The global burden of androgen excess

Transcription

1 The global burden of androgen excess Educational Slide Kit Module 1 The AWARE group is a panel of independent physicians with an expert interest in androgen excess in women. Formation of the AWARE group and its ongoing work is supported and funded by Bayer AG November 2017 G.MA.WH

2 Testing your knowledge 1. Which of these typical skin symptoms of androgen excess is the most commonly used marker? A. Seborrhea B. Hirsutism C. Acne D. Alopecia 2

3 Testing your knowledge 2. How often can hirsutism be present in women with androgen excess? A. In 2 out of 10 women B. In 4 out of 10 women C. In 6 out of 10 women D. In 8 out of 10 women 3

4 Testing your knowledge 3. How frequently does alopecia occur in women with androgen excess due to PCOS? A. Women with PCOS are not affected by alopecia B. 1 out of 3 women are affected C. 1 out of 5 women are affected D. 1 out of 10 women are affected 4

5 Testing your knowledge 4. When looking at the impact of hyperandrogenic skin symptoms, what proportion of women with hirsutism also report anxiety symptoms? A. Women with hirsutism are rarely affected by anxiety B. Approximately 25% of women are affected by anxiety C. Approximately 50% of women are affected by anxiety D. Approximately 75% of women are affected by anxiety 5

6 Module content Defining androgen excess and its prevalence The burden of androgen excess Hyperandrogenic skin symptoms impact on: Quality of life Health and wellbeing Healthcare systems 6

7 Defining androgen excess 7

8 Defining androgen excess Androgen excess in women can be characterised by either clinical symptoms of hyperandrogenism and/or biochemical hyperandrogenism 1 Clinical hyperandrogenism Biochemical hyperandrogenism Clinical hyperandrogenism, where the pilosebaceous unit has increased sensitivity to normal serum androgen levels and causes hyperandrogenic skin symptoms. Clinical and biochemical hyperandrogenism Biochemical hyperandrogenism, where there is excessive production and/or secretion of androgens, which may be of ovarian or adrenal origin 1. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 2. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:

9 Prevalence and presentation of androgen excess 9

10 Androgen excess* is the most common reproductive endocrine disorder in women 1 *Biochemical and/or clinical It affects up to 1 in 5 women of reproductive age 2 The majority of women with hyperandrogenism (80 85%) have polycystic ovary syndrome (PCOS) 3,4 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Lizneva D, et al.fertil Steril 2016;106(1):6 15; 3. Ehrmann DA. N Engl J Med 2005; 352(12): ; 4. Carmina E, et al. J Clin Endocrinol Metab 2006;91(1):2 6; 5. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:

11 Women can present with a combination of different symptoms 1,2 In some cases, women present with all four hyperandrogenic skin symptoms, described as the SAHA syndrome 3,4 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89: ; 3. Orfanos CE, et al. Horm Res. 2000;54:251-8; 4. Fauser BCJM, et al. Fertil Steril 2012;97:

12 Hirsutism is the most commonly used marker for diagnosis of androgen excess 1 It is present in up to 8 out of 10 women with androgen excess 1 * Indicated by excess body or facial terminal (coarse) hair growth in females in a male-like pattern 2 Prevalence varies according to ethnicity 2 *Depending on criteria for definition and population studies 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):

13 Acne is an extremely common, chronic skin condition 1,2 Acne is caused by androgen excess in approximately 1 in 6 women 3 1. Zhara Ghodsi S, et al. J Invest Dermatol 2009;129,: ; 2. Zouboulis CC, et al. Horm Metab Res 2007;39:85 95; 3. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:

14 Alopecia in women is most commonly caused by androgen excess 1 Affects approximately 1 in 3 of women with PCOS 2 Characterised by overall thinning of scalp hair mainly in frontal and parietal areas 1 Commonly presents with other skin symptoms of androgen excess Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:

15 Seborrhea can also present as a symptom of androgen excess 1 Causes a red, itchy rash and white scales and can affect the scalp, face and body Often occurs alongside other skin symptoms of androgen access (SAHA syndrome) 1 Presents in approximately 1 in 5 women with hyperandrogenism Is a useful marker of androgen metabolic disorders 2 1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22: ; 2. Orfanos CE. Arch Arg Derm 1982;32(suppl 1):

16 The burden of androgen excess 16

17 Hyperandrogenic skin symptoms cause significant quality of life and psychological impairment 1-3 Both hirsutism and acne can significantly and negatively impact on quality of life and cause anxiety and depression 1-3 Alopecia has a negative effect on self-esteem, psychological wellbeing and body image 3 1. Ekbäck MP, et al. Dermatology. 2013;227(3):278 84; 2. Gupta MA & Gupta AK. Br J Dermatol 1998;139(5):846 50; 3. Sawaya ME. Dermatologic Clinics 1997;15(1):37-43; 4. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):

18 Hirsutism can significantly and negatively impact on quality of life 1 Effect measured by Dermatology Life Quality Index (DLQI) n= % 19.8% 21.4% Extremely large (21-39) Very large (11-20) Moderate (6-10) 13.5% 35% Small (2-3) None (0-1) DLQI: Dermatology Quality of Life Index 1. Palmetun Ekba ck, M, et al. Dermatology 2013;227:

19 Hirsutism negatively affects multiple healthrelated quality of life domains 1 75% of women report anxiety 2 of women report 30% depression 2 29% of women report both anxiety and depression 2 1. Ekbäck MP, et al. Dermatology. 2013;227(3):278 84; 2. Lipton MG, et al. J Psychosom Res 2006;61(2):

20 Acne also has a significant impact on quality of life 1-4 Clinically important depression and anxiety have been reported in 18% and 44% of acne patients respectively 4 1. Aktan S, et al. Int J Dermatol 2000;39:354 7; 2. Koo JYM & Smith LL. Pediatr Dermatol 1991;8:185 8; 3. Stern RS. J Am Acad Dermatol 2000;43:1042 8; 4. Kellett SC & Gawkrodger DJ. Br J Dermatol 1999;140:

21 Androgen excess due to biochemical hyperandrogenism may have long-term impact on general health 1-3 With increasing age, there is a change in presenting symptoms and health implications Women with abnormalities in androgen metabolism may have accompanying anovulation and/or polycystic ovary syndrome (PCOS) These have reproductive and metabolic implications if left untreated 1. Fauser BCJM, et al. Fertil Steril. 2012;97:28 38; 2. Chittenden BG, et al. Reprod Biomed Online. 2009;19: ; 3. Barry J, et al. Human Reprod Update. 2014;20(5):

22 Androgen excess represents a significant financial burden to healthcare systems 1 Symptoms included in literature review Prevalence (%) Annual cost in millions US$ (% of total) Initial evaluation 99 (2.3) Treatment Menstrual dysfunction/abnormal uterine bleeding (30.9) Hirsutism* (14.2) Infertility (17.2) Type 2 diabetes (40.4) Total cost 4370 * Treatment of hirsutism includes both cosmetic and hormonal therapies but does not take into account management of psychological and QoL impact or women s own expenditure on treatment 1. Azziz R, et al. J Clin Endocrinol Metab 2005;90:

23 Conclusions Androgen excess affects up to 1 in 5 women of reproductive age 1 Presenting symptoms include hyperandrogenic skin symptoms (Seborrhea, Acne, Hirsutism and Alopecia) alone or in combination with menstrual irregularities and infertility 2,3,4 It is associated with significant quality of life impairment and negative quality of life 5,6,7 Although data is limited, evidence shows it can be a significant economic burden 8 1. Lizneva D, et al. Fertil Steril 2016;106(1):6 15; 2. Orfanos CE, et al. Horm Res. 2000;54: ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Ekbäck MP, et al. 2013;227(3):278 84; 5. Gupta MA & Gupta AK. Br J Dermatol 1998;139(5):846 50; 6. Sawaya ME. Dermatol Clin 1997;15(1):37-43; 7. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 8. Azziz R, et al. J Clin Endocrinol Metab 2005;90:

24 Testing your knowledge 1. Which of these typical skin symptoms of androgen excess is the most commonly used marker? A. Seborrhea B. Hirsutism C. Acne D. Alopecia 1 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):

25 Testing your knowledge 2. How often can hirsutism be present in women with androgen excess? A. In 2 out of 10 women B. In 4 out of 10 women C. In 6 out of 10 women D. In 8 out of 10 women 1 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):

26 Testing your knowledge 3. How frequently does alopecia occur in women with androgen excess due to PCOS? A. Women with PCOS are not affected by alopecia B. 1 out of 3 women are affected C. 1 out of 5 women are affected D. 1 out of 10 women are affected 1 1. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:

27 Testing your knowledge 4. When looking at the impact of hyperandrogenic skin symptoms, what proportion of women with hirsutism also report anxiety symptoms? A. Women with hirsutism are rarely affected by anxiety B. Approximately 25% of women are affected by anxiety C. Approximately 50% of women are affected by anxiety D. Approximately 75% of women are affected by anxiety 1 1. Lipton MG, et al. J Psychosom Res 2006;61(2):

28 Recognition and diagnosis of androgen excess Educational Slide Kit Module 2 The AWARE group is a panel of independent physicians with an expert interest in androgen excess in women. Formation of the AWARE group and its ongoing work is supported and funded by Bayer AG November 2017 G.MA.WH

29 Testing your knowledge 1. Which of the following could be a non-hormonal cause of acne? A. Genetic predisposition B. Medication use C. Cosmetics D. All of the above 29

30 Testing your knowledge 2. What is SAHA syndrome? A. SAHA Skin, Acne, Hyperandrogenism, Alopecia B. Simultaneous presentation of seborrhea, acne, hirsutism and alopecia C. SAHA - Serum, Androgens, Hair loss, Acne D. Simultaneous presentation of specifically distributed acne and hirsutism in androgen excess 30

31 Testing your knowledge 3. In addition to androgen-secreting tumours which of the following conditions can also cause androgen excess A. Polycystic ovary syndrome (PCOS) B. Thyroid dysfunction C. Non-classic congenital adrenal hyperplasia (NCAH) D. All of the above 31

32 Testing your knowledge 4. Why is early recognition and treatment of androgen excess important? A. Hyperandrogenic skin symptoms cause significant quality of life and psychological impairment B. Androgen excess due to biochemical hyperandrogenism may have a long-term impact on general health C. Androgen excess represents a significant health economic burden D. All of the above 32

33 Module content Challenges in the recognition of androgen excess Rationale for early diagnosis and treatment A diagnostic pathway: Ask, Assess, Consider, Test Further investigations Resources 33

34 Challenges in the recognition of androgen excess 34

35 Global and ethnic differences in prevalence and primary presentation of androgen excess 1,2 Women in far-east Asia present less frequently with hirsutism than Western women 1 Thickness of body hair is greater in Caucasian women than Asian women 2 Increased risk of insulin resistance in African- American women 2 1. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650 8; 2. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):

36 Women can present with a combination of non-specific symptoms 1,2 In some cases, women present with all four hyperandrogenic skin symptoms, described as the SAHA syndrome 3,4 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89: ; 3. Orfanos CE, et al. Horm Res. 2000;54:251-8; 4. Fauser BCJM, et al. Fertil Steril 2012;97:

37 Sometimes skin symptoms are mistakenly seen as just a cosmetic problem Women with hirsutism and some practitioners, still believe this abnormality to be primarily a cosmetic disturbance 1 Many women therefore seek help from a beautician, cosmetologist or electrologist in preference to a physician 2,3 Acne can be seen as an adolescent problem that will resolve with age 4 1. Yildiz B, et al. Hum Reprod Update 2010;16(1):51 64; 2. Dumesic DA, et al. Int J Fertil Womens Med 1997;42: ; 3. Farah L, et al. J Reprod Med 1999;44:870 4; 4. Dréno B, et al. J Eur Acad Dermatol Venereol 2014;29:

38 Not all acne is specific to a disorder of androgen metabolism Hormonal influences Menstrual cycle Pregnancy (+/- effect) Polycystic ovary syndrome (PCOS) Androgen excess is the cause of acne in approximately 1 in 6 women 1 Hormone treatment (e.g. oral contraceptives) Non-hormonal influences Genetic predisposition Medication use (e.g. iodine, lithium, isoniazid, phenytoin, cyclosporine) Cosmetics (e.g. oil- or cocoa butter-containing products) Competitive sport Lifestyle aspects (e.g. smoking or diet, the latter possibly related to consumption of dairy products or foods with a high glycemic index) Pressure or friction on the skin (e.g. bike helmet straps) 1. Sirmans S & Pate KA. Clin Epidemiol 2014;6:1 13; 2. NHS choices. Last reviewed (April 2016); 3. Redmond GP. Int J Fertil Womens Med 1998;43(2):9-17; 4. Darney PD. Int J Fertil Womens Med 1997;Suppl 1:158 69; 5. Grossman Barr N. Am Fam Physician. 2010;82(12):

39 Although hirsutism is a recognised marker of androgen excess... 1 less frequently, it can also be caused by ovarian or adrenal dysfunction 2,3 Etiology Frequency (%) 1 Polycystic ovary syndrome (PCOS) 71 Idiopathic hyperandrogenism 15 Idiopathic hirsutism 10 Non-classic congenital adrenal hyperplasia (NCCAH) Androgen-secreting tumors Yildiz, B. Best Pract Res Clin Endocrinol Metab 2006;20(2): ; 2. Bode D, et al. Am Fam Physician 2012;85(4): ; 3. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):

40 Assessment of skin symptoms is not always straightforward 1 Women may present in a variety of settings. Use of validated assessment tools outside dermatology or clinical trial settings is rare 2 When they are used, confirmation of hirsutism for example can be further complicated by: 1 The semi-quantitative approach of the modified Ferriman-Gallwey (mf-g) scale 1 High inter-observer variability Lack of consensus regarding the score that defines hirsutism Self-care such as shaving or waxing may limit full assessment of severity 1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 2. Azziz R, et al. Nat Rev Dis Primers. 2016;2:

41 Rationale for early diagnosis and treatment 41

42 Why is early recognition and treatment of androgen excess important? Hyperandrogenic skin symptoms cause significant quality of life and psychological impairment 1-4 Androgen excess due to biochemical hyperandrogenism may have a long-term impact on general health 5 Androgen excess therefore represents a significant health economic burden 6 1. Ekbäck MP, et al. Dermatology. 2013;227(3):278 84; 2. Gupta MA & Gupta AK. Br J Dermatol 1998;139(5):846 50; 3. Sawaya ME. Dermatologic Clinics 1997;15(1):37-43; 4. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 5. Fauser BCJM, et al. Fertil Steril. 2012;97:28 38; 6. Azziz R, et al. J Clin Endocrinol Metab 2005;90:

43 A diagnostic pathway Ask, Assess, Consider Test 43

44 Four key steps in the recognition and diagnosis of androgen excess 44

45 What to ask 1,2 Previous or ongoing treatment and/or self care (e.g. use of makeup, shaving, waxing) Detailed history of menstrual pattern 1 Menstrual irregularity 1 Ovulatory dysfunction Detailed family history of similar disorders 2 Why? Make-up or regular waxing or shaving can disguise the symptom severity Hyperandrogenic skin symptoms and menstrual or ovulatory dysfunction could indicate polycystic ovary syndrome (PCOS) 1. Sirmans S & Pate KA. Clin Epidemiol. 2014;6:1 13; 2. Azziz R & Kashar-Millar MD. J Pediatr Endocrinol Metab 2000;13 Suppl 5:

46 1 Seborrhea Hirsutism Alopecia Acne Body mass index (BMI) Waist/height ratio (WHR) Blood pressure (BP) 1. Sirmans S and Pate KA. Clin Epidemiol 2014;6:

47 1-2 Clinical signs of acne include greasy skin, altered keratinisation inflammation and bacterial colonisation by P Acnes 1,2 Comedonal acne Papulo-pustular acne. Nodular acne *For assistance with the identification of acne due to androgen excess, please see the AWARE Educational manual: Female acne for non-dermatologists 1. Gollnick H & Zouboulis CC. Deutsches Arzt Int 2014;111(17): ; 2. Shen Y. Acta Derm Venereol 2012;92:

48 1-4 Hirsutism is evaluated and quantified by the modified Ferriman- Gallwey score Ferriman D & Gallwey JD. J Clin Endocrinol Metab. 1961;21: ; 2. Hatch R et al. Am J Obstet Gynecol. 1981;140: ; 3. Derksen J et al. Br J Dermatol 1993;128: ; 4. Goodman NF et al. Endocr Pract. 2001;7:

49 1-5 Emotional wellbeing Quality of life Long-term health 1. Ekback MP et al. Dermatol. 2013;227: ; 2. Aktan et al. Int J Dermatol 2000;39: ; 3. Koo JYM & Smith LL. Pediatr Dermatol 1991;8: ; 4. Stern RS. Dermatol 2000;43: ; 5. Kellet SC and Gawkrodger DJ. Br J Dermatol. 1999;140(2):

50 1 A number of conditions can cause androgen excess - Polycystic ovary syndrome (PCOS) - Thyroid dysfunction - Androgen-secreting tumours - Non-classic congenital adrenal hyperplasia (NCAH) Other potential causes of skin symptoms of androgen excess - Androgenic medications - Skin irritants - Genetic predisposition 1. Sirmans S & Pate KA. Clin Epidemiol. 2014;6:

51 1 Confirming the cause of androgen excess 1-3 Laboratory tests to exclude other disorders: Serum thyroid stimulating hormone (TSH) Serum prolactin Serum 17- hydroxyprogesterone (OHP) Also important to assess: Quality of life When PCOS is suspected, additional tests are used Confirm PCOS Serum testosterone Ultrasound ovarian morphology Confirm severity of dysfunction Anti-Mullerian hormone (AMH) Sex hormone binding globulin (SHBG) Metabolic tests 1. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2. Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:

52 Essentials for the identification of androgen excess in women of reproductive age 52

53 Risk factors prompting further investigation Suspicion of androgensecreting tumour Undiagnosed bleeding Severe psychological morbidity for example, severe anxiety and/or depression Scarring acne Fertility problems 53

54 Some practical reminders 54

55 Remember The cause of androgen excess is not always detectable using biochemical tests In some cases, clinical symptoms result from the hypersensitivity of skin tissue to normal androgen levels. However, the clinical symptoms causing psychological distress or impaired quality of life should still be addressed Menstrual irregularity can be a good indicator of PCOS, particularly in combination with clinical hyperandrogenic skin symptoms 55

56 Conclusions There are a number of challenges in the recognition of androgen excess, including: Global and ethnic differences in prevalence and primary presentation 1,2 Presentation of a combination of non-specific symptoms 3,4 Difficulty assessing skin symptoms 2,5 Early recognition and diagnosis of androgen excess is important It allows prompt treatment of hyperandrogenic skin symptoms and can lead to improvements in quality of life and psychological wellbeing 6-10 Despite the challenges, there are tools and resources available to help aid awareness and aid diagnosis 1. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650 8; 2. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2): ; 3. Orfanos CE. Arch Arg Derm 1982;32(suppl 1):51 5; 4. Fauser BCJM, Tarlatzis BC, Rebar RW, et al. Fertil Steril 2012;97:28 38; 5. Yildiz, B. Best Pract Res Clin Endocrinol Metab 2006;20(2): ; 6. Ekback MP et al. Dermatol. 2013;227: ; 7. Aktan et al. Int J Dermatol 2000;39: ; 8. Koo JYM & Smith LL. Pediatr Dermatol 1991;8: ; 9. Stern RS. Dermatol 2000;43: ; 10. Kellet SC and Gawkrodger DJ. Br J Dermatol. 1999;140(2):

57 Resources 57

58 Tools and resources available to aid awareness & diagnosis of AE Checklists Manuscripts Case Studies Interactive Educational Manual for the Treatment of Acne 58

59 Testing your knowledge 1. Which of the following could be a non-hormonal cause of acne? A. Genetic predisposition B. Medication use C. Cosmetics D. All of the above 1 1. NHS choices. Acne causes Available at: (Last reviewed April 2016) 59

60 Testing your knowledge 2. What is SAHA syndrome? A. SAHA Skin, Acne, Hyperandrogenism, Alopecia B. Simultaneous presentation of seborrhea, acne, hirsutism and alopecia 1,2 C. SAHA - Serum, Androgens, Hair loss, Acne D. Simultaneous presentation of specifically distributed acne and hirsutism in androgen excess 1. Orfanos CE, et al. Horm Res. 2000;54:251-8; 2. Fauser BCJM, et al. Fertil Steril 2012;97:

61 Testing your knowledge 3. In addition to androgen-secreting tumours which of the following conditions can also cause androgen excess A. Polycystic ovary syndrome (PCOS) B. Thyroid dysfunction C. Non-classic congenital adrenal hyperplasia (NCAH) D. All of the above 1 1. Sirmans S and Pate KA. Clin Epidemiol 2014;6:

62 Testing your knowledge 4. Why is early recognition and treatment of androgen excess important? A. Hyperandrogenic skin symptoms cause significant quality of life and psychological impairment B. Androgen excess due to biochemical hyperandrogenism may have a long-term impact on general health C. Androgen excess represents a significant health economic burden D. All of the above Ekbäck MP, et al. Dermatology. 2013;227(3):278 84; 2. Gupta MA & Gupta AK. Br J Dermatol 1998;139(5):846 50; 3. Sawaya ME. Dermatologic Clinics 1997;15(1):37-43; 4. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2): ; 5. Fauser BCJM, et al. Fertil Steril. 2012;97:28 38; 6. Azziz R, et al. J Clin Endocrinol Metab 2005;90:

63 Best practice in the treatment of hyperandrogenic skin symptoms Educational Slide Kit Module 3 The AWARE group is a panel of independent physicians with an expert interest in androgen excess in women. Formation of the AWARE group and its ongoing work is supported and funded by Bayer AG November 2017 G.MA.WH

64 Testing your knowledge 1. What do you think is the most important goal of treatment of hyperandrogenic skin symptoms? A. Improve clinical symptoms i.e. reduce hair growth or number and severity of acne lesions B. Restore menstrual function C. Minimize psychological and QoL impairment D. It depends on the individual patient s needs and goals of treatment 64

65 Testing your knowledge 2. What is the aim of pharmacological treatment for the skin symptoms of androgen excess? A. Reducing amount of androgens produced B. Controlling androgen effects at tissue level C. Reducing the level of free testosterone D. All of the above 65

66 Testing your knowledge 3. Which of the following statements is true about antiandrogenic potential of EE/progestogen combinations? A. EE/progestogen combinations have no antiandrogenic potential B. Different combinations of EE/progestogen have varied antiandrogenic potential C. All EE/progestogen combinations have the same antiandrogenic potential D. None of the above 66

67 Testing your knowledge 4. A patient with androgen excess should always be referred if you suspect an androgen-secreting tumour. What other circumstances might you refer a patient with androgen excess? A. Undiagnosed bleeding B. Severe psychological morbidity for example, severe anxiety and/or depression C. Scarring acne D. Fertility problems 67

68 Module content Aims of treatment for hyperandrogenic skin symptoms Treatment options Rationale for antiandrogen treatment Role of antiandrogens as combined hormone treatment The AWARE treatment proposal 68

69 Aims of treatment for androgen excess 69

70 Goals of treatment for androgen excess 1-4 In women with clinical hyperandrogenism: Improve clinical symptoms i.e. reduce hair growth or number and severity of acne lesions Restore menstrual function (if needed) Minimize psychological and QoL impairment In women with biochemical hyperandrogenism: Reduce the risk of long-term metabolic and reproductive complications 1. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2.Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):

71 Treatment options for hyperandrogenic skin symptoms 71

72 Overview of treatment options Lifestyle management Aimed at reducing the risk of longterm metabolic consequences 1,2 Topical or cosmetic options 1 Targets hyperandrogenic skin symptoms such as hirsutism and acne Pharmacological treatment 1 Aimed at reducing the level of circulating androgens and controlling their effect at tissue level 1. Goodman NF, et al. Endocrin Pract 2015;21(11): ; 2. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD

73 Lifestyle management 1 Lifestyle management should be a core part of treatment to improve metabolic and psychological consequences associated with this condition 1-3 *Where necessary to reduce weight/bmi 1 1. Teede HJ, et al. Med J Aust Sep 19;195(6):S65-112; 2. Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD

74 Topical or cosmetic treatments options 1,2 Cosmetic options for treatment of hirsutism mainly involve hair removal Shaving, plucking, or waxing Use of depilatory creams or epilators Electrolysis or laser hair removal Eflornithine cream Topical options for treatment of acne mainly involve use of: Topical retinoids, such as isoretinoin or adpalene Azaleic acid Benzoyl peroxide Topical antiobiotics such as tetracyclines 1. Goodman NF, et al. Endocrine Pract 2015;21(11): ; 2. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD

75 Pharmacological treatment options Treatment is aimed at reducing the level of circulating androgens and controlling their effect at tissue level 1 Antiandrogens, such as cyproterone acetate and spironolactone Finasteride Insulin-sensitizers, such as metformin and pioglitazone GnRH* analogues, such as goserelin and leuprorelin *Gonadotrophin-releasing hormone 1. Goodman NF, et al. Endocrin Pract 2015;21(11):

76 Rationale for antiandrogen treatment 76

77 Antiandrogens in the treatment of skin symptoms such as hirsutism and acne 1-5 Total testosterone Sex hormone binding globulin (SHBG) Free testosterone 5 -reductase Treatment is focused on: Reducing androgen production Decreasing the fraction of circulating free testosterone Limiting androgen bioactivity to sebaceous gland and hair follicles Dihydrotestosterone (DHT) Androgen receptor in sebaceous gland Sebum production and hair growth 1. Goodman NF, et al. Endocrine Pract 2015;21(11): ; 2. Azziz R et al. Idiopathic hirsutism. Endocr Rev 2000; 21: ; 3. Mofid A et al. Hirsutism. Int J Clin Pract 2008; 62: ; 4. Neithardt AB, Barnes RB. Semin Reprod Med 2003; 21: ; 5. Azziz R. Obstet Gynecol 2003; 101:

78 Cyproterone Acetate (CPA): a steroidal antiandrogen 1-6 CPA is a steroid compound with potent Antigonadotropic properties Antiandrogenic activities Progestogenic activities 1. Neumann F. Exp Clin Endocrinol 1994;102:1 32; 2. Spona J & Huber J. Gynecol Obstet Invest 1987;23:184 93; 3. Fang S & Liao S. Mol Pharmacol 1969;5:428 31; 4. Fedele L, et al. Contraception 1987;35: ; 5. Neumann F. Postgrad Med J 1978;54 Suppl 2:11 24; 6. Aydinlik S, et al. Clinical Trials Journal 1990;27:

79 CPA targets hyperandrogenic skin symptoms via two mechanisms Total testosterone Sex hormone binding globulin (SHBG) CPA: Increases sex hormone binding globulin Free testosterone X 5 -reductase Dihydrotestosterone (DHT) Androgen receptor in sebaceous gland X CPA: Targets binding of DHT to androgen receptors Sebum production and hair growth 1. Neumann F. Exp Clin Endocrinol 1994;102:1 32; 2. Spona J & Huber J. Gynecol Obstet Invest 1987;23:184 93; 3. Fang S & Liao S. Mol Pharmacol 1969;5:428 31; 4. Fedele L, et al. Contraception 1987;35: ; 5. Neumann F. Postgrad Med J 1978;54 Suppl 2:11 24; 6. Aydinlik S, et al. Clinical Trials Journal 1990;27:

80 CPA also affects synthesis and secretion of ovarian androgens 1-3 Hypothalamus CPA interacts with GnRH receptors in the pituitary gland blocking the release of LH and FSH Brain Pituitary gland Inhibition of FSH and LH leads to a decline in ovarian androgen production and a reduction in free testosterone Ovary CPA, cyproterone acetate; FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone 1. Badawy A & Elnashar A. Int J Womens Health. 2011;3:25-35; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3): ; 3. Barbieri RL. Trends Endocrinol Metab. 1992;3(1):

81 Role of antiandrogens as combined hormone treatment 81

82 Different combinations of EE/progestogen have varied antiandrogenic potential 1-3 Decreasing antiandrogenic effect Progestogen CPA CMA DNG DRSP Mode of action Inhibits the activity of 5-alpha-reductase and androgen synthesis in the skin and decreases androgen blood concentration through an antigonadotrophic effect. Inhibits the activity of 5-alpha reductase in the skin and reduces ovarian and adrenal androgen production via its antigonadotrophic effect. Possesses strong progestational effects and moderate Antiandrogenic and antigonadotrophic effects. Blocks ovarian steroid production, reduces adrenal androgen synthesis and blocks peripheral androgen receptors in the skin. CPA/EE has the greatest antiandrogen potential of hormonal treatments containing a combination of progestogens and EE Sirmans SM, Pate KA. Clin Epidemiol 2014;6:1 13; 2. Zouboulis CC, et al. Horm Metab Res 2007;39:85 95; 3. Sitruk-Ware R. Hum Reprod Update 2006;12: ; 4. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22: ; 5. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

83 Combination CPA/EE * treatment effectively treats hyperandrogenic skin symptoms and menstrual dysfunction 1,2 Significant reduction in: 1 Acne lesions count and severity at 6 months Hirsutism score (mf-g) and use of cosmetic treatments at 6 months Sebum production and seborrhea at 9 months Additional benefits of menstrual regularity and effective contraception 2 Reduction in long-term risk of endometrial hyperplasia and endometrial cancer 2 *CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate 1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22: ; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

84 Cardiovascular safety with EE/progestogen combinations Use of estrogen/progestogen combinations is associated with an increased risk for VTE (DVT or PE) 1,2 The use of CPA/EE carries an increased risk of VTE/ATE compared with no use or LNG/EE use Highest during the 1 st year of use Highest when restarting or switching from another OC* However, the risk of VTE during COC use remains lower than that during pregnancy and childbirth 3,4 ATE, Arterial thromboembolism; LNG, levonorgestrel; COC, Combined oral contraceptive; DVT, Deep vein thrombosis; PE, Pulmonary embolism; OC, Oral contraceptive; VTE, Venous thromboembolism; CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate 1. OC class label; 2. Rosendaal MD. Lancet 1999;353(9157): ; 3. Dinger JC, et al. Contraception 2007;75(5): ; 4. Heit et al. Ann Intern Med 2005;143(10):

85 Cardiovascular safety with EE/progestogen combinations (continued) Due to its labeled indication, CPA/EE may channel use towards women with an inherently higher cardiovascular risk 1,2 Observational studies of VTE risk with CPA/EE compared to LNG-containing and other COCs (low-estrogen <0.05mg) yield varying findings Some studies reported a greater VTE risk, comparable to so-called 3rd generation COCs 3 5 Other studies showed no differences in VTE risk 1,6,7 Studies that addressed the issue of confounding or duration of use concluded that the VTE risk is not significantly higher 1,7 COC, Combined oral contraceptive; LNG, Levonorgestrel; PCOS, Polycystic ovary syndrome; VTE, Venous thromboembolism; CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate. 1. Seaman HE, et al. Pharmacoepidemiol Drug Saf 2004;13(7): ; 2. Bird ST, et al. J Thromb Haemost 2013;11(6): ; 3. Vasilakis-Scaramozza C et al. Lancet 2001;358(9291):1427 9; 4. Seaman HE, et al. Hum Reprod 2003;18(3):522 6; 5. Lidegaard Ø, et al. Acta Obstet Gynecol Scand 2013;92(10): ; 6. Lidegaard Ø, et al. J Obstet Gynaecol Can 2003;25(7):575 7; 7. EURAS

86 The AWARE treatment proposal 86

87 Challenges in the management of androgen excess 1 Identifying different presenting symptoms and their pathophysiology Understanding the role of non-hormonal and hormonal treatment Effective treatment of presenting clinical symptoms e.g. skin manifestations and menstrual dysfunction Identifying and managing associated syndromes e.g. polycystic ovary syndrome Managing patient expectations of treatment outcomes Balancing risks and benefits of long-term treatment through life stages Managing long-term metabolic syndrome and reproductive consequences 1. Redmond GP. Int J Fertil Womens Med 1998;43(2):

88 The AWARE treatment proposal addresses these challenges 88

89 Important elements of patient communication when discussing treatment Chen J, et al. Health Educ Behav 2016;43(1):25-34; 2. Brown MT & Bussell JK. Mayo Clin Proc. 2011:86(4): ; 3. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:

90 Treatment needs to be targeted at all symptoms Effective treatment of seborrhea, acne, hirsutism and alopecia can help to improve quality of life and psychological impairment associated with clinical hyperandrogenism 1,2 Hyperandrogenic skin symptoms can arise due to biochemical hyperandrogenism, treatment of which can help reduce the risk of both reproductive and metabolic/ cardiovascular consequences associated with long-term androgen excess disorders 3,4 1. Tartagni M, et al. Fertil Steril. 2000;73(4):718 23; 2. Chung JP, Yiu AK, Chung TK, et al. J Pediatr Adolesc Gynecol. 2014;27(3):166 71; 3. Fauser BCJM, et al. Am Soc Rep Med. 2012;97(1):28-38.e25; 4. Legro RS, et al. J Clin Endocrinol Metabol. 2013;98(12):

91 Factors to consider before prescribing combined hormonal treatment Use established treatment combinations for androgen excess 1,3 1,2 Screen patients using WHO MEC for guidance in the prescribing of estrogen/progestogen combinations 1 1. WHO MEC. 5th ed. 2015; 2. Yildiz BO. Semin Reprod Med. 2008;26: ; 3. Dianette SmPC 91

92 When to refer women with androgen excess 1,2 1. Fauser BCJM, et al. Am Soc Rep Med. 2012;97(1):28-38.e25; 2. Legro RS, et al. J Clin Endocrinol Metabol. 2013;98(12):

93 Conclusions Treatment of androgen excess aims to: 1-5 Reduce the level of circulating androgens and control their effect at tissue level Improve clinical hyperandrogenic skin symptoms and associated psychological impairment 6 and restore menstrual regularity where needed Reduce the risk of long-term reproductive and metabolic consequences of biochemical hyperandrogenism Options include cosmetic or topical treatments, pharmacological therapy and lifestyle management 1,7 CPA/EE offers effective treatment of hyperandrogenic skin symptoms and menstrual dysfunction 8 1. Goodman NF, et al. Endocrine Pract 2015;21(11): ; 2. Azziz R et al. Idiopathic hirsutism. Endocr Rev 2000; 21: ; 3. Mofid A et al. Hirsutism. Int J Clin Pract 2008; 62: ; 4. Neithardt AB, Barnes RB. Semin Reprod Med 2003; 21: ; 5.Azziz R. Obstet Gynecol 2003; 101: ; 6. Brady C, et al. Drug, Healthc and Patient Saf 2009:1 9-15; 7. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD doi: / CD pub2; 8. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

94 Testing your knowledge 1. What do you think is the most important goal of treatment of hyperandrogenic skin symptoms? A. Improve clinical symptoms i.e. reduce hair growth or number and severity of acne lesions B. Restore menstrual function C. Minimize psychological and QoL impairment D. It depends on the individual patient s needs and goals of treatment Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2.Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):

95 Testing your knowledge 2. What is the aim of pharmacological treatment for the skin symptoms of androgen excess? A. Reducing amount of androgens produced B. Controlling androgen effects at tissue level C. Reducing the level of free testosterone D. All of the above 1 1. Goodman NF, et al. Endocrine Pract 2015;21(11):

96 Testing your knowledge 3. Which of the following statements is true about antiandrogenic potential of EE/progestogen combinations? A. EE/progestogen combinations have no antiandrogenic potential B. Different combinations of EE/progestogen have varied antiandrogenic potential1-3 C. All EE/progestogen combinations have the same antiandrogenic potential D. None of the above 1. Sirmans SM, Pate KA. Clin Epidemiol 2014;6:1 13; 2. Zouboulis CC, et al. Horm Metab Res 2007;39:85 95; 3. Sitruk-Ware R. Hum Reprod Update 2006;12:

97 Testing your knowledge 4. A patient with androgen excess should always be referred if you suspect an androgen-secreting tumour. What other circumstances might you refer a patient with androgen excess? A. Undiagnosed bleeding B. Severe psychological morbidity for example, severe anxiety and/or depression1,2 C. Scarring acne 1,2 D. Fertility problems 1,2 1,2 1. Fauser BCJM, et al. Am Soc Rep Med. 2012;97(1):28-38.e25; 2. Legro RS, et al. J Clin Endocrinol Metabol. 2013;98(12):

98 Polycystic ovary syndrome (PCOS) Educational Slide Kit Module 4 The AWARE group is a panel of independent physicians with an expert interest in androgen excess in women. Formation of the AWARE group and its ongoing work is supported and funded by Bayer AG November 2017 G.MA.WH

99 Testing your knowledge 1. How frequently does PCOS occur in women of reproductive age? A. 1 out of 3 B. 1 out of 4 C. 1 out of 5 D. 1 out of 6 99

100 Testing your knowledge 2. How often is amenorrhea related to PCOS? A % of cases B % of cases C % of cases D. More than 60% of cases 100

101 Testing your knowledge 3. Which PCOS phenotype(s) represents a higher risk for metabolic dysfunction? A. A only B. A and B C. A, B and C D. All phenotypes A, B, C and D 101

102 Testing your knowledge 4. Which of the following approaches is most relevant in the management of PCOS? A. Lifestyle modification B. Topical or cosmetic options C. Pharmacological treatment D. All of the above 102

103 Module content Defining polycystic ovary syndrome (PCOS) Presentation and prevalence of PCOS The burden of PCOS on health and quality of life Diagnosis and exclusion of other disease causes Treatment of PCOS and management of long term implications 103

104 Defining PCOS 104

105 Defining Polycystic ovary syndrome (PCOS) 1 Rotterdam (2003) Diagnostic criteria for PCOS - two out of three of: Clinical hyperandrogenism or biochemical hyperandrogenism OR Irregular menses OR Polycystic ovaries on ultrasound, after excluding other endocrine causes such as hyperprolactinemia 1. Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Hum Reprod 2004;19:

106 The importance of phenotypic definition of PCOS 1 Those with classic PCOS phenotypes i.e. A and B are at greatest risk of metabolic dysfunction Parameter Phenotype A Phenotype B Phenotype C Phenotype D PCOS features HA/OD/PCOM HA/OD HA/PCOM OD/PCOM Hyperandrogenism (HA) Ovulatory dysfunction (OD) Polycystic ovarian morphology (PCOM) Lizneva D, et al. Fertil Steril 2016;106(1):

107 Prevalence of different phenotypes varies widely 1 Country Denmark n:447, PCOS: 86 China n:15,924, PCOS:886 Australia n:728, PCOS:129.5 Mexico n:150, PCOS:10 Iran n:929, PCOS:136 Turkey n:392, PCOS:78 Table adapted from Lizneva, 2016 Distribution of PCOS phenotypes in studies reported from unselected populations by countries (%) Phenotyp e A Phenotype B Phenotype C Phenotype D Reference Lauritsen, Li R, March, Moran, Tehrani, Yildiz, Lizneva D, et al. Fertil Steril 2016;106(1):

108 Presentation and prevalence of PCOS 108

109 The prevalence of PCOS PCOS is a common endocrine disorder affecting up to 1 in 6 women of reproductive age* 1 * When assessed using the Rotterdam criteria 2 Variability in prevalence data for PCOS is due to: 2 Different defining criteria of PCOS Geographic or ethnic variability of presenting symptoms Lack of specificity of symptoms to PCOS Variability in timing of symptom presentation 1. Azziz R, Carmina E, Chen, Z et al. Polycystic ovary syndrome. Nat Rev Dis Primers Aug 11;2:16057; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

110 Polycystic ovary syndrome (PCOS) is a common cause of menstrual dysfunction 1 PCOS causes 85% of cases of oligomenorrhea and 30-40% of cases of amenorrhea 2 1. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1 13; 2. Androgen Excess and PCOS Society Education Committee. PCOS

111 Primary presentation of PCOS symptoms may vary with age 1-4 Although PCOS presentation may be less clear in adolescents, the vast majority develop the phenotype clearly by the age of 18 years Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1 13; 2. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):

112 Long-term impact of PCOS extends to metabolic and reproductive risks 1-4 Clinical hyperandrogenic skin symptoms (hirsutism, acne, seborrhea, alopecia) 1,2 Type 2 diabetes 1 Cardiovascular disease 3 Insulin resistance 1 Menstrual dysfunction 1 Endometrial cancer 2,4 Infertility 1,3 1. Sirmans SM, Pate KA.. Clin Epidemiol 2014;6:1 13; 2. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 3. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 4. Haoula Z, et al. Human Reprod. 2012;27(5):

113 The burden of PCOS on health and quality of life 113

114 PCOS has a negative impact on healthrelated quality of life 1-5 Scale score 100 HRQL measured with the German version of the SF-36 in women with PCOS and healthy controls. 80 ** * * PCOS Controls 60 ** ** 40 ** 20 0 Physical functioning Physical role function Bodily pain General health Vitality SF-36 Scales Social function Emotional role function Mental health Graph adapted from Elsenbruch S, Elsenbruch S, et al. Quality-of-life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88(12):5801 7; 2. Sirmans SM & Pate KA. Clin Epidemiol. 2014;6:1 13; 3. Zafari Zangeneh F, et al. J Reprod Infertil. 2012;13(2):111 5; 4. Jones GL, et al. Hum Reprod Update. 2008;14:15 25; 5. Azziz R, et al. J Clin Endocrinol Metab. 2005;90:

115 Infertility contributes to quality of life impairment Women with PCOS are 3x more worried about their fertility than women with normal androgen levels 1 Women with PCOS and fertility problems experience a 50% reduction in health-related quality of life 2 1. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 2. Legro RS, et al. Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2013;98:

116 Women with PCOS have multiple long-term health implications 1-3 1,2 2 2,3 1. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1 13; 3. Fauser BCJM, et al. Fertil Steril 2012;97:

117 Management of PCOS represents a significant financial burden to healthcare systems 1 Symptoms included in literature review Prevalence amongst women with PCOS (%) Annual cost in millions US$ (% of total) Initial evaluation 99 (2.3) Treatment Menstrual dysfunction/abnormal uterine bleeding (30.9) Hirsutism* (14.2) Infertility (17.2) Type 2 diabetes (40.4) Total cost 4370 (100.0) * Treatment of hirsutism includes both cosmetic and hormonal therapies but does not take into account management of psychological and QoL impact or women s own expenditure on treatment 1. Azziz R, et al. J Clin Endocrinol Metab 2005;90:

118 Diagnosis of PCOS and exclusion of other causes 118

119 The global AWARE group PCOS Checklist 119

120 Confirming a diagnosis of PCOS and establishing phenotype 1-3 Women in parts of Asia more commonly present with menstrual irregularities than hyperandrogenic skin symptoms 4 Regular waxing or shaving can disguise the severity of hyperandrogenic skin symptoms such as hirsutism 1. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2. Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:

121 Additional tests and investigations are needed to exclude other causes of androgen excess 121

122 Treatment of PCOS and management of long term implications 122

123 Goals of treatment for PCOS 1-4 Improve skin symptoms Restore menstrual function Resolve infertility Improve quality of life Protect from long-term health problems 1. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 2. Goodman NF, et al. Endocrin Pract 2015;21(11): ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):

124 Overview of treatments for PCOS Lifestyle modification 1 Maintaining a healthy diet, exercise and achievement of weight reduction Topical or cosmetic options 2 Targets androgenic skin symptoms such as hirsutism and acne Pharmacological treatment 2 Aimed at reducing the level of circulating androgens and controlling their effect at tissue level 1. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):

125 Selection of appropriate antiandrogen therapy in PCOS Decreasing antiandrogenic effect Progestogen CPA CMA DNG DRSP Mode of action Inhibits the activity of 5-alpha-reductase and androgen synthesis in the skin and decreases androgen blood concentration through an antigonadotrophic effect. Inhibits the activity of 5-alpha reductase in the skin and reduces ovarian and adrenal androgen production via its antigonadotrophic effect. Possesses strong progestational effects and moderate Antiandrogenic and antigonadotrophic effects. Blocks ovarian steroid production, reduces adrenal androgen synthesis and blocks peripheral androgen receptors in the skin. A combination of EE with a progestogen that possesses antiandrogenic activity is regarded as the most appropriate choice for treatment of PCOS 1 Antiandrogenic potential of EE/progestogen combinations varies according to the dose and type of progestogens used 2,3,4 1. Yildiz BO. Semin Reprod Med 2008;26: ; 2. Sirmans SM, Pate KA. Clin Epidemiol 2014;6:1 13; 3. Zouboulis CC, et al. Horm Metab Res 2007;39:85 95; 4. Sitruk-Ware R. Hum Reprod Update 2006;12:

126 CPA/EE offers effective treatment of androgen levels, hyperandrogenic skin symptoms and menstrual dysfunction 1,2 Significant reduction in: 1 Acne lesion count and severity at 6 months Hirsutism score (mf-g) and use of cosmetic treatments at 6 months Sebum production at 9 months Additional benefits of menstrual regularity and effective contraception 2 Reduction in long-term risk of endometrial hyperplasia and endometrial cancer 2 1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22: ; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

127 Metabolic effects of CPA/EE in women with PCOS Clinical studies confirm an effect of CPA/EE on lipid metabolism 1 Changes are generally within normal limits and of little clinical relevance Improvement of biochemical hyperandrogenism with CPA/EE leads to a reduction in long-term risks of PCOS: 2 Arterial diseases such as myocardial infarction Metabolic syndrome Onset of new diabetes 1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22: ; 2. Meyer C, et al. Diabetes Care 2007;30(3): ; 3. Bhattacharya SM & Jhan A. Fertil Steril. 2012; 98(4): ; 4. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):

128 Cardiovascular safety with EE/progestogen combinations Use of estrogen/progestogen combinations is associated with an increased risk for VTE (DVT or PE) 1,2 The use of CPA/EE carries an increased risk of VTE/ATE compared with no use or LNG/EE use Highest during the 1 st year of use Highest when restarting or switching from another OC* However, the risk of VTE during COC use remains lower than that during pregnancy and childbirth 3,4 ATE, Arterial thromboembolism; COC, Combined oral contraceptive; DVT, Deep vein thrombosis; PE, Pulmonary embolism; OC, Oral contraceptive; VTE, Venous thromboembolism; CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate 1. OC class label; 2. Rosendaal MD. Lancet 1999;353(9157): ; 3. Dinger JC, et al. Contraception 2007;75(5): ; 4. Heit et al. Ann Intern Med 2005;143(10):

129 Cardiovascular safety with EE/progestogen combinations (continued) Due to its labeled indication, CPA/EE may channel use towards women with an inherently higher cardiovascular risk 1,2 Observational studies of VTE risk with CPA/EE compared to LNG-containing and other COCs (low-estrogen <0.05mg) yield varying findings Some studies reported a greater VTE risk, comparable to so-called 3rd generation COCs 3 5 Other studies showed no differences in VTE risk 1,6,7 Studies that addressed the issue of confounding or duration of use concluded that the VTE risk is not significantly higher 1,7 COC, Combined oral contraceptive; LNG, Levonorgestrel; PCOS, Polycystic ovary syndrome; VTE, Venous thromboembolism; CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate. 1. Seaman HE, et al. Pharmacoepidemiol Drug Saf 2004;13(7): ; 2. Bird ST, et al. J Thromb Haemost 2013;11(6): ; 3. Vasilakis-Scaramozza C et al. Lancet 2001;358(9291):1427 9; 4. Seaman HE, et al. Hum Reprod 2003;18(3):522 6; 5. Lidegaard Ø, et al. Acta Obstet Gynecol Scand 2013;92(10): ; 6. Lidegaard Ø, et al. J Obstet Gynaecol Can 2003;25(7):575 7; 7. EURAS

130 Factors to consider before prescribing combined hormonal treatment The WHO MEC provides guidance on contraindications when prescribing combined hormonal treatment 1 1. WHO MEC, 5 th Ed

131 AWARE group recommendations for safe and effective prescribing in PCOS 131

132 Position papers, consensus statements and guidelines are available to guide the management of PCOS 1-5 Providing physicians with: Overview of important clinical issues 1-4 Summary of best practice 1-5 Guidance on the management of long-term consequences 5 1. Goodman NF, et al. Endocrinol Pract. 2015;21(12): ; 2. Legro RS, et al. J Clin Endocrinol Metab 2013;98: ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28 38; 4. Conway G, et al. Eur J Endocrinol. 2014;171:1 29; 5. RCOG. Green-top Guideline No. 33. November