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PCOS PG course

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					PCOS, dyslipidemia and CVD

      Nelly Pitteloud, MD

   Reproductive Endocrine Unit
         Massachusetts
        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

                         GnRH

Pituitary

             LH                 E2
            FSH


   Ovary
POLYCYSTIC OVARIAN SYNDROME
  Definition 1990 NIH Workshop

     CHRONIC OLIGO/ANOVULATION

     HYPERANDROGENISM


 in the absence of other known causes of androgen
                       excess
          (tumor, CAH, hyperprolactinemia)
POLYCYSTIC OVARIAN SYNDROME
   2003 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
Normal ovary
 Few follicles

 Random distribution

 No increased stroma




Polycystic ovary (PCO)

•   Ovarian vol >10 ml or
•    >12 small follicles (2-8 mm)
•   Peripheral distribution
•   Increased stromal vol
                (Jonard et al, 2003)
                                               %69       MOCP
                                               %58       T
                                               %48       T eerF
                                               %38       HL
                                               %67       HSF/HL
                                               %46       erocS GF
                                               %73       h42PHO71
                                               %32       A MO H
                                                100%
001         57             05          52            0
       80           60          40     20       0
                 stcejbuS SOCP fo noitroporP
  Proportion of Anovulatory PCOS Subjects
                   egnaR lamroN eht evobA
    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
            Pathophysiology of PCOS



             Neuro-
            endocrine
                                  Menstrual
                                 Irregularity
                                      +
                               Hyperandrogenism
Androgens
                  Insulin
             Pathophysiology of PCOS

Hyperandrogenism


                     ovary
                     1o or 2o


                                morphology

                   adrenal
                                   5
      Testosterone (ng/mL)              17Hydroxyprogesterone (ng/mL)
300
                                   4

                                   3
200

                                   2

100
                                   1

                                   0
  0

                                  600
  8   Free Testosterone (ng/mL)         DHEAS (g/dL)
                                  500

  6                               400

  4                               300

                                  200
  2
                                  100
  0
                                    0

          PCOS           Normal           PCOS           Normal
                                                                Taylor et al, 1994
           Pathophysiology of PCOS

Neuroendocrine
 abnormalities

                        1o or 2o?


                                     LH
                                    FSH
                 Hypothalamus
                   Pituitary
      Gonadotropin Abnormalities in PCOS

100               LH IU/L

 50    PCOS
                                     Normalized
 25                                  transiently after
                                     ovulatory cycle
                                     or progestin
                  FSH IU/L
20

10


                   Yen et al, 1970
Obesity results in decreased serum LH


      LH
                       LH
           Pathophysiology of PCOS

Hyperinsulinemia


                                insulin



                   signaling

                                 SHBG
       Insulin 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
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 PCOS

                                OBESE                                                        LEAN
                                    *         *         *
            200            *                                         200            *         *         *
INSULIN



                                                              PCOS                                                *
            150                                                      150
                                                                                                                        PCOS
            100                                                      100
                                                              NL
            50                                                       50
                                                                                                                        NL
             0                                                        0
                  0   20       40   60   80       100   120                0   20       40    60   80       100   120


            200                                                      200
  GLUCOSE




                           *        *         *          *
            150                                               PCOS 150
                                                                                                                        PCOS
            100                                                      100
                                                              NL                                                        NL
            50                                                       50

             0                                                        0
                  0   20       40   60   80       100   120                0   20       40    60   80       100   120

                                                    MINUTES                                                  Dunaif A et al, 1987
IR is present in both lean and obese PCOS compared to
         their BMI and age matched counterpart
 Insulin Sensitivity




                       Nl     Nl      PCOS   PCOS
                       Lean   Obese   Lean   Obese
                                                     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 women
         with PCOS 14-44 yr old



    61,3%




                31.1%

                              7.5%



     NGT          IGT        Type II DM
                            Legro et al, JCEM, 1999
       Conversion 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
      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
              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 β-Cell dysfunction

                             Ek I et al JCEM 1997
                             Ek I et al, Diabetes 2002
                             Kelsey ES, JCEM 2007
PCOS and Metabolic Syndrome
Metabolic Syndrome NCEP 2001 ATP III


> 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
Prevalence 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
   Apridonidze T eta al JCEM 2005
                                    girls
                                              (Coviello et al 2006)
 Prevalence of Metabolic syndrome in PCOS
       compared to NHANES women
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
                              Apridonidze T eta al JCEM 2005

  U.S. females (%)   1           14            43
PCOS and CVD
         CV 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
Distribution of CHD risk factors in premenopausal
             women PCOS vs. control
Variable                   PCOS (n=36)   NL (n=71)      Pvalue
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             <0.0001
Free T (ng/dl)                 0.19          0.12           <0.0001
                                              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 anomalies
        In 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 for
         PCOS 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)


                                           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
Metformin 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
Metformin 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 p< 0.01
                 Absolute risk of DM   6% decrease 95% CI 4 to 8
                 No data on subgroups.



                                          Sharma et al End. Pract, 2007
           PCOS: Management
Metabolic Abnormalities

      1.       INTENSIVE LIFE STYLE CHANGES

           •    Diet low in CH
           •    Exercise
           •    ? Surgery for morbid obesity

      1.       Medication to enhance insulin sensitivity

           •       Metformin
           •       Thiazolidinedione (rosiglitazone, pioglitazone)
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 :

        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
                             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
Insulin Signaling Pathways in PCOS – Differential Effects




   IRS1/2 mediation of PI3 kinase
          glucose transport & carbohydrate metabolism
   MAP kinase  mitogenesis
POLYCYSTIC OVARIAN SYNDROME
      2000 NIH Workshop

        PCO                      Idiopathic Hirsutism
     Morphology
                                     Hyperandrogenism

                      PCOS
Hypothalamic          PCOS
Amenorrhea




                  Irregular cycles
  Implications 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
      POLYCYSTIC OVARIAN SYNDROME
         2003 Rotterdam Workshop

                PCO
                                          Idiopathic Hirsutism
             Morphology

                                              Less obese
                                              Less hyperandrogenic
                               PCOS
                               PCOS
      Hypothalamic
                               PCOS           No increase in LH
                                              No IR
      Amenorrhea
Less obese
Increased LH
Mild IR (1 of 3 studies)
No hyperandrogenism        Irregular cycles
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 – CYP11a (P450scc) (Waterworth et
               al, 1997); HSD17B5 SNP-71G (Qin et al 2006)

             • ~D19S884 (chromosome 19p13.2) (Urbanek et al 2005)
      What is the Role of Genetics in PCOS?

• 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
    POLYCYSTIC OVARIAN SYNDROME:
      PRINCIPLES OF MANAGEMENT



   MENSTRUAL CYCLE IRREGULARITY/
     ENDOMETRIAL PROTECTION

   HYPERANDROGENIC SYMPTOMS

   CONTRACEPTION / INFERTILITY

   METABOLIC RISK
       Effect of Metformin on Lean PCOS


140
120              Before                     Improvement in:
100              After                      • menstrual pattern
                                            • fertility +/- clomid
 80
 60
 40
 20
  0
      Fast.     Free T        SHBG
      Insulin   pmol/L        nmol/L
      pmol/L
                          Nestler, JCEM, 1997
      MENSTRUAL CYCLE IRREGULARITY/
        ENDOMETRIAL PROTECTION


WEIGHT LOSS

WITHDRAWAL BLEEDING IF CYCLES > 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
       HYPERANDROGENIC SYMPTOMS

Cosmetic Approaches
     - electrolysis, laser         No primary treatment
Oral Contraceptives                established
Anti-androgens
                                   Combination
Insulin Sensitizing Agents         treatments better than
Inhibitors of Steroidogenesis      single-agent approaches
Direct inhibitors of hair growth


Glucocorticoids
GnRH Analogs
                              ORAL CONTRACEPTIVES:
                                Androgenic Potential
                       Levonorgestrol         Nordette, Triphasil

                       Ethynodiol Diacetate
Androgenic Potential




                                              Demulen


                       Norethindrone          Brevicon, Modicon


                       Desogestrel            Desogen, Ortho-Cept

                       Norgestimate           Ortho-Cyclen, Ortho Tri-Cyclen

                       Drospirenone           Yasmin
               ANTIANDROGENS


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
          TREATMENT OF HIRSUTISM

Vaniqa

  •   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 PROVERA
FOR ENDOMETRIAL PROTECTION
                 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
                  METABOLIC 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 A1995;Ehrmann DA, 1995.




PCOS women are at risk for IGT and DM II at all weights
  detection is markedly improved by the use of post-
  challenge glucose values
                    METABOLIC 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)
          METABOLIC RISK



Screen for -
   GLUCOSE INTOLERANCE
   HYPERTENSION
   DYSLIPIDEMIA
   RISK FACTORS FOR HEART DISEASE
           Therapeutic 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
   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
  Effect of 1000 Kcal diet for 7 months in 13 women
      with PCOS (< 5 % weight loss, mean 12%)



            Free T                            SHBG
pg/mL                          Ug/dL
   20                             1.0                 *
   15
                      *
                                  0.8
   10
    0                             0.6
         Baseline    After              Baseline      After
                                         * = P<0.05
Improvement in - menstrual pattern 11/13
               - 5 conceived
                - hirsutism (40%)
                                          Kiddy, Clin Endo, 1992
   Therapeutic 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
     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
                 Theca Cell
                                                    LH
              Cholestrol




                                                     b
                      Androstenedione
                                                         a
                              Testosterone
                                                         Insulin
                                                           IGF

          Androstenedione               Estrone
            Testosterone aromatase      Estradiol
                                                         FSH

Granulosa Cell

				
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