the global burden of androgen excess · •it affects up to 1 in 5 women of reproductive age2...

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 2017G.MA.WH.11.2017.0498

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

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


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


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


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

Defining androgen excess

7

Defining androgen excess

Biochemical hyperandrogenism

Clinical hyperandrogenism

Clinical hyperandrogenism, where

the pilosebaceous unit has

increased sensitivity to normal

serum androgen levels and causes

hyperandrogenic skin symptoms.

Biochemical hyperandrogenism,

where there is excessive production

and/or secretion of androgens,

which may be of ovarian or adrenal

origin

Clinical and biochemical

hyperandrogenism

8

Androgen excess in women can be characterised by either clinical symptoms of hyperandrogenism and/or biochemical hyperandrogenism1

1. Fauser BCJM, et al. Fertil Steril 2012;97:28–38; 2. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182

Prevalence and presentation of androgen excess

9

• It affects up to 1 in 5 women of reproductive age2

• The majority of women with hyperandrogenism

(80–85%) have polycystic ovary syndrome (PCOS)3,4

Androgen excess* is the most common reproductive endocrine disorder in women1

1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Lizneva D, et al.Fertil Steril 2016;106(1):6–15; 3. Ehrmann DA. N Engl J Med 2005; 352(12):1223–1236; 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;22:172-182

10

*Biochemical and/or clinical

Women can present with a combination of different symptoms1,2

In some cases, women present with all four hyperandrogenic skin symptoms, described as the SAHA syndrome3,4

1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:199–204; 3. Orfanos CE, et al. Horm Res. 2000;54:251-8; 4. Fauser BCJM, et al. Fertil Steril 2012;97:28–38 11

• It is present in up to 8 out of 10 women with androgen excess1* Indicated by excess body or facial terminal (coarse) hair growth in females in a male-like pattern2

• Prevalence varies according to ethnicity2

12

Hirsutism is the most commonly used marker for diagnosis of androgen excess1

*Depending on criteria for definition and population studies

1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):146–170

• Acne is caused by androgen excess in approximately

1 in 6 women3

Acne is an extremely common, chronic skin condition1,2

131. Zhara Ghodsi S, et al. J Invest Dermatol 2009;129,:2136–2141; 2. Zouboulis CC, et al. Horm Metab Res 2007;39:85–95; 3. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:199–204

• Affects approximately 1 in 3 of women with PCOS2

• Characterised by overall thinning of scalp hair mainly in frontal and parietal areas1

• Commonly presents with other skin symptoms of androgen excess1

Alopecia in women is most commonly caused by androgen excess1

--------------------

141. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:199–204

• 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 disorders2

Seborrhea can also present as a symptom of androgen excess1

151. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182; 2. Orfanos CE. Arch Arg Derm 1982;32(suppl 1):51–5

The burden of androgen excess

16

• Both hirsutism and acne can significantly and negatively impact on quality of life and cause anxiety and depression1-3

• Alopecia has a negative effect on self-esteem, psychological wellbeing and body image3

Hyperandrogenic skin symptoms cause significant

quality of life and psychological impairment1-3

171. 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):167–176

18

Hirsutism can significantly and negatively impact on quality of life1

DLQI: Dermatology Quality of Life Index

Effect measured by Dermatology Life Quality Index (DLQI)n=127

Extremely large (21-39)

Very large (11-20)

Moderate (6-10)

Small (2-3)

None (0-1)

10.3%19.8%

35%

13.5%

21.4%

1. Palmetun Ekback, M, et al. Dermatology 2013;227:278–284

Hirsutism negatively affects multiple health-

related quality of life domains1

19

of women report anxiety275% of women report

depression230% of women report both anxiety and depression229%

1. Ekbäck MP, et al. Dermatology. 2013;227(3):278–84; 2. Lipton MG, et al. J Psychosom Res 2006;61(2):161–8

Clinically important depression and anxiety have been reported in

18% and 44% of acne patients respectively4

Acne also has a significant impact on quality of life1-4

201. 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;140:273–282

Androgen excess due to biochemical hyperandrogenism may have long-term impact on general health1-3

21

• 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

• With increasing age, there is a change in presenting symptoms and health

implications

1. Fauser BCJM, et al. Fertil Steril. 2012;97:28–38; 2. Chittenden BG, et al. Reprod Biomed Online. 2009;19:398–405; 3. Barry J, et al. Human Reprod Update. 2014;20(5):748–758

Symptoms included in literature review

Prevalence (%)

Annual cost inmillions

US$ (% of total)

Initial evaluation 99 (2.3)

Treatment

Menstrual dysfunction/abnormal uterine bleeding

75 1350 (30.9)

Hirsutism* 70 622 (14.2)

Infertility 50 533 (17.2)

Type 2 diabetes 7.2 1766 (40.4)

Total cost 4370

Androgen excess represents a significant financial burden to healthcare systems1

* 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

221. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650–8

• Androgen excess affects up to 1 in 5 women of reproductive age1

• Presenting symptoms include hyperandrogenic skin symptoms (Seborrhea, Acne, Hirsutism and Alopecia) alone or in combination with menstrual irregularities and infertility2,3,4

• It is associated with significant quality of life impairment and negative quality of life5,6,7

• Although data is limited, evidence shows it can be a significant economic burden8

Conclusions

231. Lizneva D, et al. Fertil Steril 2016;106(1):6–15; 2. Orfanos CE, et al. Horm Res. 2000;54:251-258; 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):167–176; 8. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650–8

1. Which of these typical skin symptoms of androgen excess is the most commonly used marker?

A. Seborrhea

B. Hirsutism

C. Acne

D. Alopecia

24


1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176

1

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

25


1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176

1

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. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:199–204 26


1

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. Lipton MG, et al. J Psychosom Res 2006;61(2):161–8 27


1

Recognition and diagnosis of androgen excess


Module 2



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


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


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


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


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

• Women in far-East Asia present less frequently with hirsutism than Western women1

• Thickness of body hair is greater in Caucasian women than Asian women2

• Increased risk of insulin resistance in African-American women2

Global and ethnic differences in prevalence and primary presentation of androgen excess1,2

351. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650–8; 2. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):146–170

Women can present with a combination of non-specific symptoms1,2

36

In some cases, women present with all four hyperandrogenic skin symptoms, described as the SAHA syndrome3,4

1. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Ozdemir S, et al. Acta Obstet Gynecol Scand 2010;89:199–204; 3. Orfanos CE, et al. Horm Res. 2000;54:251-8; 4. Fauser BCJM, et al. Fertil Steril 2012;97:28–38

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

disturbance1

• Many women therefore seek help from a

beautician, cosmetologist or electrologist in

preference to a physician2,3

• Acne can be seen as an ‘adolescent problem’ that

will resolve with age4

371. Yildiz B, et al. Hum Reprod Update 2010;16(1):51–64; 2. Dumesic DA, et al. Int J Fertil Womens Med 1997;42:255–260; 3. Farah L, et al. J Reprod Med 1999;44:870–4; 4. Dréno B, et al. J Eur Acad Dermatol Venereol 2014;29:1096–106

Not all acne is specific to a disorder of androgen metabolism

38

Hormonal influences Non-hormonal influences

• Menstrual cycle• Pregnancy (+/- effect)• Polycystic ovary syndrome (PCOS)• Androgen excess is the cause of

acne in approximately 1 in 6 women1

• Hormone treatment (e.g. oral contraceptives)

• 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):1499–1506

39

Although hirsutism is a recognised marker of androgen excess...1

Etiology Frequency (%)1

Polycystic ovary syndrome (PCOS) 71

Idiopathic hyperandrogenism 15

Idiopathic hirsutism 10

Non-classic congenital adrenal hyperplasia (NCCAH)

3

Androgen-secreting tumors 0.3

…less frequently, it can also be caused by ovarian or adrenal dysfunction2,3

1. Yildiz, B. Best Pract Res Clin Endocrinol Metab 2006;20(2):167–176; 2. Bode D, et al. Am Fam Physician 2012;85(4):373–380; 3. Escobar-Morreale HF, et al. Hum Reprod Update 2012;18(2):146–170

• Women may present in a variety of settings.

• Use of validated assessment tools outside dermatology or clinical trial settings is rare2

• 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) scale1

– 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

Assessment of skin symptoms is not always straightforward1

401. Yildiz, B. Best Practice Res Clin Endocrinol Metabol 2006;20(2):167–176; 2. Azziz R, et al. Nat Rev Dis Primers. 2016;2:16057

41

Rationale for early diagnosis and treatment

• Hyperandrogenic skin symptoms cause significant quality of life and psychological impairment1-4

• Androgen excess due to biochemical hyperandrogenism may have a long-term impact on general health5

Why is early recognition and treatment of androgen excess important?

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):167–176; 5. Fauser BCJM, et al. Fertil Steril. 2012;97:28–38; 6. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650–8

42

Androgen excess therefore represents a significant health economic burden6

43

A diagnostic pathway –Ask, Assess, Consider Test

Four key steps in the recognition and diagnosis of androgen excess

44

What to ask1,2

Previous or ongoing treatment and/or self care (e.g. use of make-up, shaving, waxing)

Detailed history of menstrual pattern1

Menstrual irregularity1

Ovulatory dysfunction

Detailed family history of similar disorders2

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 5:1303-6 45

46

Body mass index (BMI)

Waist/height ratio (WHR)

Blood pressure (BP)

Seborrhea

AcneHirsutism

Alopecia

1. Sirmans S and Pate KA. Clin Epidemiol 2014;6:1–13

1

47

Comedonal acnePapulo-pustular

acneNodular acne

.

Clinical signs of acne include greasy skin, altered keratinisation inflammation and bacterial colonisation by P Acnes 1,2

*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):301–312; 2. Shen Y. Acta Derm Venereol 2012;92: 40–4

1-2

Hirsutism is evaluated and quantified by the modified

Ferriman-Gallwey score1-4

1. Ferriman D & Gallwey JD. J Clin Endocrinol Metab. 1961;21:1440–1447; 2. Hatch R et al. Am J Obstet Gynecol. 1981;140:815–830; 3. Derksen J et al. Br J Dermatol 1993;128:259–263; 4. Goodman NF et al. Endocr Pract. 2001;7:120–134 48

1-4

Emotional wellbeing

Quality of life

Long-term health

1. Ekback MP et al. Dermatol. 2013;227:278-284; 2. Aktan et al. Int J Dermatol 2000;39:354–357; 3. Koo JYM & Smith LL. Pediatr Dermatol 1991;8:185–188;4. Stern RS. Dermatol 2000;43:1042–1048; 5. Kellet SC and Gawkrodger DJ. Br J Dermatol. 1999;140(2):273-82 49

1-5

• 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;6:1–13 50

1

51

Laboratory tests to exclude other disorders:• Serum thyroid

stimulating hormone (TSH)

• Serum prolactin

• Serum 17-hydroxyprogesterone (OHP)

Also important to assess:Quality of life

Confirm PCOS

• Serum testosterone

• Ultrasound ovarian morphology

• Anti-Mullerian hormone (AMH)

• Sex hormone binding globulin (SHBG)

• Metabolic tests

Confirm severity of dysfunction

When PCOS is

suspected, additional tests

are used

Confirming the cause of androgen excess1-3

1. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28–38

1

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

52

Risk factors prompting further investigation

• Suspicion of androgen-secreting tumour

• Undiagnosed bleeding

• Severe psychological morbidity for example, severe anxiety and/or depression

• Scarring acne

• Fertility problems

53

54

Some practical reminders

• 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

Remember…

55

• There are a number of challenges in the recognition of androgen excess, including:• Global and ethnic differences in prevalence and primary

presentation1,2

• Presentation of a combination of non-specific symptoms3,4

• Difficulty assessing skin symptoms2,5

• 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 wellbeing6-10

• Despite the challenges, there are tools and resources available to help aid awareness and aid diagnosis

Conclusions

56

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):146–170; 3. Orfanos CE. Arch Arg Derm1982;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):167–176; 6. Ekback MP et al. Dermatol. 2013;227:278-284; 7. Aktan et al. Int J Dermatol 2000;39:354–357; 8. Koo JYM & Smith LL. Pediatr Dermatol 1991;8:185–188; 9. Stern RS. Dermatol 2000;43:1042–1048; 10. Kellet SC and Gawkrodger DJ. Br J Dermatol. 1999;140(2):273-82

57

Resources

ChecklistsManuscripts

Interactive Educational Manual for the Treatment of Acne

Case Studies

Tools and resources available to aid awareness & diagnosis of AE

58

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. NHS choices. Acne – causes Available at: http://www.nhs.uk/Conditions/Acne/Pages/Causes.aspx (Last reviewed April 2016) 59


1

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

60


1. Orfanos CE, et al. Horm Res. 2000;54:251-8; 2. Fauser BCJM, et al. Fertil Steril 2012;97:28–38

1,2

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. Sirmans S and Pate KA. Clin Epidemiol 2014;6:1–13 61


1

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

62


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):167–176; 5. Fauser BCJM, et al. Fertil Steril. 2012;97:28–38; 6. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650–8

1-6

Best practice in the treatment of hyperandrogenic skin symptoms


Module 3



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


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


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


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


Module content

• Aims of treatment for hyperandrogenicskin symptoms

• Treatment options

• Rationale for antiandrogen treatment

• Role of antiandrogens as combined hormone treatment

• The AWARE treatment proposal

68

Aims of treatment for androgen excess

69

Goals of treatment for androgen excess1-4

• 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

701. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 2.Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):6–15

Treatment options for hyperandrogenic skin symptoms

71

• Lifestyle management

– Aimed at reducing the risk of long-term metabolic consequences1,2

• Topical or cosmetic options1

– Targets hyperandrogenic skin symptoms such as hirsutism and acne

• Pharmacological treatment1

– Aimed at reducing the level of circulating androgens and controlling their effect at tissue level

Overview of treatment options

721. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 2. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506

73

Lifestyle management1

*Where necessary to reduce weight/BMI1

Lifestyle management should be a core part of treatment to

improve metabolic and psychological consequences

associated with this condition1-3

1. Teede HJ, et al. Med J Aust. 2011 Sep 19;195(6):S65-112; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506

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

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 or cosmetic treatments options1,2

741. Goodman NF, et al. Endocrine Pract 2015;21(11):1291–1300; 2. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506

75

Pharmacological treatment options

Treatment is aimed at reducing the level of circulating androgens

and controlling their effect at tissue level1

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):1291–1300

Rationale for antiandrogen treatment

76

Treatment is focused on:

Reducing androgen production

Decreasing the fraction of circulating free testosterone

Limiting androgen bioactivity to sebaceous gland and hair follicles

Antiandrogens in the treatment of skin symptoms such as hirsutism and acne1-5

5-reductase

Free testosterone

Total testosterone

Dihydrotestosterone (DHT)

Androgen receptor in sebaceous gland

Sex hormone binding globulin (SHBG)

77

Sebum production and hair growth

1. Goodman NF, et al. Endocrine Pract 2015;21(11):1291–1300; 2. Azziz R et al. Idiopathic hirsutism. Endocr Rev 2000; 21: 347–62; 3. Mofid A et al. Hirsutism. Int J Clin Pract 2008; 62: 433–43; 4. Neithardt AB, Barnes RB. Semin Reprod Med 2003; 21: 285–93; 5. Azziz R. Obstet Gynecol 2003; 101: 995–1007

CPA is a steroid compound with potent…

78

Cyproterone Acetate (CPA): a steroidal antiandrogen1-6

…Antigonadotropicproperties

…Antiandrogenic activities

…Progestogenicactivities

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;35:497–505; 5. Neumann F. Postgrad Med J 1978;54 Suppl 2:11–24; 6. Aydinlik S, et al. Clinical Trials Journal 1990;27:392–402

CPA targets hyperandrogenic skin symptoms via two mechanisms

CPA:Increases sex

hormone binding globulin

CPA:Targets binding of DHT to androgen

receptors

79

5-reductase

Free testosterone

Total testosterone

Dihydrotestosterone (DHT)

Androgen receptor in sebaceous gland

Sebum production and hair growth

Sex hormone binding globulin (SHBG)

X

X

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;35:497–505; 5. Neumann F. Postgrad Med J 1978;54 Suppl 2:11–24; 6. Aydinlik S, et al. Clinical Trials Journal 1990;27:392–402

CPA also affects synthesis and secretion of ovarian androgens1-3

CPA, cyproterone acetate; FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone

CPA interacts with GnRH receptors in the pituitary

gland blocking the release of LH and FSH

Inhibition of FSH and LH leads to a decline in ovarian androgen production and a

reduction in free testosterone

801. 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):183-190; 3. Barbieri RL. Trends Endocrinol Metab. 1992;3(1):30-4

Hypothalamus

Ovary

Brain

Pituitary gland

Role of antiandrogens as combined hormone treatment

81

• CPA/EE has the greatest antiandrogen potential of hormonal treatments containing a combination of progestogens and EE4-5

82

Different combinations of EE/progestogen have varied antiandrogenic potential1-3

Inhibits the activity of 5-alpha-reductase and androgen synthesis in the skin and decreases

androgen blood concentration through an antigonadotrophic

effect.

Decreasing antiandrogenic 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 CMA DNG DRSP

Mode of

action

Progestogen

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;12:169–178; 4. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182; 5. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190

• 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 contraception2

• Reduction in long-term risk of endometrial hyperplasia and endometrial cancer2

Combination CPA/EE* treatment effectively treats hyperandrogenic skin symptoms and menstrual dysfunction1,2

83

*CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate

1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190

Cardiovascular safety with EE/progestogen combinations

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

84

However, the risk of VTE during COC use remains lower than that during pregnancy and childbirth3,4

The use of CPA/EE carries an increased risk of VTE/ATE compared with no use or LNG/EE use

Highest during the 1st year of use

Highest when restarting or switching from another OC*

Use of estrogen/progestogen combinations is associated with an increased risk for VTE (DVT or PE)1,2

1. OC class label; 2. Rosendaal MD. Lancet 1999;353(9157):1167–1173; 3. Dinger JC, et al. Contraception 2007;75(5):344–354; 4. Heit et al. Ann Intern Med 2005;143(10):697–706

Cardiovascular safety with EE/progestogen combinations (continued)

Observational studies of VTE risk with CPA/EE compared to LNG-containing and other COCs (low-estrogen <0.05mg) yield varying findings

Due to its labeled indication, CPA/EE may channel use towards women with an inherently higher cardiovascular risk1,2

Some studies reported a greater VTE risk,

comparable to so-called 3rd generation COCs3–5

Other studies showed no differences in VTE risk1,6,7

Studies that addressed the issue of confounding or

duration of use concluded that the VTE risk is not significantly higher1,7

COC, Combined oral contraceptive; LNG, Levonorgestrel; PCOS, Polycystic ovary syndrome; VTE, Venous thromboembolism; CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate.

851. Seaman HE, et al. Pharmacoepidemiol Drug Saf 2004;13(7):427–436; 2. Bird ST, et al. J Thromb Haemost 2013;11(6):1059–1068; 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):1135–1142; 6. Lidegaard Ø, et al. J Obstet Gynaecol Can 2003;25(7):575–7; 7. EURAS 2007

The AWARE treatment proposal

86

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

Challenges in the management of androgen excess1

871. Redmond GP. Int J Fertil Womens Med 1998;43(2):91–7

The AWARE treatment proposal addresses these challenges

88

Important elements of patient communication when discussing treatment1-3

891. Chen J, et al. Health Educ Behav 2016;43(1):25-34; 2. Brown MT & Bussell JK. Mayo Clin Proc. 2011:86(4):304-314; 3. Bitzer J, et al. Eur J Contracept ReprodHealth Care. 2017;22:172-182

• Effective treatment of seborrhea, acne, hirsutism and alopecia can help to improve quality of life and psychological impairment associated with clinical hyperandrogenism1,2

• 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 disorders3,4

90

Treatment needs to be targeted at all symptoms

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):4565–4592

91

Factors to consider before prescribing combined hormonal treatment

• Use established treatment combinations for androgen excess

• Screen patients using WHO MEC for guidance in the prescribing of estrogen/progestogen combinations1

1,2

1,3

1. WHO MEC. 5th ed. 2015; 2. Yildiz BO. Semin Reprod Med. 2008;26:111–120; 3. Dianette SmPC

When to refer women with androgen excess1,2

921. 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):4565–4592

• 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 impairment6 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 management1,7

• CPA/EE offers effective treatment of hyperandrogenic skin symptoms and menstrual dysfunction8

Conclusions

93

1. Goodman NF, et al. Endocrine Pract 2015;21(11):1291–1300; 2. Azziz R et al. Idiopathic hirsutism. Endocr Rev 2000; 21: 347–62; 3. Mofid A et al. Hirsutism. Int J Clin Pract 2008; 62: 433–43; 4. Neithardt AB, Barnes RB. Semin Reprod Med 2003; 21: 285–93; 5.Azziz R. Obstet Gynecol 2003; 101: 995–1007; 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):CD007506. doi: 10.1002/14651858.CD007506.pub2; 8. RuanX, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190

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

94


1-4

1. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 2.Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):6–15

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

95


1. Goodman NF, et al. Endocrine Pract 2015;21(11):1291–1300

1

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

96


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;12:169–178

1-3

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

97


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):4565–4592

1,2

1,2

1,2

1,2

Polycystic ovary syndrome (PCOS)


Module 4



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


2. How often is amenorrhea related to PCOS?

A. 10 – 30% of cases

B. 30 – 40% of cases

C. 40 – 60% of cases

D. More than 60% of cases

100


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


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


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

Defining PCOS

104

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;19:41–7 105

106

The importance of phenotypic definition of PCOS1

• 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)

+ – + +

1. Lizneva D, et al. Fertil Steril 2016;106(1):6–15

Prevalence of different phenotypes varies widely1

Country Phenotype A

Phenotype B

Phenotype C

Phenotype D

Reference

Denmarkn:447, PCOS: 86

4.7 4.7 72.1 18.6Lauritsen,2014

Chinan:15,924, PCOS:886

28.7 19.0 37.3 15.0 Li R, 2013

Australian:728, PCOS:129.5

21.2 27.5 18.9 32.5 March, 2010

Mexicon:150, PCOS:10

70 20 0 10 Moran, 2010

Irann:929, PCOS:136

12.9 22.4 49.4 15.3 Tehrani, 2014

Turkeyn:392, PCOS:78

25.6 5.1 46.2 23.1 Yildiz, 2012

Table adapted from Lizneva, 2016

Distribution of PCOS phenotypes in studies reported from unselected populations by countries (%)

1. Lizneva D, et al. Fertil Steril 2016;106(1):6–15 107

Presentation and prevalence of PCOS

108

• PCOS is a common endocrine disorder

affecting up to 1 in 6 women of reproductive age*1

The prevalence of PCOS

* When assessed using the Rotterdam criteria2

• 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

Variability in prevalence data for

PCOS is due to:2

1. Azziz R, Carmina E, Chen, Z et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016 Aug 11;2:16057; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190 109

Polycystic ovary syndrome (PCOS) is a common cause of menstrual dysfunction1

110

…and 30-40% of cases of amenorrhea

PCOS causes 85% of cases of oligomenorrhea…

1. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1–13; 2. Androgen Excess and PCOS Society Education Committee. PCOS. 2016

2

Primary presentation of PCOS symptoms may vary with age1-4

111

Although PCOS presentation may be less clear in adolescents, the vast majority develop the phenotype clearly by the age of 18 years.4

1. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1–13; 2. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):6–15

Long-term impact of PCOS extends to metabolic and reproductive risks1-4

112

Clinical hyperandrogenic skin symptoms

(hirsutism, acne, seborrhea, alopecia)1,2

Cardiovascular disease3

Insulin resistance1

Type 2 diabetes1

Menstrual dysfunction1

Infertility1,3Endometrial cancer2,4

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;98:4565–4592; 4. Haoula Z, et al. Human Reprod. 2012;27(5):1327-1331

The burden of PCOS on health and quality of life

113

PCOS has a negative impact on health-related quality of life1-5

1. Elsenbruch S, et al. Quality-of-life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome. J Clin Endocrinol Metab2003;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;90:4650–8

114

Physical functioning

20

40

60

100

***80

**

** **

*

Scal

e s

core

0Physical

role function

Bodily pain

General health

Vitality Social function

Emotional role

function

Mental health

SF-36 Scales

PCOS

Controls

Graph adapted from Elsenbruch S, 2003

HRQL measured with the German version of the SF-36 in women with PCOS and healthy controls.

Infertility contributes to quality of life impairment

• Women with PCOS are 3x more worried

about their fertility than women with normal androgen levels1

• Women with PCOS and fertility problems

experience a 50% reduction in health-related

quality of life2

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;98:4565–4592 115

116

1,2

2

2,3

Women with PCOS have multiple long-term health implications1-3

1. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 2. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1–13; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38

Symptoms included in literature review

Prevalence amongstwomen with PCOS

(%)

Annual cost inmillions

US$ (% of total)

Initial evaluation 99 (2.3)

Treatment

Menstrual dysfunction/abnormal uterine bleeding

75 1350 (30.9)

Hirsutism* 70 622 (14.2)

Infertility 50 533 (17.2)

Type 2 diabetes 7.2 1766 (40.4)

Total cost 4370 (100.0)

Management of PCOS represents a significant financial burden to healthcare systems1

* 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

1171. Azziz R, et al. J Clin Endocrinol Metab 2005;90:4650-8

Diagnosis of PCOS and exclusion of other causes

118

The global AWARE group PCOS Checklist

119

Confirming a diagnosis of PCOS and establishing phenotype1-3

Regular waxing or shaving can disguise the severity of

hyperandrogenic skin symptoms such as hirsutism

Women in parts of Asia more commonly present with menstrual irregularities than

hyperandrogenic skin symptoms4

1201. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38

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

121

Treatment of PCOS and management of long term implications

122

Goals of treatment for PCOS1-4

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;98:4565–4592; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38; 4. Lizneva D, et al. Fertil Steril 2016;106(1):6–15 123

• Lifestyle modification1

– Maintaining a healthy diet, exercise and achievement of weight reduction

• Topical or cosmetic options2

– Targets androgenic skin symptoms such as hirsutism and acne

• Pharmacological treatment2

– Aimed at reducing the level of circulating androgens and controlling their effect at tissue level

Overview of treatments for PCOS

1. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300 124

• A combination of EE with a progestogen that possesses antiandrogenic activity is regarded as the most appropriate choice for treatment of PCOS1

• Antiandrogenic potential of EE/progestogen combinations varies according to the dose and type of progestogens used2,3,4

125

Selection of appropriate antiandrogen therapy in PCOS

Inhibits the activity of 5-alpha-reductase and androgen synthesis in the skin and decreases

androgen blood concentration through an antigonadotrophic

effect.

Decreasing antiandrogenic 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 CMA DNG DRSP

Mode of

action

Progestogen

1. Yildiz BO. Semin Reprod Med 2008;26:111–120; 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;12:169–178

CPA/EE offers effective treatment of androgen levels, hyperandrogenic skin symptoms and menstrual dysfunction1,2

• 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 contraception2

• Reduction in long-term risk of endometrial hyperplasia and endometrial cancer2

1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190 126

• Clinical studies confirm an effect of CPA/EE on lipid metabolism1

– 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

127

Metabolic effects of CPA/EE in women with PCOS

1. Bitzer J, et al. Eur J Contracept Reprod Health Care. 2017;22:172-182; 2. Meyer C, et al. Diabetes Care 2007;30(3):471–478; 3. Bhattacharya SM & Jhan A. FertilSteril. 2012; 98(4): 1053-59; 4. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190

Cardiovascular safety with EE/progestogen combinations

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

128

However, the risk of VTE during COC use remains lower than that during pregnancy and childbirth3,4

The use of CPA/EE carries an increased risk of VTE/ATE compared with no use or LNG/EE use

Highest during the 1st year of use

Highest when restarting or switching from another OC*

Use of estrogen/progestogen combinations is associated with an increased risk for VTE (DVT or PE)1,2

1. OC class label; 2. Rosendaal MD. Lancet 1999;353(9157):1167–1173; 3. Dinger JC, et al. Contraception 2007;75(5):344–354; 4. Heit et al. Ann Intern Med 2005;143(10):697–706

Cardiovascular safety with EE/progestogen combinations (continued)

Observational studies of VTE risk with CPA/EE compared to LNG-containing and other COCs (low-estrogen <0.05mg) yield varying findings

Due to its labeled indication, CPA/EE may channel use towards women with an inherently higher cardiovascular risk1,2

Some studies reported a greater VTE risk,

comparable to so-called 3rd generation COCs3–5

Other studies showed no differences in VTE risk1,6,7

Studies that addressed the issue of confounding or

duration of use concluded that the VTE risk is not significantly higher1,7

COC, Combined oral contraceptive; LNG, Levonorgestrel; PCOS, Polycystic ovary syndrome; VTE, Venous thromboembolism;

CPA/EE, 0.035mg ethinylestradiol/2mg cyproterone acetate.

1291. Seaman HE, et al. Pharmacoepidemiol Drug Saf 2004;13(7):427–436; 2. Bird ST, et al. J Thromb Haemost 2013;11(6):1059–1068; 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):1135–1142; 6. Lidegaard Ø, et al. J Obstet Gynaecol Can 2003;25(7):575–7; 7. EURAS 2007

• The WHO MEC provides guidance on contraindications when prescribing combined hormonal treatment1

130

Factors to consider before prescribing combined hormonal treatment

1. WHO MEC, 5th Ed. 2015.

AWARE group recommendations for safe and effective prescribing in PCOS

131

– Overview of important

clinical issues1-4

– Summary of best practice1-5

– Guidance on the

management of long-term

consequences5

Position papers, consensus statements and guidelines are available to guide the management of PCOS1-5

132

• Providing physicians with:

1. Goodman NF, et al. Endocrinol Pract. 2015;21(12):1415–26; 2. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 3. Fauser BCJM, et al. Fertil Steril2012;97:28–38; 4. Conway G, et al. Eur J Endocrinol. 2014;171:1–29; 5. RCOG. Green-top Guideline No. 33. November 2014

• PCOS is a common cause of menstrual dysfunction1

• Other common presenting symptoms include hyperandrogenic skin

symptoms1 (seborrhea, acne hirsutism, or alopecia), infertility2 and

clinical elements of the metabolic syndrome1,3,4,5

• PCOS has a negative impact on health-related quality of life1,6,7,8,9

associated with multiple long-term health risks1,3,4

• PCOS can be treated both with pharmacological methods and lifestyle

modification10-11

• WHO MEC provides guidance on contraindications when prescribing

combined hormonal treatment12

Conclusions

1. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1–13; 2. Androgen Excess and PCOS Society Education Committee.2016 Accessed at: http://www.ae-society.org/pdf/handouts/pcos.pdf ; 3. Fauser BCJM, et al. Fertil Steril 2012;97:28–38; 4. Legro RS, et al. J Clin Endocrinol Metab 2013;98:4565–4592; 5. Haoula Z, Salman M, Atiomo W. Human Reprod. 2012;27(5):1327-1331; 6. Elsenbruch S, et al. J Clin Endocrinol Metab 2003;88(12):5801–7; 7. Zafari Zangeneh F, et al. J Reprod Infertil. 2012;13(2):111–5; 8. Jones GL, et al. Hum Reprod Update. 2008;14:15–25; 9. Azziz R, et al. J Clin Endocrinol Metab. 2005;90:4650–8; 10. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506; 11. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300; 12. WHO MEC, 5th ed. 2015

133

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

1. Azziz R, et al. Nat Rev Dis Primers. 2016 Aug 11;2:16057; 2. Ruan X, et al. Eur J Contracept Reprod Health Care. 2017;22(3):183-190 134


1,2

2. How often is amenorrhea related to PCOS?

A. 10 – 30% of cases

B. 30 – 40% of cases

C. 40 – 60% of cases

D. More than 60% of cases

135


1. Sirmans SM & Pate KA. Clin Epidemiol 2014;6:1–13

1

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

1. Lizneva D, et al. Fertil Steril 2016;106(1):6–15 136


1

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

1. Moran LJ, et al. Cochrane Database Syst Rev 2011;16(2):CD007506; 2. Goodman NF, et al. Endocrin Pract 2015;21(11):1291–1300 137


1,2

the global burden of androgen excess · •it affects up to 1 in 5 women of reproductive age2...

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