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PCOS, dyslipidemia and CVD
Nelly Pitteloud, MD
Reproductive Endocrine UnitMassachusetts
General Hospital
COI: Repros Consultant
Objectives
PCOS
• Definition
• Pathophysiology
• Metabolic features
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
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?
Hypothalamic-Pituitary-Gonadal Axis
Hypothalamus
LH
GnRH
FSH
Pituitary
Ovary
E2
POLYCYSTIC OVARIAN SYNDROMEDefinition 1990 NIH Workshop
CHRONIC OLIGO/ANOVULATION
HYPERANDROGENISM in the absence of other known causes of androgen
excess(tumor, CAH, hyperprolactinemia)
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
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
The Polycystic Ovary
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
Proportion of Anovulatory PCOS Subjects
0 20 40 60 80 100%
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
InsulinAndrogens
Neuro-endocrine Menstrual
Irregularity+
Hyperandrogenism
Pathophysiology of PCOS
Hyperandrogenism
Pathophysiology of PCOS
adrenal
morphology
ovary1o or 2o
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
Neuroendocrineabnormalities
Pathophysiology of PCOS
HypothalamusPituitary
1o or 2o?
LHFSH
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
LH
LH
Obesity results in decreased serum LH
Hyperinsulinemia
Pathophysiology of PCOS
signaling
insulin
SHBG
• 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
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)
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
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
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
Prevalence of Glucose intolerance and Diabetes in PCOS
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
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
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
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
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
PCOS and Metabolic Syndrome
> 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
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)
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
PCOS and CVD
• 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
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
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
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
Evaluation of metabolic anomaliesIn PCOS patients
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
Traditional and novel therapy forPCOS patients
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
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)
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
PCOS: Management
Infertility
•Weight loss!
•Ovulation induction (metformin vs clomiphene)
PCOS: Management
Prevention of IGT and Type II diabetes
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
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
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
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.
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
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
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
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
IRS1/2 mediation of PI3 kinase glucose transport & carbohydrate metabolism
MAP kinase mitogenesis
Insulin Signaling Pathways in PCOS – Differential Effects
POLYCYSTIC OVARIAN SYNDROME2000 NIH Workshop
Irregular cycles
Hyperandrogenism
PCOSPCOS
PCOMorphology
Idiopathic Hirsutism
HypothalamicAmenorrhea
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
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
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)
• 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?
POLYCYSTIC OVARIAN SYNDROME:PRINCIPLES OF MANAGEMENT
MENSTRUAL CYCLE IRREGULARITY/
ENDOMETRIAL PROTECTION
HYPERANDROGENIC SYMPTOMS
CONTRACEPTION / INFERTILITY
METABOLIC RISK
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
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
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
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
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
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
CONTRACEPTION
OLIGO/OVULATORY STATUS
BARRIER METHODS WITH USE OF PROVERAFOR ENDOMETRIAL PROTECTION
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
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
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
Screen for -
GLUCOSE INTOLERANCE
HYPERTENSION
DYSLIPIDEMIA
RISK FACTORS FOR HEART DISEASE
METABOLIC RISK
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
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
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
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
• 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
Theca Cell
AndrostenedioneTestosterone
EstroneEstradiolaromatase
FSH
Granulosa Cell
LHCholestrol
Androstenedione Testosterone
Insulin
IGF