning – Rates of distess were higher than for other skin disorders reported in literature – Mean clinical rated was 8.6 MFG, patient rated was 13 Pasch et al Clinician vs Self-ratings of Hirsutism in Patients With Polycystic Ovarian Syndrome. Associations With Quality of Life and Depression.JAMA Dermatol. 2016;152(7):783-788.

Pharmacologic Interventions for Hirsutism Hirsutism and Ethnicity ● Pharmacologic: Androgen Suppression:  OCP  Anti-androgens (spironolactone, flutamide, finasteride)  Insulin Sensitizers/Lifestyle ● Topical: Eflornithine ● Cosmetic Direct Removal ● Choices depend on:  Plans for pregnancy  Degree of hirsutism  Patient preferences Afifi, L. et al. Association of ethnicity, Fitzpatrick skin type, and hirsutism: A retrospective cross-sectional study of women with polycystic ovarian syndrome. Adapted from Reid RL ( 2015 ) Polycystic Ovary Syndrome . http :// dx . doi . org / 10.15226/2374-6890/2/4/00132 International Journal of Women’s Dermatology. Published online 2017 Mar 13. doi: 10.1016/j.ijwd.2017.01.006. Oral Contraceptives: But which route/dose of estrogen? Oral Contraceptives Estrogen Dose: ● Progestins cause suppression of LH levels and inhibition of LH- Varies from 10 ug-35 ug mediated ovarian androgen synthesis. Low-dose (20-25 ug) similar to higher dose ● EE in OCPs leads to increase in SHBG which reduces free T. ● 60%-100% see reduction in hirsutism with OCPs = sufficient to 30-35 ug in T suppression, but has less SHBG effect recommend as a mono-therapy Oral vs. Non-oral ● Variables to consider: Most studies show equivalent effects on SHBG, thus likely similar  Oral versus non-oral? effects for treating symptoms of estrogen excess.  Type of progestin?  Dose of estrogen?  Continuous versus cyclic?