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