I am familiar with polycystic I am familiar with polycystic ovary - - PDF document

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Polycystic Ovary Syndrome: Polycystic Ovary Syndrome: Pharmacologic Considerations Pharmacologic Considerations

Susan M. Sirmans, Pharm.D., BCPS Susan M. Sirmans, Pharm.D., BCPS Associate Professor Associate Professor College College of Pharmacy

• f Pharmacy

University of Louisiana at Monroe University of Louisiana at Monroe

I am familiar with polycystic I am familiar with polycystic

• vary syndrome.
• vary syndrome.

25% 25% 25% 25%

1.

• 1. Strongly disagree

Strongly disagree

2.

• 2. Disagree

Disagree

S t r

• n

g l y d i s a g . . . D i s a g r e e A g r e e S t r

• n

g l y a g r e e

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3.

• 3. Agree

Agree

4.

• 4. Strongly agree

Strongly agree

I know someone with polycystic I know someone with polycystic

• vary syndrome.
• vary syndrome.

33% 33% 33%

1.

• 1. Disagree

Disagree

2.

• 2. Agree

Agree

D i s a g r e e A g r e e N

• t

s u r e

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3.

• 3. Not sure

Not sure

PCOS PCOS PCOS PCOS

http://www.implementingdesignism.org/posteranne.html

PCOS PCOS

http://www.implementingdesignism.org/posterjames.html

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PCOS PCOS

http://www.implementingdesignism.org/posteridriss.html

PCOS PCOS

http://www.implementingdesignism.org/posterchristi.html

Polycystic Ovary Syndrome (PCOS) Polycystic Ovary Syndrome (PCOS)

• Stein

Stein Leventhal Leventhal Syndrome Syndrome

• Affects 5

Affects 5-

• 10 % of pre

10 % of pre-

• menopausal women

menopausal women

• Affects 28% of overweight or obese

Affects 28% of overweight or obese g

• Varying number and degree of signs and

Varying number and degree of signs and symptoms symptoms

– Menstrual disturbances Menstrual disturbances – Hormonal abnormalities Hormonal abnormalities-

• hyperandrogenic

hyperandrogenic – Polycystic ovaries Polycystic ovaries

Pathophysiology Pathophysiology

• Primary defect unknown

Primary defect unknown

• Inappropriate LH secretion

Inappropriate LH secretion – – 30 30-

• 90%

90%

– Increased LH Increased LH Increased LH:FSH Increased LH:FSH >2 >2 3:1 3:1 – Increased LH:FSH Increased LH:FSH -

• >2

>2-3:1 3:1

• Hyperandrogenism

Hyperandrogenism

– Increased testosterone Increased testosterone – – ovarian origin

• varian origin

– Increased Increased dihydroepiandrosterone dihydroepiandrosterone sulfate sulfate -

• adrenal

adrenal

• Hyperinsulinemia

Hyperinsulinemia→ →decreased decreased SHBG SHBG

Diagnostic criteria Diagnostic criteria

• Androgen Excess Society Criteria

Androgen Excess Society Criteria

• Rotterdam Criteria

Rotterdam Criteria

• NIH criteria

NIH criteria

• Features considered

Features considered

– Oligo Oligo-

• or
• r anovulation

anovulation – Clinical and/or biochemical signs of Clinical and/or biochemical signs of hyperandrogenism hyperandrogenism – Polycystic ovaries Polycystic ovaries

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.Fertil Steril. 2004;81:19-25

I know someone with polycystic I know someone with polycystic

• vary syndrome.
• vary syndrome.

33% 33% 33%

1.

• 1. Disagree

Disagree

2.

• 2. Agree

Agree

D i s a g r e e A g r e e N

• t

s u r e

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3.

• 3. Not sure

Not sure

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PCOS affects ______ percent of PCOS affects ______ percent of women. women.

25% 25% 25% 25%

1.

• 1. 5-
• 10

10

2.

• 2. 20

20-

• 30

30

Answer Now

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3.

• 3. 40

40-

• 50

50

4.

• 4. > 50

> 50

All women with polycystic All women with polycystic

• varies have PCOS.
• varies have PCOS.

50% 50%

1.

• 1. True

True

2.

• 2. False

False

T r u e F a l s e

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2.

• 2. False

False

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Ovulatory Ovulatory disorders disorders

• Menstrual abnormalities

Menstrual abnormalities

– Inconsistent Inconsistent – Oligomenorrhea Oligomenorrhea – Amenorrhea Amenorrhea – 20 20-

• 30 %

30 % -

• normal menses

normal menses – 5 5-

• 15% polymenorrhea, menorrhagia

15% polymenorrhea, menorrhagia

• Decreased fertility

Decreased fertility

• Endometrial cancer

Endometrial cancer

Hyperandrogenic Hyperandrogenic

• Ovarian or adrenal gland abnormalities

Ovarian or adrenal gland abnormalities

• Clinical picture

Clinical picture

– Hirsutism Hirsutism – 70 % 70 % Hirsutism Hirsutism 70 % 70 % – Acne Acne

• 25

25-

• 35%

35%

• Severe acne

Severe acne – – high incidence of PCOS high incidence of PCOS

– Alopecia Alopecia – – 10 % 10 %

Hyperandrogenic Hyperandrogenic

http://img.webmd.com/dtmcms/live/webmd/consumer_assets/site_images/articles/health_tools/weight_gain_shockers_slideshow/PRinc_rm_photo_of_hirsutism.jpg

Hirsutism Hirsutism

http://www.endotext.org/female/female4/figures/figure4.jpg

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Modified Modified Ferriman Ferriman Galwey Galwey Score Score

Yildiz BO (2008) Assessment, diagnosis and treatment of a patient with hirsutism. Nat Clin Pract Endocrinol Metab doi:10.1038/ncpendmet0789

Polycystic Ovaries Polycystic Ovaries

www.advancedfertility.com/pics/pco.jpg www.advancedfertility.com/pics/singlefollicle...

Polycystic Ovary Normal Ovary Single Follicle

Insulin resistance Insulin resistance

• 50

50-

• 70%

70%

• Obese and non

Obese and non-

• obese women
• bese women
• Hyperinsulinemia

Hyperinsulinemia

• Increased androgen secretion

Increased androgen secretion

• Inappropriate LH secretion

Inappropriate LH secretion

• Impaired glucose tolerance, diabetes

Impaired glucose tolerance, diabetes

• Dyslipidemia

Dyslipidemia

Insulin resistance detection Insulin resistance detection

• No clear agreement on preferred

No clear agreement on preferred diagnostic criteria diagnostic criteria

• Clinical picture of metabolic syndrome

Clinical picture of metabolic syndrome Clinical picture of metabolic syndrome Clinical picture of metabolic syndrome

– Blood pressure ≥130/85 Blood pressure ≥130/85 – Waist circumference ≥ 35 inches Waist circumference ≥ 35 inches – Fasting glucose ≥ 100 mg/ Fasting glucose ≥ 100 mg/dL dL – HDL HDL-

• C ≤ 50 mg/

C ≤ 50 mg/dL dL – Triglycerides ≥ 150 mg/ Triglycerides ≥ 150 mg/dL dL

http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

Acanthosis Acanthosis Nigricans Nigricans

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/2353.jpg

Endocrine consequences Endocrine consequences

• Reproductive and cosmetic consequences

Reproductive and cosmetic consequences

– Infertility Infertility – Hirsutism Hirsutism – Acne Acne

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Cardiometabolic Cardiometabolic Consequences Consequences

• Insulin resistance

Insulin resistance – – 50 50-

• 70%

70%

• Obesity

Obesity – – 30 30-

• 60%

60%

• Impaired glucose tolerance

Impaired glucose tolerance – 35% 35%

• Impaired glucose tolerance

Impaired glucose tolerance 35% 35%

• Diabetes

Diabetes – – 7.5 7.5-

• 10%

10%

• Dyslipidemia

Dyslipidemia – – 70% 70%

• Hypertension

Hypertension – – 28% 28%

• Metabolic syndrome

Metabolic syndrome – – 43% 43%

Subclinical Atherosclerosis Subclinical Atherosclerosis

• Coronary artery calcification

Coronary artery calcification

• Aortic calcification

Aortic calcification

• Increased carotid

Increased carotid intima intima-media wall media wall

• Increased carotid

Increased carotid intima intima media wall media wall thickness thickness

• Increased left ventricular mass

Increased left ventricular mass

• Left ventricular diastolic dysfunction

Left ventricular diastolic dysfunction

Atherosclerotic events Atherosclerotic events

• Clinical features of PCOS

Clinical features of PCOS

– 3.3 fold greater risk of cardiovascular death 3.3 fold greater risk of cardiovascular death and myocardial infarction and myocardial infarction

• Irregular menses

Irregular menses – – relative risk of CAD relative risk of CAD 1.34 vs. those with normal menses 1.34 vs. those with normal menses

Shaw LJ, Bairey Merz CN, Azziz R, et al. J Clin Endocrinol Metab. 2008;93(4): 1276-84. Solomon CG, Hu FB, Dunaif A, et al. J Clin Endocrinol Metab. 2002;87(5):2013-17.

Treatment goals Treatment goals

• Maintain normal

Maintain normal endometrium endometrium

• Block androgen effects on targets

Block androgen effects on targets

• Reduce insulin resistance

Reduce insulin resistance l l

• Correct

Correct anovulation anovulation

• Improve infertility

Improve infertility

• Weight reduction

Weight reduction

• Prevent long

Prevent long-

• term complications

term complications

– AGGRESSIVE MANAGEMENT OF CV RISK AGGRESSIVE MANAGEMENT OF CV RISK FACTORS FACTORS

Not wishing to conceive Not wishing to conceive

• Menstrual disorders

Menstrual disorders

– COC COC – Insulin sensitizers Insulin sensitizers

• Hirsutism

Hirsutism

– Antiandrogens Antiandrogens – Nonpharmacologic Nonpharmacologic

• Cardiovascular risk factors

Cardiovascular risk factors

– Insulin sensitizers Insulin sensitizers – Statins Statins

Weight reduction Weight reduction – – 5 5-

• 10%

10%

• Decreases insulin concentration/resistance

Decreases insulin concentration/resistance

• Reduces

Reduces hirsutism hirsutism

• Reduces acne

Reduces acne

• Reduces acne

Reduces acne

• Reduces androgens

Reduces androgens

• Improves ovulation, fertility

Improves ovulation, fertility

SLIDE 6

6 Combination Oral Contraceptives Combination Oral Contraceptives (COC) (COC)

• Reduces endometrial hyperplasia/cancer risk

Reduces endometrial hyperplasia/cancer risk

• Reduces ovarian cancer risk

Reduces ovarian cancer risk

• Normalizes menstrual cycle

Normalizes menstrual cycle

• Reduces acne

Reduces acne

• Reduces

Reduces hirsutism hirsutism

Choice of COC Choice of COC

• Low or non

Low or non-

• androgenic progestin

androgenic progestin

– Desogestrel Desogestrel – Norgestimate Norgestimate g – Drospirenone Drospirenone

• Avoid norgestrel and norethindrone

Avoid norgestrel and norethindrone

Choice of COC Choice of COC

• Start with low dose estrogen

Start with low dose estrogen

– 35 mcg 35 mcg ethinyl ethinyl estradiol estradiol or less

• r less

– Increase to slow hair growth, prevent Increase to slow hair growth, prevent b kth h bl di d h l b kth h bl di d h l breakthrough bleeding, reduce hormonal breakthrough bleeding, reduce hormonal abnormalities abnormalities – Obese Obese

• COC with increased estrogenic properties

COC with increased estrogenic properties

– Progestin Progestin – – ethynodiol ethynodiol acetate acetate – Higher Higher ethinyl ethinyl estradiol estradiol dose dose – Increase contraceptive failure Increase contraceptive failure -

• > 154 pounds

> 154 pounds

Hirsutism Hirsutism

• Antiandrogens

Antiandrogens

– Spironolactone Spironolactone – Flutamide Flutamide – Finasteride Finasteride

• Eflornithine

Eflornithine – – 6 months use 6 months use

• Gonadotropin

Gonadotropin-

• releasing Hormone Analogs

releasing Hormone Analogs

Spironolactone Spironolactone

• Aldosterone antagonist

Aldosterone antagonist

• Alone or in combination with COC

Alone or in combination with COC

• 50

50-

• 100 mg BID

100 mg BID – – effect is dose related effect is dose related

• Reduces hair growth

Reduces hair growth – – 40 40-

• 88%

88%

• 6-
• 9 months for improvement

9 months for improvement

• May reduce insulin resistance

May reduce insulin resistance

• Little beneficial effect on androgens and LH

Little beneficial effect on androgens and LH

Spironolactone Spironolactone

• Adverse effects

Adverse effects

– Hyperkalemia Hyperkalemia – Category C Category C g y g y – Polyuria Polyuria, , polydipsia polydipsia on initiation

• n initiation

– Menstrual irregularities, Menstrual irregularities, mastodynia mastodynia, , headaches, mood swings, fatigue, decreased headaches, mood swings, fatigue, decreased libido, libido, gi gi discomfort discomfort

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Flutamide Flutamide

• Non

Non-

• steroidal antiandrogen

steroidal antiandrogen

• Efficacy equal or superior to spironolactone

Efficacy equal or superior to spironolactone

• 250 mg qd or bid

250 mg qd or bid E li t f ti E li t f ti 3 th 3 th

• Earlier onset of action

Earlier onset of action – 3 months 3 months

• May produce ovulation

May produce ovulation

• Little effect on insulin resistance

Little effect on insulin resistance

• Adverse effects

Adverse effects – – rare hepatotoxicity, pregnancy rare hepatotoxicity, pregnancy category D, dry skin, glactorrhea, diarrhea, category D, dry skin, glactorrhea, diarrhea, abdominal distress abdominal distress

Finasteride Finasteride

• 5

5 α reductase reductase inhibitor inhibitor

• 50% improvement in

50% improvement in hirsutism hirsutism

• Less effective than

Less effective than flutamide flutamide

• Less effective than

Less effective than flutamide flutamide

• Equal to or less effective than

Equal to or less effective than spironolactone spironolactone

• 5-
• 7.5 mg per day

7.5 mg per day

• Treatment for androgenic alopecia

Treatment for androgenic alopecia

Finasteride Finasteride

• Adverse effects

Adverse effects

– Minor GI complaints Minor GI complaints – Pregnancy category X Pregnancy category X – abnormal genitalia in abnormal genitalia in g y g y g y g y g male fetus male fetus – DO NOT HANDLE DO NOT HANDLE – – women who are or may women who are or may be pregnant be pregnant

Gonadotropin Gonadotropin-

• releasing Hormone

releasing Hormone Analogs Analogs

• Non

Non-

• responders to antiandrogenic and

responders to antiandrogenic and COC COC

• Decrease LH

Decrease LH Decrease LH Decrease LH

• Decrease ovarian hormone production

Decrease ovarian hormone production

• Slows with hair growth

Slows with hair growth

• Use with COC

Use with COC

• Expensive

Expensive

Gonadotropin Gonadotropin-

• releasing Hormone

releasing Hormone Analogs Analogs

• Adverse effects

Adverse effects

– Estrogen deficiency Estrogen deficiency

• Bone loss

Bone loss

• Hot flashes

Hot flashes

• Atrophic vaginitis

Atrophic vaginitis

• Requires add back estrogen (COC)

Requires add back estrogen (COC)

Insulin sensitizers Insulin sensitizers

• Metformin

Metformin

• Thiazolidinediones

Thiazolidinediones – – weight gain weight gain

– Troglitazone Troglitazone Troglitazone Troglitazone

• Most information

Most information

• Removed from market

Removed from market

– Rosiglitazone Rosiglitazone – Pioglitazone Pioglitazone – – new concerns of bladder cancer new concerns of bladder cancer

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Insulin sensitizers Insulin sensitizers

• Metformin

Metformin – – biguanide biguanide

– Decreases insulin and testosterone 20 Decreases insulin and testosterone 20-

• 50%

50% – Increases SHBG Increases SHBG D BMI D BMI – Decreases BMI Decreases BMI – Improves menstrual Improves menstrual cyclicity cyclicity – – 68 68-

• 96%

96% – Improves spontaneous ovulation Improves spontaneous ovulation

• Improved with addition of

Improved with addition of clomiphene clomiphene

– Promotes fertility Promotes fertility – Anti Anti-

• inflammatory

inflammatory

Metformin Metformin

• Effects independent of weight loss

Effects independent of weight loss

• Predictors of success

Predictors of success

– Higher plasma insulin Higher plasma insulin – Lower serum androstenedione Lower serum androstenedione – – Less severe menstrual irregularities Less severe menstrual irregularities

• Other clinical symptoms

Other clinical symptoms

– Reduces hirsutism scores Reduces hirsutism scores – Reduces body weight Reduces body weight – 10 fold reduction in gestational diabetes 10 fold reduction in gestational diabetes – 30 30-

• 45% reduction in early pregnancy loss

45% reduction in early pregnancy loss – Increases HDL Increases HDL

Metformin Metformin

• 500 mg TID

500 mg TID

• 850 mg BID

850 mg BID

• up to 2550 mg daily

up to 2550 mg daily

• up to 2550 mg daily

up to 2550 mg daily

• Start 500 mg daily to reduce GI upset

Start 500 mg daily to reduce GI upset

• Adverse effects

Adverse effects

– Diarrhea, nausea, vomiting, bloating Diarrhea, nausea, vomiting, bloating – Rare fatal acidosis Rare fatal acidosis

Metformin Metformin

• Combinations

Combinations

– Metformin plus flutamide Metformin plus flutamide

• Increases insulin sensitivity

Increases insulin sensitivity

• Decreases androgens

Decreases androgens

• Improves cholesterol measurements

Improves cholesterol measurements

• Increases monthly ovulation rates

Increases monthly ovulation rates

Metformin Metformin

• Combinations

Combinations

– Metformin Metformin added to COC added to COC

• Improves insulin sensitivity

Improves insulin sensitivity

• Decreases BMI and WHR

Decreases BMI and WHR

• Further suppresses androgens

Further suppresses androgens

Thiazolidinediones Thiazolidinediones

• Rosiglitazone

Rosiglitazone and and pioglitazone pioglitazone

– Reduces insulin/insulin resistance Reduces insulin/insulin resistance – Decreases androgens Decreases androgens – Increases SHBG Increases SHBG – Increases ovulation Increases ovulation – Restores menstrual cycle regularity Restores menstrual cycle regularity – Reduces Reduces hirsutism hirsutism score score

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Rosiglitazone Rosiglitazone

• Adverse effects

Adverse effects

– Edema Edema – Weight gain Weight gain g g g g – Anemia Anemia – Heart failure Heart failure – Bone fractures Bone fractures – Caution in hepatic impairment Caution in hepatic impairment – Box warning Box warning – – CHF and MI CHF and MI

Pioglitazone Pioglitazone

• Adverse effects

Adverse effects

– Edema Edema – Weight gain Weight gain g g g g – Anemia Anemia – Heart failure Heart failure – Bone fractures Bone fractures – Caution in hepatic impairment Caution in hepatic impairment – Bladder cancer Bladder cancer – Box warning Box warning -

• CHF

CHF

Treating menstrual disorders Treating menstrual disorders

• Those not wishing to conceive

Those not wishing to conceive

– COC COC – Insulin sensitizers Insulin sensitizers

• Discuss contraception

Discuss contraception

Reducing CVD and DM Risks Reducing CVD and DM Risks

• Those not wishing to conceive

Those not wishing to conceive

– Lifestyle modification Lifestyle modification

• Reduced caloric intake

Reduced caloric intake

• Increase exercise

Increase exercise

– Insulin sensitizers Insulin sensitizers -

• Metformin

Metformin – Statins Statins

Lifestyle modification Lifestyle modification

• 5-
• 10% of body weight

10% of body weight

• Improves insulin sensitivity

Improves insulin sensitivity

• Decreases insulin

Decreases insulin

• Decreases insulin

Decreases insulin

• Decreases androgens

Decreases androgens

• Increases SHBG

Increases SHBG

• Decreases

Decreases dyslipidemia dyslipidemia

Metformin Metformin – – best best risk:benefit risk:benefit

• Delays development of diabetes in men

Delays development of diabetes in men

– 850 mg BID 850 mg BID

• Antiatherosclerotic

Antiatherosclerotic Antiatherosclerotic Antiatherosclerotic

• Antithrombotic

Antithrombotic

• Anti

Anti-

• inflammatory

inflammatory

Katski N and Hatzilolios AI. Curr Opin Obstet Gynecol. 2010;22:466-476 ACOG Practice Bulletin No. 108: Polycystic Ovary Syndrome. Obstetrics and Gynecology. 2009;114:936-949. Diabetes Prevention Program Research Group. N Engl J Med 2002;344:1343-1350.

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Statins Statins

• HMG Co A

HMG Co A reductase reductase inhibitors inhibitors

• Up regulate hepatic LDL receptors

Up regulate hepatic LDL receptors

• Inhibit cell proliferation

Inhibit cell proliferation

• Inhibit cell proliferation

Inhibit cell proliferation

• Antioxidant

Antioxidant

• Anti

Anti-

• inflammatory

inflammatory

• Reduce testosterone

Reduce testosterone

• Improve insulin sensitivity

Improve insulin sensitivity

PCOS PCOS

• Most common

Most common endocrinopathy endocrinopathy in women in women

• Associated with

Associated with

– Ovulatory Ovulatory dysfunction, dysfunction, hyperandrogenism hyperandrogenism, Ovulatory Ovulatory dysfunction, dysfunction, hyperandrogenism hyperandrogenism, , multiple ovarian cysts multiple ovarian cysts – Dermatologic abnormalities Dermatologic abnormalities

• Hirsutism

Hirsutism

• Acne

Acne

• Alopecia

Alopecia

– Increased prevalence of CV risk factors Increased prevalence of CV risk factors

PCOS PCOS

• Treatments for those not wishing to conceive

Treatments for those not wishing to conceive

– Hirsutism Hirsutism

• Antiandrogens

Antiandrogens

• Gonadotropin

Gonadotropin-

• releasing hormone analogs

releasing hormone analogs

Improve ovarian function Improve ovarian function – Improve ovarian function Improve ovarian function

• Weight loss

Weight loss

• COC

COC

• Insulin sensitizers

Insulin sensitizers

– Reduce risk of CVD and DM Reduce risk of CVD and DM

• Lifestyle modification

Lifestyle modification

• Metformin

Metformin

• Statins

Statins

Which is a sign of insulin Which is a sign of insulin resistance? resistance?

25% 25% 25% 25%

1.

• 1. Hirsutism

Hirsutism

2.

• 2. Acne

Acne

3 A

th i A th i

H i r s u t i s m A c n e A c a n t h

• s

i s n i g . . . A l

• p

e c i a

3.

• 3. Acanthosis

Acanthosis nigricans nigricans

4.

• 4. Alopecia

Alopecia

Answer Now

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Which is a component of Which is a component of metabolic syndrome? metabolic syndrome?

25% 25% 25% 25%

1.

• 1. BP ≥ 140/90 mm Hg

BP ≥ 140/90 mm Hg

2.

• 2. Fasting glucose ≥

Fasting glucose ≥ 100 mg/ 100 mg/dL dL

F a s t i n g g l u c

• s

. . . T r i g l y c e r i d e s . . . W a i s t c i r c u m f e . . .

100 mg/ 100 mg/dL dL

3.

• 3. Triglycerides ≥ 130

Triglycerides ≥ 130 mg/ mg/dL dL

4.

• 4. Waist circumference

Waist circumference ≥ 30 inches ≥ 30 inches

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In PCOS which progestin In PCOS which progestin component in a COC is should component in a COC is should be avoided? be avoided?

25% 25% 25% 25%

1.

• 1. Desogestrel

Desogestrel

2

D e s

• g

e s t r e l D r

• s

p e r i n

• n

e N

• r

g e s t i m a t e N

• r

g e s t r e l

2.

• 2. Drosperinone

Drosperinone

3.

• 3. Norgestimate

Norgestimate

4.

• 4. Norgestrel

Norgestrel

Answer Now

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SLIDE 11

11

Which of the following reduces Which of the following reduces gestational diabetes in PCOS? gestational diabetes in PCOS?

25% 25% 25% 25%

1.

• 1. Finasteride

Finasteride

2.

• 2. Flutamide

Flutamide

F i n a s t e r i d e F l u t a m i d e M e t f

• r

m i n S p i r

• n
• l

a c t

• n

e

Answer Now

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2.

• 2. Flutamide

Flutamide

3.

• 3. Metformin

Metformin

4.

• 4. Spironolactone

Spironolactone