Polycystic Ovarian Syndrome A Hidden Epidemic

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Polycystic Ovarian SyndromeA Hidden Epidemic

• Gad Lavy, M.D.
• New England Fertility Institute
• Lifeline Cryogenics

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PCOS-Taking points

• A common condition recognized for decades and
  familiar to all Ob/Gyns and general
  practitioners.
• Fertility and esthetic concerns often bring it to
  attention.
• New information suggests it to be a more serious
  medical condition and a significant public
  health problem.
• Treatment is focused on the metabolic defect.
• A team approach to therapy is essential.

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Stein-Leventhal Syndrome 1935

• Amenorrhea associated with bilateral polycystic
  ovaries Stein I.F. and Leventhal M.L. (1935). Am.
  J. Obstet. Gynecol. 29181-189.
• Wedge Resection restored normal menses

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Stein-Leventhal Syndrome

• Stein-Leventhal Syndrome The Triad
• Amenorrhea
• Obesity
• Hirsutism
• Many cases do not conform to the classic
  description.
• The polycystic ovaries are not the primary cause
  but one of the manifestation of the underlying
  endocrine disorder which results in anovulation.

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320,000 Google pages.
5000 publications (2000 since 2002).
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PCOS in the Limelight

• PCOS no longer a primarily gynecological
  disorder.
• Associated with cardiovascular disease and
  diabetes, the most significant cause of morbidity
  and mortality in women.

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Origins

• Genetic disorder Potential present at birth.
• Manifests often at puberty.
• Ovarian function is necessary.
• A history of PCOS carries major long term
  consequences of cardiovascular disease even after
  menopause.

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PCOS Prevalence

• Affects 6-10 of women in childbearing age (4-5
  million women).
• Most common cause of anovulatory infertility
  (50-60).
• Most common endocrine disorder in young women.
• It is one of the major and unrecognized public
  health problems in this country

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PCOS

• Insulin resistance is a prominent feature.
• Hyperandrogenism secondary to high insulin
• Chronic anovulation A result of both

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The Faces of PCOS
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When to Suspect PCOS

• Irregular or infrequent menses.
• Increased androgens causing hirsutism and acne.
• Polycystic ovaries by ultrasound.
• Exclusion of other endocrine disorders (thyroid,
  adrenal, ovary).

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When to Suspect PCOSAdditional clues

• Infertility or pregnancy loss
• Problems maintaining normal weight
• Family history of PCOS, infertility of irregular
  cycles
• Family history of diabetes or CVD
• Hyper or hypoglycemia
• Hypertension
• Dark skin patches in skin fold
• Scalp hair loss
• High LDL, TG and low HDL
• Sleep apnea, Depression and anxiety

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PCOS Diagnostic Criteria

• Anatomical
• Biochemical
• Clinical

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PCOS Diagnostic Criteria

• Anatomical
• Ultrasound
• Surgery
• Pathology
• Biochemical
• Altered androgens
• Reverse in LH/FSH
• Altered fasting/stimulated glucose/insulin
• Clinical
• Ovulatory dysfunction
• Body weightgt110 of ideal
• Hyperandrogenism

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Anatomy of PCOS
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PCOS Diagnostic Criteria

• Anatomical
• Ultrasound
• Surgery
• Pathology
• Biochemical
• Altered androgens
• Reverse in LH/FSH
• Altered fasting/stimulated glucose/insulin
• Clinical
• Ovulatory dysfunction
• Body weightgt110 of ideal
• Hyperandrogenism

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PCOS Diagnostic Criteria

• Anatomical
• Ultrasound
• Surgery
• Pathology
• Biochemical
• Altered androgens
• Reverse in LH/FSH
• Altered fasting/stimulated glucose/insulin
• Clinical
• Ovulatory dysfunction
• Body weightgt110 of ideal
• Hyperandrogenism

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Hyperandrogenism Hyperinsulinemia
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Diagnosis of PCOS

• Ovarian/menstrual dysfunction (stein-Leventhal
  1935)
• Clinical/biochemical evidence of increased
  androgens (1990 NIH conference of PCOS)
• Ultrasound Showing polycystic ovaries (2003
  consensus conference)
• Insulin resistance and metabolic syndrome
  glucose tolerance test

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PathophysiologyInsulin Resistance and PCOS

• Hyper-insulinemic insulin resistance is a
  universal feature of PCOS
• PCOS is associated with a unique form of insulin
  resistance.
• Hyper-insulinemic insulin resistance is present
  in obese and non-obese PCOS women

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Insulin Resistance in Women with PCOS
Insulin Sensitivity decreases
Insulin release and circulating levels increase
Normal glucose tolerance
Compensatory Hyperinsulinemic Insulin Resistance
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Hyperinsulinemia and Hyperandrogenism
Hyper-insulinemia
Disordered LH/FSH release
Ovarian androgen production
SHBG production
Anovulation
Hyperandrogenism
PCOS
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Impact of PCOS

• Gynecological ovulatory dysfunction
• Cosmetic Hyperandrogenism
• Metabolic Insulin resistance and
  hyperandrogenism

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Impact of PCOS

• Gynecological ovulatory dysfunction
• Infertility
• Endometrial cancer
• Cosmetic Hyperandrogenism
• Hirsutism
• Acne
• Metabolic Insulin resistance and
  hyperandrogenism
• Type 2 Diabetes
• Dyslipedemia
• Cardiovascular disease
• Hypertension

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PCOS and Infertility

• Ovulatory dysfunction
• Hyper-insulinemia
• Hyper-androgenism
• Ovulation Induction therapy
• Pregnancy loss
• Pregnancy complications

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PCOS Ovulation Induction

• Poor response to standard ovulation drugs
• Multiple pregnancy
• Ovarian Hyper-stimulation
• Once pregnant
• Pregnancy Loss
• Gestational Diabetes

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Metformin and Ovulation

• Ovulation Rate
• 3.9 fold increase (plt0.00001)
• 46 with metformin compared to 24 with placebo
• NNT4.4
• Clinical Pregnancy
• 2.8 fold increase (p0.09)

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Metformin and Clomiphene

• Ovulation rate
• 4.4 fold increase
• 76 with metformineclomid vs. 42 with clomid
  alone
• NNT3.0 (1.5 for clomid resistant women)
• Clinical Pregnancy Rate
• 4.4 fold increase

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PCOS and Pregnancy Loss

• Women with PCOS have a very high incidence of
  pregnancy loss (30-50)
• Insulin resistance underlies the pregnancy loss
  (glycodelins endometrial proteins).
• Insulin sensitizers reduce the risk of pregnancy
  loss.
• No evidence that IS should be continued past the
  first trimester.

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Impact of PCOS

• Gynecological ovulatory dysfunction
• Infertility
• Endometrial cancer
• Cosmetic Hyperandrogenism
• Hirsutism
• Acne
• Metabolic Insulin resistance and
  hyperandrogenism
• Type 2 Diabetes
• Dislipedemia
• Cardiovascular disease
• Hypertension

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Skin Manifestations of PCOS

• Acne
• Hirsutism
• Alopecia
• Acanthosis Nigricans

Hyperandrogenism
Hyperinsulinemia
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Treatment of Skin Manifestations of PCOS

• Drug therapy
• Cosmetic therapy
• Skin care
• Hair removal

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PCOS Treatment of Hyperandrogenism

• Inhibit ovarian/adrenal androgen production
• Block androgen receptor
• Block 5 alpha reductase in the hair follicle

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Drug therapy for hyperandrogenism

• Flutamide
• Spironolactone
• Cyprotarome Acetate (in OCP)
• Thiazolidinediones (TZDs)
• OCP
• Metformin
• Finestimide

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Impact of PCOS

• Gynecological ovulatory dysfunction
• Infertility
• Endometrial cancer
• Cosmetic Hyperandrogenism
• Hirsutism
• Acne
• Metabolic Insulin resistance and
  hyperandrogenism
• Type 2 Diabetes
• Dislipedemia
• Cardiovascular disease
• Hypertension

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Metabolic Impact of PCOS Syndrome X
Insulin Resistance and Hyper-insulinemia
Diabetes
PCOS
hypertension
Dyslipidemia
Atherosclerosis
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Metabolic Syndrome(NHANES III criteria)- three
of five needed for dx

• Increased waist circumference (gt36 in)
• Elevated TGs (gt149 mg/dl)
• Decreased HDL cholesterol (lt50 mg/dl)
• High blood pressure gt130/85
• Fasting glucose gt 100 mg/dl

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PCOS and Type 2 Diabetes

• 30-50 of obese women with PCOS develop IGT or
  DM2 by age 30
• 25-28 of pre-menopausal women with DM2 have
  PCOS (often undiagnosed).
• 82 of pre-menopausal women with DM2 have
  anatomically polycystic ovaries.

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Cardiovascular Risks Factorsand PCOS

• Obesity
• Hypertension
• Vascular dysfunction
• Decreased HDL
• Increased TG
• Increased CRP, Endothelin-1 and PAI-1

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PCOS and Cardiovascular Risk

• Retrospective study of Swedish women who had
  ovarian wedge resection RR for MI of 7.4 (acta
  Obstet Gynecol 1992, 71599)
• Association between PCOs and extent of CAD in
  women undergoing cardiac cath (Ann Intern
  Med.12632)

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PCOS and Cardiovascular Disease

• Nurses Health Study
• 82,439 women followed for 14 years
• Women with irregular menses
• RR for CHD1.5
• RR for fatal MI1.9 (JCEM 2002 872013)

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PCOS Cardiovascular Risk Factors

• Postmenopausal women with history of irregular
  cycles are at a higher risk of MI

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Evaluation of Women with PCOSGeneral Health
Issues

• Glucose Tolerance Test (2 hour OGTT)
• Monitor BP Hypertension
• Check lipid profile Dyslipidemia
• Assess risk factors for heart disease

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Impact of PCOS
Goal of Therapy

• Gynecological
• Infertility
• Endometrial cancer
• Cosmetic
• Hirsutism
• Acne
• Metabolic
• Type 2 Diabetes
• Dislipedemia
• Cardiovascular disease
• Hypertension

• Gynecological
• Improve reproductive function
• Reduce risk of endometrial cancer
• Reduce serum androgens
• Metabolic Ameliorate complications due to IR
• Glucose intolerance
• Dyslipidemia
• Atherogenesis
• Hypertension

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PCOS Drug Therapy

• Anti-androgens
• OCP
• Insulin Sensitizers

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OCP and Insulin Sensitizers

• OCP
• Worsen insulin resistance
• Induce glucose intolerance
• Increase serum TG
• Increase risk of DM2
• Increase risk of CVD
• Reduce ovarian androgens (acne, hirsutism)
• Reduce risk of endometrial carcinoma

• Insulin Sensitizers
• Improve insulin sensitivity
• Improve Glucose tolerance
• Reduce serum TG
• Reduce CRP, Endothelin-1 and PAI-1 (and risk of
  CVD)
• No effect on androgens (acne, hirsutism)
• No reduction in endometrial cancer risk

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PCOS Surgical Therapy

• Wedge resection
• Ovarian drilling
• Bariatric surgery

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Team Approach to PCOS A coordinated approach
Fertility
Metabolic Disorder
Risk of Endometrial cancer
Hirsutism and Acne
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Team Approach to PCOS A coordinated approach
Psychological counseling
Drug Therapy
Cosmetic therapy
Nutritional counseling
Exercise
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The PCOS ClinicA Team Approach

• Eight week treatment and education program
• Intended for all women with PCOS (regardless of
  desire to conceive)
• Initial assessment medical, Psychological and
  Fitness
• Weekly group Education and support

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PCOS ClinicEducational Component

• The science of PCOS
• Women and heart disease
• Nutrition and low glycemic index diets
• Intervention for hirsutism and Acne
• Stress reduction

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PCOS ClinicPsychological Support

• Individual weekly assessment
• Weekly support groups
• Couples week (get your partner involved)

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PCOS ClinicFitness

• Individual assessment and recommendations
• Group education and instruction

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Summary

• Insulin resistance prominent feature of PCOS in
  obese and non-obese women.
• Increases risk of DM2 and CVD.
• Plays a pathogenic role in the development of PCOS

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Summary Insulin Sensitizers

• Administration of insulin sensitizers
• Decreases circuiting androgens
• Improves ovulation and fertility

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Summary PCOS and general Health Issue

• OCP may worsen risk of DM2 and CVD
• Insulin sensitizers may reduce risk of DM2 and CVD

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PCOS Summary

• A combination of drug therapy, counseling, and
  cosmetic procedures is needed
• Dramatic Lifestyle change are needed
• A team approach to PCOS will maximize results

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