Title: PCOS, dyslipidemia and CVD Nelly Pitteloud, MD Reproductive Endocrine Unit Massachusetts General Hospital COI: Repros Consultant
1PCOS, dyslipidemia and CVDNelly Pitteloud, MD
Reproductive Endocrine UnitMassachusettsGenera
l HospitalCOI Repros Consultant
2Objectives
- PCOS
- Definition
- Pathophysiology
- Metabolic features
322 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
4Examination
- Weight 178, height 55, 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?
5Hypothalamic-Pituitary-Gonadal Axis
Hypothalamus
GnRH
Pituitary
LH
E2
FSH
Ovary
6POLYCYSTIC OVARIAN SYNDROMEDefinition 1990 NIH
Workshop
-
- CHRONIC OLIGO/ANOVULATION
- HYPERANDROGENISM
-
-
in the absence of other known causes of
androgen excess (tumor, CAH, hyperprolactinemia)
7POLYCYSTIC OVARIAN SYNDROME2003 Rotterdam
Workshop
- 2 of 3
- CHRONIC OLIGO/ANOVULATION
- HYPERANDROGENISM
- POLYCYSTIC OVARIAN MORPHOLOGY
in the absence of other known causes of
androgen excess
8Polycystic 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
9The Polycystic Ovary
10- Normal ovary
- Few follicles
- Random distribution
- No increased stroma
- Polycystic ovary (PCO)
- Ovarian vol gt10 ml or
- gt12 small follicles (2-8 mm)
- Peripheral distribution
- Increased stromal vol
- (Jonard et al, 2003)
11Proportion of Anovulatory PCOS Subjects
0 20 40 60 80
100
12POLYCYSTIC 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
13Pathophysiology of PCOS
Menstrual Irregularity Hyperandrogenism
14Pathophysiology of PCOS
Hyperandrogenism
ovary 1o or 2o
morphology
adrenal
15PCOS
PCOS
Normal
Normal
Taylor et al, 1994
16Pathophysiology of PCOS
Neuroendocrine abnormalities
1o or 2o?
LH FSH
Hypothalamus Pituitary
17Gonadotropin Abnormalities in PCOS
Normalized transiently after ovulatory cycle or
progestin
18Obesity results in decreased serum LH
LH
LH
19Pathophysiology of PCOS
Hyperinsulinemia
? insulin
signaling
SHBG
20Insulin Resistance and PCOS
- Insulin resistance is a very common feature of
women with PCOS (60-75)
- Insulin resistance occurs in both obese and
non-obese women with PCOS
- Anomalies in insulin Receptor mediated
transduction
- Obesity has a synergystic effect on glucose
metabolism and IR
Palomba S, Endocrine Review, 2009
21WHO 2006 Criteria to define hyperglycemia 2-h
glucose/OGTT NGT lt140 mg/dl (7.8
mmol/liter) IGT gt140 mg/dl (7.8
mmol/liter) and lt 200 mg/dl (11.1 mmol/L)
DM or gt 200 mg (11.1 mmol/liter Fasting
glucose Normal FG lt110 mg/dl (6.1
mmol/liter) IGT 110 mg/dl (6.1 mmol/liter)
to 125 mg/dl (6.9 mmol/L) Diabetes
or gt 126 mg/dl (7.0 mmol/liter)
22Insulin and Glucose Responses in PCOS
OBESE
INSULIN
GLUCOSE
MINUTES
Dunaif A et al, 1987
23IR is present in both lean and obese PCOS
compared to their BMI and age matched counterpart
Insulin Sensitivity
PCOS Obese
PCOS Lean
Nl Obese
Nl Lean
Dunaif A et al, 1987
24PCOS 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
25Prevalence of Glucose intolerance and Diabetes
in PCOS
26Prevalence of IGT (by OGTT ) in 254 womenwith
PCOS 14-44 yr old
61,3
31.1
7.5
NGT
IGT
Type II DM
Legro et al, JCEM, 1999
27Conversion rate to IGT and type II DM
- Controlled Study
- Baseline OGTT
- 71 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
28Development 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
29PCOS 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
30Mechanisms of Predisposition to the development
Type 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 ß-Cell dysfunction
- Ek I et al JCEM 1997
- Ek I et al, Diabetes 2002
- Kelsey ES, JCEM 2007
31PCOS and Metabolic Syndrome
32Metabolic Syndrome NCEP 2001 ATP III
gt 3 of the following for women Triglycerides gt15
0 mg/dL HDL Cholesterol (F) lt 50 mg/dL Blood
Pressure gt130/85 mm/Hg Waist gt 88 cm Glucose
(fasting) gt 100 mg/dL
33Prevalence of Metabolic syndrome in PCOS
- 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)
Apridonidze T eta al JCEM 2005
34Prevalence of Metabolic syndrome in PCOS
compared to NHANES women
Age Group BMI (kg/m2) lt25 2
530 gt30 2029 yr (n
29) PCOS () 17 58 45 U.S.
females () 0.8 8.3 27 3039 yr (n
49) PCOS () 23 40 62 U.S.
females () 1 14 43
Apridonidze T eta al JCEM 2005
35PCOS and CVD
36CV Risk Factor in PCOS
- 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
-
37Distribution of CHD risk factors in premenopausal
women PCOS vs. control
PCOS (n36)
NL (n71)
Pvalue
Variable
- Age (yr) 38.5 39.0 0.40
- BMI (kg/m2) 31.4 31.2 0.26
- Waist (cm) 94.75 94.5 0.14
- Ferriman-Gallwey 16.0 4.0 0.0001
- Systolic BP (mm Hg) 116 116 0.73
- Diastolic BP (mm Hg) 74.8 71.5 0.03
- Smoking 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 0.04
- TG (mg/dl) 125 118
0.33 - SHBG (nmol/liter 31.7 38.5 0.04
- Total T (ng/dl) 47.5 34 lt0.0001
- Free T (ng/dl) 0.19 0.12 lt0.0001
-
Christian RC, JCEM, 2003
38PCOS 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, 199271599
- Death certificates from women with PCOS in the UK
showed no - Increase in MI above expected number
- J. Clin. Epidemiol 1998 51581
39PCOS 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 872013
Prospective controlled studies on CVD morbidity
and mortality in PCOS are LACKING
40Evaluation of metabolic anomalies In PCOS patients
41Evaluation 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
42Traditional and novel therapy for PCOS patients
43Traditional 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
44PCOS 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)
45PCOS 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
-
-
46PCOS Management
- Infertility
- Weight loss!
- Ovulation induction (metformin vs clomiphene)
-
-
47PCOS Management
- Prevention of IGT and Type II diabetes
-
-
48Prevention 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
49Prevention of DMII in non-PCOS Population (DPP)
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
DPP Group, NEJM, 2002
50Metformin and Prevention of IGT in PCOS
- 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
NGT - ? 11-fold decrease in the annual conversion rate
from NGT to IGT - with 55 of IGT patients reverting to NGT
Sharma et al End. Pract, 2007
51Metformin and Prevention of IGT in PCOS
Meta-analysis (Salpeter et al, Am J Med.
2008) Goals To assess the effect of metformin
on metabolic risk in patients at high 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 -3 Fasting 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 plt
0.01 Absolute risk of DM 6 decrease 95 CI 4
to 8 No data on subgroups.
Sharma et al End. Pract, 2007
52PCOS Management
Metabolic Abnormalities
- INTENSIVE LIFE STYLE CHANGES
- Diet low in CH
- Exercise
- ? Surgery for morbid obesity
- Medication to enhance insulin sensitivity
- Metformin
- Thiazolidinedione (rosiglitazone,
pioglitazone)
53Insulin 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
54Summary
- PCOS is a GENERAL HEALTH ISSUE
- Evaluation should include screen for
- IGT
- Dyslipidemia
- HTA
- CV risk factors
- Novel Goals of Therapy
- Decrease risk for type II DM
- Decrease risk for early CV disease
- Life style modification
- Insuline sensitizing agents
55Return 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
56(No Transcript)
57(No Transcript)
58Insulin Signaling Pathways in PCOS Differential
Effects
IRS1/2 mediation of PI3 kinase ? glucose
transport carbohydrate metabolism MAP kinase ?
mitogenesis
59POLYCYSTIC OVARIAN SYNDROME2000 NIH Workshop
60Implications of Rotterdam Criteria
-
- Ovulatory vs anovulatory bleeding
- PCOS vs hypothalamic amenorrhea
- Estrogen status
- LH/FSH ratio
- Is insulin resistance present in all patients?
- Risk for diabetes
- OGTT
- What are the cardiovascular implications?
- Lipids, hypertension
61POLYCYSTIC OVARIAN SYNDROME2003 Rotterdam
Workshop
Less obese Less hyperandrogenic No increase in LH
No IR
Less obese Increased LH Mild IR (1 of 3
studies) No hyperandrogenism
62WHAT 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 CYP11a (P450scc) (Waterworth
et al, 1997) HSD17B5 SNP-71G (Qin et al 2006) - D19S884 (chromosome 19p13.2) (Urbanek et al 2005)
63What is the Role of Genetics in PCOS?
- association studies
- marker D19S884 (chromosome 19p13.2) near the
insulin receptor - Tucci S, JCEM 2001 p0.006, corrected p0.042
- 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
64POLYCYSTIC OVARIAN SYNDROMEPRINCIPLES OF
MANAGEMENT
-
- MENSTRUAL CYCLE IRREGULARITY/
- ENDOMETRIAL PROTECTION
- HYPERANDROGENIC SYMPTOMS
- CONTRACEPTION / INFERTILITY
- METABOLIC RISK
65Effect of Metformin on Lean PCOS
- Improvement in
- menstrual pattern
- fertility /- clomid
Nestler, JCEM, 1997
66 MENSTRUAL CYCLE IRREGULARITY/ENDOMETRIAL
PROTECTION
WEIGHT LOSS WITHDRAWAL BLEEDING IF CYCLES gt 60
DAYS cyclic medroxyprogesterone 5 to 10 mg/day x
10-14 days cyclic micronized progesterone 200
mg/day x 10-14 days oral contraceptives
67HYPERANDROGENIC 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
68ORAL CONTRACEPTIVES Androgenic Potential
- Levonorgestrol Nordette, Triphasil
- Ethynodiol Diacetate Demulen
- Norethindrone Brevicon, Modicon
- Desogestrel Desogen, Ortho-Cept
- Norgestimate Ortho-Cyclen, Ortho Tri-Cyclen
- Drospirenone Yasmin
Androgenic Potential
69ANTIANDROGENS
- spironolactone (off label use)
- aldosterone antagonist, competitive inhibitor
of DHT, 5-a reductase inhibitor, inhibits p450
enzymes, decreases androgens - cyproterone acetate
- competitive inhibitor of DHT, 5-a reductase
inhibitor, decreased LH - flutamide (off label use)
- non-steroidal anti-androgen, competitive
inhibitor of DHT, inhibits p450 enzymes
70TREATMENT OF HIRSUTISM
- 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
71 CONTRACEPTION
OLIGO/OVULATORY STATUS BARRIER METHODS WITH USE
OF PROVERA FOR ENDOMETRIAL PROTECTION
72 INFERTILITY
WEIGHT LOSS obesity - infertility and
obstetrical risks OVULATION INDUCTION clomiphine
/- metformin controversial aromatase
inhibitors more data needed low dose
gonadotropins PCOM generally responds like
PCOS WEDGE RESECTION / LASER SURGERY 8-34
incidence of pelvic adhesions ovulatory status -
60 ovulatory, 30 oligo/ovulatory ASSISTED
REPRODUCTIVE TECHNOLOGIES high of follicles
and oocytes retrieved fertilization, cleavage
rate low risk of ovarian hyperstimulation
73METABOLIC RISK
35 to 50 of obese women with PCOS develop either
impaired glucose tolerance or type 2 diabetes by
the age of 30!
Legro RS 1999 Dahlgren E 1992 Dunaif
A1995Ehrmann DA, 1995.
PCOS women are at risk for IGT and DM II at all
weightsdetection is markedly improved by the use
of post-challenge glucose values
74METABOLIC RISK
- 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)
75METABOLIC RISK
Screen for - GLUCOSE INTOLERANCE HYPERTENSION
DYSLIPIDEMIA RISK FACTORS FOR HEART DISEASE
76Therapeutic Options
- weight loss
- diet
- surgery
- diet modification
- exercise
- medication to enhance insulin sensitivity
- metformin
-
DPP importance of lifestyle interventions and
metformin in preventing DM in IGT insufficient
data to warrant prophylactic use of metformin in
all women with PCOS
77Metformin Meta-analysis of RTC in PCOS
(n13)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
78Effect of 1000 Kcal diet for 7 months in 13
women with PCOS (lt 5 weight loss, mean 12)
Improvement in - menstrual pattern 11/13
- 5 conceived - hirsutism
(40) Kiddy, Clin Endo,
1992
79Therapeutic Options Metabolic Risk
- weight loss
- diet
- surgery
- diet modification
- exercise
- medication to enhance insulin sensitivity
- metformin
-
DPP importance of lifestyle interventions and
metformin in preventing DM in IGT insufficient
data to warrant prophylactic use of metformin in
all women with PCOS
80 Hirsutism
- 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
81Theca Cell
Granulosa Cell