PCOS is an intergenerational problem having its origin in adolesence with lot of metabolic dysfunction.

1. PCOS
Dr.Veerendrakumar C.M
MD.,DNB
Professor
Dept of OBG,VIMS,Bellary
veerendrakumarcm@gmail.com

2. 
1st described by Irving Stein and Michael Leventhal as a triad of
amenorrhea, obesity and hirsutism (1935)

The most common endocrine disorder in women of reproductive
age ~ 2%-8% of women
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
2

3.  Intergenerational
problem
POLYCYSTIC OVARIAN SYNDROME
POLYCYSTIC OVARIAN SYNDROME


Normal ovaries
Polycystic ovaries
 volume < 8 cm3
 mildly enlarged
 scattered follicles  generally > 8 cm3
 peripheral distribution
of follicles

increased stroma
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
3

4.  EVOLVED….
From gynecological curiosity to
a multi system endocrinopathy
Hamburg 1996

Most common but most poorly understood condition with
complex pathophysiology with considerable scientific debate.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
4

5. 

Oligo-ovulation or anovulation
Clinical or laboratory evidence of hyperandrogenism
and

Polycystic ovaries as defined by ultrasonography
In addition, the definition requires the exclusion of other
medical conditions that cause irregular menses and
androgen excess
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
5

6.  Ultrasound
criteria:
--- increased ovarian area/volume
--- 10-15 microcyst(<10 mm diameter)
organized in a peripheral rosary pattern.
--- increased echogenicity of ovarian stroma.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
6

7.  Increased
ovarian stroma is the most valuable
diagnostic factor for PCOS
 Absence
of it does not exclude the diagnosis.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
7

8.  Transvaginal
US Scan – gold standard.
 Follicles of 2 -9 mm, at least 12 in number.
 Bilateral or unilateral
 Ovarian volume >10 cm³
prolate ellipsoid formula for volume
L x B x T x 0.513
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
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9.  Use
high resolution equipment
 Do on day 3 -5
 If dominant follicle or corpus luteum found, repeat in
next cycle.
 Whenever possible, use TVS
 Follicle number estimated in longitudinal and cross
sectional views.
 Remember, all women with polycystic appearance need
not have PCOS.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
9

10. 
should remember that 20 to 30 % of
women in general population have
polycystic ( multi follicular) ovaries
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
10

11.  17-23%
of population can have polycystic
ovaries
 76%-80%
of these women had clinical
manifestations
Polson 1988,Botsis 1995
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
11

12. Concept of a spectrum
PCO
PCOS
increasing BMI
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
12

13. PCO




MFO
Small follicles
Dense stroma
Increased ovarian volume
No dominant follicle




Larger follicles
Lesser stroma density
Normal volume
Dominant follicle seen
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
13

14. 




Delayed normal puberty
Central precocious puberty
Hypothalamic anovulation
Hyperprolactinemia
Early normal follicular dominant phase
Carefully consider clinical/biological components of
consensual definition.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
14

15.  Early
follicular growth is excessive
 Recruitment
of dominant follicle do not occur
Excessive AMH is involved in follicular arrest.
Jonard 2004
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
15

16.  3D
USG – not superior to 2D USG
 MRI-main role is to exclude virilizing ovarian
tumor.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
16

17. 
increased LH pulse frequency and amplitude.
secondary to increased pulse frequency of
gonadotropin-releasing hormone, which
selectively increases LH release,
 resultant
elevation of the absolute level of
circulating LH
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
17

18.  Androgen
production by ovarian thecal
cells is LH-dependent, and the elevated
LH likely contributes to the excess
androgens.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
18

19.  FSH
levels chronically remain in the
midfollicular range,which is an insufficient
level
 Follicle
growth and development is
arrested and anovulation results
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
19

20.  Adrenal
androgen production is also
increased in many PCOS patients
 There
may be a common defect in ovarian
and adrenal biosynthesis
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
20

21.  Possible
theories
(1) insulin resistance
(2) Obesity
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
21

22.  Many
PCOS women, both obese and nonobese,
are insulin resistant and
insulin resistance is believed to play a
prominent role in the pathophysiology of the
syndrome
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
22

23. Hyperinsulinemia
1)Increases P450c activity, which converts P to 17-OH
progesterone then to androstenedione and testosterone
2) Insulin decreases hepatic synthesis of SHBG and IGF-BP1
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
23

24.  Post
binding defect in signalling
 Insulin receptor alteration
 Pancreatic beta cell dysfunction
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
24

25. Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
25

26. 
Familial clustering of PCOS common
Yildiz BO et al, Journal of Clinical Endocrinology & Metabolism, 2003.
“PCOS is a genetically determined ovarian disorder…
Franks S et al, International Journal of Andrology, 2006.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
26

27.  Believed
to be
? autosomal dominant,
? ?X-linked inheritance
 Dysregulation
of the P450c17 gene controlling
steroidogenesis,CYP11a is suspected
 Insulin receptor gene defect
 Follistatin gene defect
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
27

28.  Adiponectin produced in adipose tissue and has
anti atherogenic effect.
- Lower levels in PCOS
 Resistin- antagonizes insulin action
-Higher levels in PCOS
 Proportion
of adiponectin and resistin influence
cardio-metabolic risk in PCOS
Seow 2004 Hum Reprod
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
28

29.  Ghrelin
controls food intake and energy
balance
 Lower
levels found in PCOS
Gambineri 2002 Int j obes
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
29

30. emerging as a common cause of
menstrual disturbances in the adolescent population
Guttmann-Bauman I, Journal of Pediatric Endocrinology & Metabolism, 2005.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
30

31.  >75% of women with anovulation infertility
Franks et al, International Journal of Andrology, 2006.

Follicular arrest
• Impaired selection of dominant follicle
•Risk of multiple pregnancy with treatment
Jonard S, Dewailly D, Human Reproduction Update, 2004.
Prof.Veerendrakumar CM, VIMS,Bellary.
31

32. 40 to 50 % of PCOS women are obese.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
32

33. 
Spontaneous Abortions
• Increased in high BMI/PCOS patients

Wang JX et al, Human Reproduction, 2001.
Impaired Glucose Tolerance
Turhan NO et al, International Journal of Gynecology & Obstetrics, 2003.

Gestational Diabetes

Hypertension

Small for Gestational Age
Bjercke S et al, Gynecologic and Obstetric Investigation, 2002.
Weerakiet S et al, Gynecological Endocrinology, 2004.
Sir-Petermann T et al, Human Reproduction, 2005.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
33

34. •
Racial difference exists
•
More in South Asians
•
Less in Eastern Asians
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
34

35. PCOS
PCOS is also associated with a characteristic
metabolic syndrome that includes:
insulin resistance
dyslipidemia
hypertension
These features are linked with increased risks of
type 2 diabetes and possibility of premature
cardiovascular diseaseVIMS,Bellary. November 24, 2013
Prof.Veerendrakumar CM,
35

36.  Endometrial
Cancer
• Long-term follow-up of 786 PCOS women found an
increased risk of endometrial cancer
Wild S et al, Human Fertility, 2000.
Pillay OC et al, Human Reproduction, 2006.
 Cardiovascular
Disease
• PCOS is characterized by endothelial dysfunction and
resistance to vasodilating action of insulin
Dahlgren E et al, Acta Obstetricia et Gynecologica Scandinavica, 1992.
Paradisi G et al, Circulation, 2001.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
36

37.  Sleep
Apnea
• Increased Sleep Disordered Breathing (SDB) and daytime sleepiness in
PCOS vs. controls
Vgontzas AN et al, Sleep Medicine Reviews, 2005.
 Depression
• Higher prevalence in PCOS patients, associated with higher body mass
index (BMI, P=0.05) and greater insulin resistance (P=0.02)
Rasgon NL et al, Journal of Affective Disorders, 2003.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
37

38. 
PCOS women with the metabolic syndrome
had more hyperandrogenemia than PCOS
women without the metabolic syndrome
Apridonidze et al
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
38

39. May be a severe form of PCOS
 HA - Hyperandrogenism
 IR - Insulin Resistance
 AN - Acanthosis Nigricans
May have clitoromegaly, temporal
balding, deepening of voice.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
39

40. Hyperprolactinemia
1.
•
•
Prominent menstrual dysfunction
Little hyperandrogenism
2. Congenital Adrenal Hyperplasia
•
•
morning serum 17-hydroxyprogesterone concentration
greater than 200 ng/dL in the early follicular phase
strongly suggests the diagnosis
confirmed by a high dose (250 mcg) ACTH stimulation
test: post-ACTH serum 17-hydroxyprogesterone value
less than 1000 ng/dL
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
40

41. 3. Ovarian and adrenal tumors
• serum testosterone concentrations are always higher
than 150 ng/dL
• adrenal tumors: serum DHEA-S concentrations higher
than 800 mcg/dL
• LOW serum LH concentrations
4. Cushing’s syndrome
5. Drugs: danazol; OCPs with high
androgenicity
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
41

42.  IRREGULAR
MENSES
10 YRS
 SCALP HAIR LOSS
6 YRS
 EXCESSIVE HAIR GROWTH 6 YRS
 AMENORRHEA
1 YR
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
42

43.  Case
scenario to differentiate severe form of
PCOS from that of androgen secreting ovarian
tumor…
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
43

44. 



FRONTAL BALDNESS +, HIRSUTISM +
SYSTEMIC EXAMINATION – NORMAL
USG – (11/12/2001) – POLYCYSTIC
OVARIES
DOPPLER STUDY OF OVARIAN VESSELS
NORMAL
SUPRARENAL AREA NORMAL
Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
44

45. 






TESTOSTERONE
358 ng/dL (20-80)
17-OH PROGESTERONE 0.66 ng/ml (0.1-1.36)
DHEA-SULPHATE
224mcg/dL (35-430)
THYROID FUNCTION TESTS-NORMAL
FSH- 3.8miu/ml
LH - 3.6miu/ml
PRL - 24ng/ml
Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
45

46. FINASTERIDE 5mg OD
 FEMILON X 21DAYS
 MINOXIDIL LOTION FOR TOPICAL
APPLICATION
PATIENT GOT HER MENSES BACK &
SYMPTOMATICALLY IMPROVED

Prof.Veerendrakumar
CM, VIMS,Bellary.
November 24, 2013
46

47. 



LOW DOSE OC PILL STOPPED
OI WITH CLOMIPHENE TRIED WITHOUT ANY
SUCCESS
USG REPEATED ON 12/5/2003 – PCOD WITH
A WELL DEFINED ROUND HYPER ECHOIC MASS
OF 3.5 X 3.4 X 3 cm IN RIGHT OVARY
TESTOSTERONE 570 ng/dL
Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
47

48. 



UTERUS & TUBES NORMAL
POD CLEAR
RT OVARY ENLARGED, EXT SURFACE NORMAL
LT OVARY NORMAL
Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
48

49. 


RT SIDED SALPINGO OVARIOTOMY DONE
SPECIMEN SUBJECTED FOR HPE
REPORT WAS
STEROID CELL TUMOR
Prof.Veerendrakumar
CM, VIMS,Bellary.
November 24, 2013
49

50. Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
50

51. PATIENT UNDERWENT LSCS ON MAY 2004 &DELIVERED
MONOZYGOTIC TWINS.
Prof.Veerendrakumar CM,
VIMS,Bellary.
November 24, 2013
51

52.  Fasting
glucose: elevated
 2 hour OGTT: elevated
 Fasting insulin: elevated
 Free testosterone: elevated
 DHEA-S: normal
 17-hydroxyprogesterone: normal
 Pelvic US
 Lipids
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
52

53.  Serum
HCG
 Serum prolactin
 Thyroid panel
 FSH: r/o ovarian failure
 Serum luteinizing hormone (LH)—
elevated
 Serum estradiol—normal
 Serum estrone—elevated
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
53

54. Consume more foods
 rich in complex
carbohydrates
 monounsaturated fat
 fiber
 with a decreased ratio
of omega-6 to omega-3
fatty acids
Reduce
 Total caloric intake
 Saturated fat
 Cholesterol
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
54

55. 
Frequency of obesity in women with anovulation and PCO: 30%75%
Ehrmann DA, New England Journal of Medicine, 2005.

Six month weight-loss program for overweight anovulatory women
•
Lost an average of 6.3 kg (13.9 lbs)
•
Decreased fasting insulin and testosterone levels
•
92% resumed ovulation (12/13)
•
85% became pregnant (11/13)
Clark AM et al, Human Reproduction, 1995.
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
55

56. Focus on lowering dietary fat as a means for promoting
negative energy balance has led to an underestimation of
the potential role of dietary composition in promoting
reductions in energy intake and weight loss

Roberts SB, et al:J Am Coll Nutr 21:140S, 2002

Diets based on low-GI foods produced greater weight
loss than did equivalent diets based on high-GI foods.

Low GI diet more effect than low fat in obese children
Spieth LE, et al: Arch Ped Adol, 154:947, 2000
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
56

57.  Hypocaloric


diets reduce insulin resistance
10-20% protein, ~50% carbohydrates
< 30% total fat, < 10% saturated fat
ADA nutritional recommendations: Diabetes Care 20S:14, 1997
Further improvement with 5-10kg weight
reduction
 Two fold increase glucose disposal rate with 16%
decrease weight

Niskanen L, et al: J Obes Relat Metab Disord 20:154, 1996
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
57

58. 
Substitute nonhydrogenated unsaturated fats for saturated
and trans-fats

increase omega-3 fatty acids from fish, fish oil supplements,
or plant sources


increase fruits, vegetables, nuts, and whole grains
avoid refined grain products.

Simply lowering the percentage of energy from total fat in
the diet is unlikely to improve lipid profile or reduce CHD
incidence.
Willet WC, et al: JAMA 288:2569, 2002
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
58

59.  Peripheral
muscle cells metabolize 80% of
glucose
 Aerobic exercise
3-4x/wk 20-30 min/session
Burns 100-200 kcal
 40% improvement in insulin sensitivity within
48 hrs.
J Appl Physiol 71:2502, 1991
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
59

60.  Metformin
 Pioglitazone,rosiglitazone
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
60

61.  Decreases
hepatic glucose production
 Improves insulin sensitivity
 Antilipolytic effect
 Increases SHBG
 Reduces leptin production
 Endometrial action-IGFBP-1 increased
 LH mediated action on theca cells reduced
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
61

62.  Metformin
• 500 mg daily
• Increase by 500 mg each week until:
 Normal menses
 Reached max dose
 Side-effects
 Clomid
• 50 mg days 3-7 for 3 months
• 100 mg days 3-7 for 3 months
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
62

63.  Metformin
500 mg b.i.d. 6 weeks, t.i.d. thereafter
 Clomiphene added if anovulatory at 12 weeks
 31/48
(64.5%) resumed spontaneous menses
 16/31 (52%) conceived within the first six months
 3/16 (19%) had spontaneous abortions
Heard MJ, et al: Abstract 140, Society of Gynecologic
Investigation, 2001
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
63

64.  26
women received – Placebo- 1 ovulated
 35 women received – Metformin- 14 ovulated
 1500 mg/day
Nestler et al. N Engl J Med 1998
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
64

65.  Target—1500-2500
mg per day
 Clinically
significant responses not regularly
observed at doses less than 1000 mg per day
 Extended
release formulations—fewer sideeffects. Entire dose should be given with
dinner
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
65

66.  Diarrhea,
nausea, vomiting, flatulence,
indigestion, abdominal discomfort
• Caused by lactic acid in the bowel wall
• Minimized by slow increase in dosage
 Lactic
acidosis—rare
• Avoid in CHF, renal insufficiency, sepsis
• Discontinue for procedures using contrast (withhold
X 48 hours)
• Temporarily suspend for all surgical procedures that
involve fluid restriction
• Cimetidine causes increased metformin levels
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
66

67.  Clomiphene
 Aromatase
citrate
inhibitors e.g. Letrazol
 Gonadotrophins
 Risk
of hyperstimulation is high
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
67

68.  Wedge
resection – obsolete
 Laparoscopic
ovarian drilling
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
68

69. 4
to 5 holes on anterior surface of ovaries.
 40
watts current, cutting mode
 Depth
of 4mm
 Current
passed for 4 seconds
 Surface
–intermittent irrigation & suction with
saline
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
69

70.  Weight
loss—reduction in serum testosterone
concentration and resumption of ovulation
 Clomid: 80% will ovulate, 50% will conceive
 Metformin: when added to clomid, improves
ovulatory rates
 FSH injections
 Laparoscopic surgery: wedge
resections, laparoscopic ovarian laser electrocautery
 IVF
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
70

71. ADVANTAGES






DISADVANTAGES
High success rate
Prolonged response
Multiple births
OHSS
Dose, duration ovulation
Induction







Adhesion formation
Interceed not beneficial
Requires surgery
1/3 require ovulation
medications
POF risk
Less successful in smokers
25% vs 95%
Prof.Veerendrakumar CM, VIMS,Bellary.
November 24, 2013
71

72. Learning by sharing…..