Download - PCOS, dyslipidemia and CVD
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PCOS, dyslipidemia and CVD
Nelly Pitteloud, MD
Reproductive Endocrine UnitMassachusetts
General Hospital
COI: Repros Consultant
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Objectives
PCOS
• Definition
• Pathophysiology
• Metabolic features
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22 yo woman with oligomenorrhea
• 22 yo with 9 months oligoamenorrhea
• Menarche age 11 yrs, cycles approx 45 days
• Slightly overweight since elementary school
• Acne with menses
• Waxes upper lip, chin weekly for one year
• Family history of type 2 diabetes
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Examination
• Weight 178, height 5’5”, BMI 29 kg/m2
• Terminal hair on face
• Acanthosis nigricans
Work-up: Neg hCG, FSH 5.2 IU/L, Prl 10 ng/ml, TSH 2.0 uU/ml, T 90 ng/dL
Diagnosis?Further work-up?
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Hypothalamic-Pituitary-Gonadal Axis
Hypothalamus
LH
GnRH
FSH
Pituitary
Ovary
E2
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POLYCYSTIC OVARIAN SYNDROMEDefinition 1990 NIH Workshop
CHRONIC OLIGO/ANOVULATION
HYPERANDROGENISM in the absence of other known causes of androgen
excess(tumor, CAH, hyperprolactinemia)
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POLYCYSTIC OVARIAN SYNDROME2003 Rotterdam Workshop
2 of 3:
CHRONIC OLIGO/ANOVULATION
HYPERANDROGENISM
POLYCYSTIC OVARIAN MORPHOLOGY
in the absence of other known causes of androgen excess
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Polycystic Ovarian Syndrome
Affects 6-10% of women of childbearing age (3.2 to 5.4
million women in the U.S.)
Chronic anovulation and hyperandrogenism
Most common cause of female infertility (approximately 50-60%)• Anovulation• Early miscarriage
Most common endocrinopathy in young women
Insulin resistance is a prominent feature
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The Polycystic Ovary
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Polycystic ovary (PCO)
• Ovarian vol >10 ml or• >12 small follicles (2-8 mm)• Peripheral distribution• Increased stromal vol
(Jonard et al, 2003)
Normal ovary Few follicles Random distribution No increased stroma
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Proportion of Anovulatory PCOS Subjects
0 20 40 60 80 100%
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POLYCYSTIC OVARY SYNDROME: Clinical concerns
• Menstrual cycle irregularity/Chronic unopposed estrogen exposure
• Hyperandrogenic symptoms (hirsutism, acne, alopecia)
• Anovulatory infertility (but risk of intermittent ovulation)
• Metabolic risks
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InsulinAndrogens
Neuro-endocrine Menstrual
Irregularity+
Hyperandrogenism
Pathophysiology of PCOS
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Hyperandrogenism
Pathophysiology of PCOS
adrenal
morphology
ovary1o or 2o
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17Hydroxyprogesterone (ng/mL)
0
1
2
3
4
5Testosterone (ng/mL)
0
100
200
300
Free Testosterone (ng/mL)
0
2
4
6
8 DHEAS (g/dL)
0
100
200
300
400
500
600
PCOS NormalTaylor et al, 1994
PCOS Normal
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Neuroendocrineabnormalities
Pathophysiology of PCOS
HypothalamusPituitary
1o or 2o?
LHFSH
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Gonadotropin Abnormalities in PCOS
PCOS50
25
100
20
10
LH IU/L
FSH IU/L
Yen et al, 1970
Normalized transiently after ovulatory cycle or progestin
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LH
LH
Obesity results in decreased serum LH
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Hyperinsulinemia
Pathophysiology of PCOS
signaling
insulin
SHBG
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• Insulin resistance is a very common feature of women with PCOS (60-75%)
Insulin Resistance and PCOS
• Insulin resistance occurs in both obese and non-obese women with PCOS
• Obesity has a synergystic effect on glucose metabolism and IR
Palomba S, Endocrine Review, 2009
• Anomalies in insulin Receptor mediated transduction
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WHO 2006 Criteria to define hyperglycemia
2-h glucose/OGTT
NGT <140 mg/dl (7.8 mmol/liter)
IGT >140 mg/dl (7.8 mmol/liter) and < 200 mg/dl (11.1 mmol/L)
DM = or > 200 mg (11.1 mmol/liter
Fasting glucose
Normal FG <110 mg/dl (6.1 mmol/liter)
IGT 110 mg/dl (6.1 mmol/liter) to 125 mg/dl (6.9 mmol/L)
Diabetes = or > 126 mg/dl (7.0 mmol/liter)
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Insulin and Glucose Responses in PCOSIN
SU
LIN
GL
UC
OS
E
MINUTES Dunaif A et al, 1987
0 20 40 60 80 100 1200
50
100
150
200 ****
NL
PCOS
0 20 40 60 80 100 1200
50
100
150
200
* * * *
NL
PCOS
0 20 40 60 80 100 1200
50
100
150
200
NL
PCOS
0 20 40 60 80 100 1200
50
100
150
200 * * * *
NL
PCOS
LEANOBESE
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Insu
lin
Sen
siti
vity
PCOSObese
PCOSLean
NlObese
NlLean
IR is present in both lean and obese PCOS compared totheir BMI and age matched counterpart
Dunaif A et al, 1987
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PCOS and Obesity
• 60% of US women with PCOS are obese
• Distribution of fat: visceral adiposity (Android pattern)
• Known to be metabolically active• Highly associated with hyperinsulinemia• Central obesity correlates with CV risk.
• 70% of lean PCOS women have an android pattern of fat distribution.
Is obesity an intrinsic clinical sign of PCOS or promoting environmental factor?
Nelson SM, 2007
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Prevalence of Glucose intolerance and Diabetes in PCOS
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Prevalence of IGT (by OGTT ) in 254 womenwith PCOS 14-44 yr old
NGT IGT Type II DM
61,3%
31.1%
7.5%
Legro et al, JCEM, 1999
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Conversion rate to IGT and type II DM
• Controlled Study
Baseline OGTT71 PCOS and 23 normal F/U 2-3 yr
PCOS:
• 37% IGT and 10% DM2 at baseline
• 16% conversion/year from NGT to IGT
• 2% conversion/year from IGT to DM2
The conversion from IGT to frank diabetes is substantially
enhanced in women with PCOS
Legro et al, JCEM, 2005
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Development of Gestational DM
Meta-analysis
• 720 women with PCOS and 4505 controls
• RR 2.94 (CI 1.70-5.08) of developing GDM than control women
Besides converting to IGT or type 2 DM, women with PCOS are also at high risk for developing gestational DM
Boomsma et al, Hum Reprod Update, 2006
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PCOS and Type II diabetes
• Nurses’ Health Study II (NHSII): 101.073 women
• Women followed for 8 years
• Conversion rate to DMII was 2-fold higher in oligo- menorrheic women, independent of weight
• By age 30, 30-50% of obese PCOS developed IGT or DM
• 3-7x increase as compared to the general population
Legro et al, JCEM, 1999
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Mechanisms of Predisposition to the development Mechanisms of Predisposition to the development Type II DM in PCOSType II DM in PCOS
• Women with PCOS are insulin resistant independent of obesity
• Defects in insulin receptor or post-receptor signal transduction
• Altered adipocyte lipolysis
• Decrease GLUT-4 expression in the adipocytes
• Many PCOS women exhibit β-Cell dysfunction
Ek I et al JCEM 1997Ek I et al, Diabetes 2002Kelsey ES, JCEM 2007
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PCOS and Metabolic Syndrome
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> 3 of the following for women:
Triglycerides >150 mg/dL
HDL Cholesterol (F) < 50 mg/dL
Blood Pressure >130/85 mm/Hg
Waist > 88 cm
Glucose (fasting) > 100 mg/dL
Metabolic Syndrome NCEP 2001 ATP III
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Prevalence of Metabolic syndrome in PCOS
Apridonidze T eta al JCEM 2005
33.4% of obese PCOS (Ehrmann et al, 2006)
24% of PCOS (BMI = 31 kg/m2)
(Welt et al, 2007)
37% of adolescent girls
(Coviello et al 2006)
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Prevalence of Metabolic syndrome in PCOS compared to NHANES women
Apridonidze T eta al JCEM 2005
Age Group BMI (kg/m2)
<25 25–30 >30
20–29 yr (n = 29)
PCOS (%) 17 58 45
U.S. females (%) 0.8 8.3 27
30–39 yr (n = 49)
PCOS (%) 23 40 62
U.S. females (%) 1 14 43
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PCOS and CVD
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• Surrogate endpoints suggest increased CV risk:
Hypertension, Obesity, WHI, Insulin resistanc, HDL
TG , Chronic inflammation, C-reactive protein & PAI-1
Likely due to both:
Hyperandrogenism
Impaired insulin sensitivity
CV Risk Factor in PCOS
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Age (yr) 38.5 39.0 0.40BMI (kg/m2) 31.4 31.2 0.26Waist (cm) 94.75 94.5 0.14Ferriman-Gallwey 16.0 4.0 0.0001Systolic BP (mm Hg) 116 116 0.73Diastolic BP (mm Hg) 74.8 71.5 0.03Smoking status 8.3% 11.4%Fasting insulin (µIU/ml) 7.65 6.3 0.11 Fasting glucose (mg/dl) 90.5 93.0 0.43 IGT 36.1% 23.2% 0.18 Cholesterol (mg/dl) 190 174 0.008 HDL (mg/dl) 48 48 0.49 LDL (mg/dl) 111 99 0.04TG (mg/dl) 125 118 0.33 SHBG (nmol/liter 31.7 38.5 0.04Total T (ng/dl) 47.5 34 <0.0001 Free T (ng/dl) 0.19 0.12 <0.0001
Distribution of CHD risk factors in premenopausal women PCOS vs. control
Variable PCOS (n=36) NL (n=71) Pvalue
Christian RC, JCEM, 2003
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PCOS AND CARDIOVASCULAR DISEASE
• Retrospective study of Swedish women who had ovarian wedge resection in 1950s’: RR for MI of 7.4
Acta Obstet Gynecol Scand, 1992;71;599
•Death certificates from women with PCOS in the UK showed no Increase in MI above expected number
J. Clin. Epidemiol 1998; 51;581
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PCOS AND CARDIOVASCULAR DISEASE
• Nurse Health Study: 82.439 women followed for 14 years. In women with very irregular menses:
RR for CHD was 1.5 (CI 1.3-1.9)
RR for fatal MI was 1.9 (CI 1.3-2.7)
JCEM, 2002; 87;2013
Prospective controlled studies on CVD morbidity and mortality in PCOS are LACKING
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Evaluation of metabolic anomaliesIn PCOS patients
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Evaluation of Women with PCOS: Metabolic issues
• Check for :
• Glucose intolerance (OGTT)
Position of the Androgen Excess Society (2008)Women with PCOS regardless of their weight should be Screened for IGT and DMII by an OGTT at presentation And every 2 yrs. • HTA
• Dyslipidemia
• Risk factors for heart disease
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Traditional and novel therapy forPCOS patients
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Traditional and Novel Goals of Therapy in PCOS
• Improve reproductive function/fertility
• Decrease risk of endometrial cancer
• Treatment of acne and hirsutism
• Ameliorate complications putatively due to insulin resistance
• Prevent IGT and DM• Prevent ATS and acute cardiac events
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PCOS: Management
Menstrual cycle irregularity/Chronic unopposed estrogen exposure:
Oral contraceptives (avoid levonorgestrel)
Cyclic progestin therapy• medroxyprogesterone acetate 10mg x10d every other month• Natural progesterone 200mg x 12d every month
Metformin? (need for monitoring)
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PCOS: Management
Hirsutism
•Oral contraceptives
•Oral contraceptives + antiandrogen (spironolactone)
•Insulin lowering agents ineffective
•Direct hair removal (laser and electrolysis)
•Topical agents (eflornithine)
Martin et al. JCEM 2008
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PCOS: Management
Infertility
•Weight loss!
•Ovulation induction (metformin vs clomiphene)
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PCOS: Management
Prevention of IGT and Type II diabetes
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Prevention of type II DM in non-PCOS Population
• Diabetes Prevention Program Research Group 2002 (DPP)
• Large placebo controlled RCT on 3234 subjects in the US with high risk of developing DM
• Gestational DM• Presence of IGT• First degree relative with DM
• Subjects were randomized to
• Standard management• Intensive life style intervention• Metformin • Troglitazone (discontinued after 18 M– hepatic dysfct)
DPP Group, NEJM, 2002
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Prevention of DMII in non-PCOS Population (DPP)
DPP Group, NEJM, 2002
Mean F/U of 2.8 yr
• Intensive life style intervention incidence of new type II DM by 58%• Metformin incidence of new type II DM by 31%
Improvement in insulin sensitivity either through intensive life Style modification ++ or metformin reduces the risk of developing DM in High risk population
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Metformin and Prevention of IGT in PCOS
Sharma et al End. Pract, 2007
• Limited data on the long-term beneficial effect of Metformin on the risk for type II DM in women with PCOS.
• One retrospective study of PCOS women treated with metformin for an average of 43 M
• At baseline: 78% had NGT & 22% had IGT
• At F/U: No woman developed DM IGT group: 45% continued IGT 55% revert to NGT
NGT group: 5% converted to IGT 95% continued NGT11-fold decrease in the annual conversion rate from NGT to IGTwith 55% of IGT patients reverting to NGT
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Metformin and Prevention of IGT in PCOS
Sharma et al End. Pract, 2007
Meta-analysis (Salpeter et al, Am J Med. 2008)
Goals: To assess the effect of metformin on metabolic risk in patients athigh risk for DM
Inclusions: 31 clinical trials (n= 4570) including 620 PCOS subjects
F/U: Average 2 yrs
Results: Fasting glucose Reduction - 4.5 mg/dL; 95% CI -6 to -3Fasting insulin Reduction - 14.4 IU/L 95% CI -19 to -9
PCOS vs non-PCOS & obese vs nonobese -- p value NS
New onset DM 40% decrease p< 0.01Absolute risk of DM 6% decrease 95% CI 4 to 8No data on subgroups.
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PCOS: Management
1. INTENSIVE LIFE STYLE CHANGES
• Diet low in CH• Exercise• ? Surgery for morbid obesity
1. Medication to enhance insulin sensitivity
• Metformin• Thiazolidinedione (rosiglitazone, pioglitazone)
Metabolic Abnormalities
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Insulin Sensitizing Drug in PCOS
• Insulin sensitizing drug in PCOS
• Improves insulin sensitivity
• Improve glucose tolerance
• May reduce serum TG • Reduce plasma PAI-1 & CRP
• Insulin sensitizing drug in IGT or GDM
• Prevent progression to DM2
• May decrease CV disease
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Summary
• PCOS is a GENERAL HEALTH ISSUE
• Evaluation should include screen for :
IGTDyslipidemiaHTACV risk factors
• Novel Goals of Therapy
Decrease risk for type II DM Decrease risk for early CV disease
Life style modification Insuline sensitizing agents
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Return to patient• Irregular menses
• Hyperandrogenism (acne and hirsutism, high serum T)
• Nl Prolactin, not pregnant
= PCOS
High BMI, acanthosis nigricans, FH of type II diabetes
BP normal, Waist 89 cm
Fasting glucose : normal
OGTT: 2h glucose was 190 mg/dL
Lipid profile: Cholesterol 210, HDL 53, TG 160, LDL 126
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IRS1/2 mediation of PI3 kinase glucose transport & carbohydrate metabolism
MAP kinase mitogenesis
Insulin Signaling Pathways in PCOS – Differential Effects
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POLYCYSTIC OVARIAN SYNDROME2000 NIH Workshop
Irregular cycles
Hyperandrogenism
PCOSPCOS
PCOMorphology
Idiopathic Hirsutism
HypothalamicAmenorrhea
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Implications of Rotterdam Criteria Ovulatory vs anovulatory bleeding
PCOS vs hypothalamic amenorrheaEstrogen statusLH/FSH ratio
Is insulin resistance present in all patients?Risk for diabetesOGTT
What are the cardiovascular implications?Lipids, hypertension
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PCOMorphology
POLYCYSTIC OVARIAN SYNDROME2003 Rotterdam Workshop
Irregular cycles
Less obeseLess hyperandrogenicNo increase in LH No IR
Idiopathic Hirsutism
PCOSPCOSPCOSHypothalamicAmenorrhea
Less obeseIncreased LHMild IR (1 of 3 studies)No hyperandrogenism
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WHAT IS THE ROLE OF GENETICS IN PCOS?• familial clustering of PCOS
• not every obese woman develops PCOS, not all women with PCO morphology develop PCOS
• in vitro
• theca cells from PCOS ovaries are more efficient at synthesizing androgens from precursors
• insulin stimulates androgen production by ovaries of PCOS women, but not by ovaries of normal women
• complex multigenic disorder
• candidate genes -
• steroid pathways – CYP11 (P450scc) (Waterworth et
al, 1997); HSD17B5 SNP-71G (Qin et al 2006)
• ~D19S884 (chromosome 19p13.2) (Urbanek et al 2005)
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• association studies
–marker ~D19S884 (chromosome 19p13.2) near the insulin receptor
• Tucci S, JCEM 2001 p=0.006, corrected p=0.042
• Urbanek M, JCEM 2005, 2006• linkage and association now confirmed in 3 independent data
sets
• fine mapping of insulin receptor region, including an intragenic marker: no other positive associations
• marker is within fibrillin 3
• evidence of regulatory regions near D19S884
What is the Role of Genetics in PCOS?
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POLYCYSTIC OVARIAN SYNDROME:PRINCIPLES OF MANAGEMENT
MENSTRUAL CYCLE IRREGULARITY/
ENDOMETRIAL PROTECTION
HYPERANDROGENIC SYMPTOMS
CONTRACEPTION / INFERTILITY
METABOLIC RISK
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0Fast.Insulinpmol/L
Free Tpmol/L
SHBGnmol/L
20
40
60
80
100
120
140
BeforeAfter
Effect of Metformin on Lean PCOS
Nestler, JCEM, 1997
Improvement in:• menstrual pattern• fertility +/- clomid
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MENSTRUAL CYCLE IRREGULARITY/ENDOMETRIAL PROTECTION
WEIGHT LOSS
WITHDRAWAL BLEEDING IF CYCLES > 60 DAYScyclic medroxyprogesterone 5 to 10 mg/day x 10-14 dayscyclic micronized progesterone 200 mg/day x 10-14 days
oral contraceptives
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HYPERANDROGENIC SYMPTOMS
Cosmetic Approaches
- electrolysis, laser
Oral Contraceptives
Anti-androgens
Insulin Sensitizing Agents
Inhibitors of Steroidogenesis
Direct inhibitors of hair growth
Glucocorticoids
GnRH Analogs
No primary treatment established
Combination treatments better than single-agent approaches
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ORAL CONTRACEPTIVES:
Androgenic PotentialLevonorgestrol Nordette, Triphasil
Ethynodiol Diacetate Demulen
Norethindrone Brevicon, Modicon
Desogestrel Desogen, Ortho-Cept
Norgestimate Ortho-Cyclen, Ortho Tri-Cyclen
Drospirenone Yasmin
An
dro
gen
ic P
ote
nti
al
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ANTIANDROGENS
spironolactone (off label use)
aldosterone antagonist, competitive inhibitor of DHT, 5-reductase inhibitor, inhibits p450 enzymes, decreases androgens
cyproterone acetate
competitive inhibitor of DHT, 5-reductase inhibitor, decreased LH
flutamide (off label use)
non-steroidal anti-androgen, competitive inhibitor of DHT, inhibits p450 enzymes
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TREATMENT OF HIRSUTISM
VaniqaVaniqa
• anhydrous eflornithine hydrochloride
• irreversibly inhibits ornithine decarboxalase activity in the skin inhibits cell division and synthetic functions decreases hair growth
• apply bid, improvement expected in 4 to 6 weeks
• can use in conjunction with other hair removal techniques
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CONTRACEPTION
OLIGO/OVULATORY STATUS
BARRIER METHODS WITH USE OF PROVERAFOR ENDOMETRIAL PROTECTION
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INFERTILITY
WEIGHT LOSS obesity - infertility and obstetrical risks
OVULATION INDUCTIONclomiphine +/- metformin
controversialaromatase inhibitors – more data needed low dose gonadotropins
PCOM – generally responds like PCOS
WEDGE RESECTION / LASER SURGERY8-34% incidence of pelvic adhesionsovulatory status - 60% ovulatory, 30% oligo/ovulatory
ASSISTED REPRODUCTIVE TECHNOLOGIEShigh # of follicles and oocytes retrievedfertilization, cleavage rate lowrisk of ovarian hyperstimulation
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Legro RS 1999; Dahlgren E 1992;Dunaif A1995;Ehrmann DA, 1995.
35 to 50% of obese women with PCOS develop either impaired glucose tolerance or type 2
diabetes by the age of 30!
METABOLIC RISK
PCOS women are at risk for IGT and DM II at all weightsdetection is markedly improved by the use of post-challenge glucose values
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HEART DISEASE• no prospective studies have documented an
increased risk
• increased prevalence of subclinical atherosclerosis
• surrogate endpoints suggest increased risk
hypertension, obesity, increased WHR, insulin resistance, lipids (~70%)
METABOLIC SYNDROME• 33.4% of adults with PCOS (Ehrmann et al, 2006)
waist circ 80%, HDL 66%, TG 32%, BP 21%, FBS 5%• 37% of adolescent girls (Coviello et al 2006)
METABOLIC RISK
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Screen for -
GLUCOSE INTOLERANCE
HYPERTENSION
DYSLIPIDEMIA
RISK FACTORS FOR HEART DISEASE
METABOLIC RISK
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Therapeutic Options
• weight lossdietsurgery
• diet modification• exercise• medication to enhance insulin sensitivity
metformin
DPP: importance of lifestyle interventions and metformin in preventing DM in IGTinsufficient data to warrant prophylactic use of metformin in all women with PCOS
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Metformin: Meta-analysis of RTC in PCOS (n=13)
Lord, Flight, Norman BMJ 2003
Ovulation– metformin alone vs placebo OR 3.88– metformin + clomid vs clomid OR 4.41 endometrial surveillance if used alone
Pregnancy*– metformin + clomid OR 4.41
* no teratogenecity in in vitro models, no teratogenecity when administered during pregnancy - limited data; may decrease miscarriage
Metabolic Syndrome– positive effect on fasting insulin, BP, LDL– no effect on weight loss
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10
15
20
Baseline After0.6
0.8
1.0
Baseline After
* *
* = P<0.05
Free T SHBGUg/dLpg/mL
0
Effect of 1000 Kcal diet for 7 months in 13 women with PCOS (< 5 % weight loss, mean 12%)
Improvement in - menstrual pattern 11/13 - 5 conceived
- hirsutism (40%) Kiddy, Clin Endo, 1992
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Therapeutic Options – Metabolic Risk
• weight lossdietsurgery
• diet modification• exercise• medication to enhance insulin sensitivity
metformin
DPP: importance of lifestyle interventions and metformin in preventing DM in IGTinsufficient data to warrant prophylactic use of metformin in all women with PCOS
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• Defined as presence of terminal (coarse) hair in male pattern
• Interaction between circulating androgens and sensitivity of the hair follicle
• Majority of women with hirsutism have underlying endocrine disorder
--75-80% have PCOS (Azziz,Carmina)--Nonclassic CYP21A2 deficiency--Androgen-secreting tumors
Hirsutism
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Theca Cell
AndrostenedioneTestosterone
EstroneEstradiolaromatase
FSH
Granulosa Cell
LHCholestrol
Androstenedione Testosterone
Insulin
IGF