Polycystic ovary syndrome

Dr. Gurpreet Kaur
1

Introduction
    

Also known as Stein-Leventhal syndrome Incidence - 1% Age group – 15-25 years Heterogeneous collection of signs and symptoms Ranging from women with polycystic ovary & no overt abnormality at one end, to those with severe clinical and biochemical disorders at the other end
Polycystic ovary is sign not a disease
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Definition
Rotterdam criteria(2003) • Oligo and / or anovulation • Clinical and / or biochemical evidence of hyperandrogenism, excluding other etiologies • Polycystic ovaries in USG Presence of any 2 of the above is PCOS

3

Oligovulation and anovulation
Anovulatory cycles Lack of cyclical progesterone Irregular uterine bleeding
Raised estradiol levels Diminished FSH Raised LH

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Hyperandrogenism
Clinical and biochemical parameters Clinical Biochemical Hirsutism ↑ Testosterone Acne ↑ Free androgen index Alopecia ↑ DHEAS Clitoromegaly ↑ Androstenedione 17 alpha hydroxy progesterone
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Ultrasonography
 In

20 – 25% women without PCOS – USG features of polycystic ovary are seen

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Pathophysiology Clinical features…
Cause

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Pathophysiology

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Pathophysiology Clinical features…
Hypothalamus Pituitary

Ovary
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Pathophysiology Clinical features…
Hypothalamus & pituitary

GnRH Pulsatility⇑

LH ⇑

FSH (⇓or⇔)
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Pathophysiology
 Raised

E2 level causes negative feed back  Decreased FSH  But increased LH

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Pathophysiology Clinical features…
Normal

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Pathophysiology Clinical features…

ANOVULATION

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Pathophysiology & Clinical features
⇑LH

Theca cell hyperplasia

⇑Testosterone

⇑Androstenedione

⇓SHBG

Estrogen

⇑free estradiol

⇑Free testosterone

Endometrial Ca
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Pathophysiology & Clinical features

Free Testosterone⇑

Hirsutism

Acne

Clitoromegaly

Alopecia

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Pathophysiology & Clinical features
↔↓ FSH

Follicular growth

2-9 mm follicle No ovulation

Infertility Menstrual disturbances

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Associated Factors
 Hyperinsulinemia  Obesity

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Hyperinsulinemia
 Insulin

resistance occur irrespective of BMI  Obesity and hyperinsulinemia have synergetic effect

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Obesity
 50%  Android

type  BMI ≥ 25 kg/m2  Waist hip ratio > 0.85  Visceral obesity is metabolically more active  Metabolic syndrome is common in PCOS

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Obesity
Metabolic Syndrome X  Abdominal obesity > 88 cm  Triglycerides ≥ 150 mg/dl  HDL < 50 mg/dl  B.P ≥ 130/85 mm of Hg  Abnormal GTT Three of the above have to be present for diagnosis
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Metabolic syndrome X
Insulin resistance syndrome

HTN

Cardiovascular disorders

Glucose intolerance

Dyslipidemia

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Infertility and PCOS

PCOS is the cause of anovulatory infertility in 75% Factors implicated in chronic anovulation

Factor FSH LH Insulin

Abnormality Relative deficiency
↑↑ ↑↑

Consequence Inadequate follicle stimulation Hyperandrogenemia Follicle growth arrest Hyperandrogenemia Follicle growth arrest Abnormal gonadotropin release & follicle growth arrest

Androgen ↑ ↑

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Early pregnancy loss and PCOS
    

⇑LH Hyperandrogenism Hyperinsulinemia Endometrial non receptivity Obesity

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Clinical Manifestations
Menstrual disturbances : 70% of cases
-

Oligomenorrhoea – Amenorrhea – Normal cycles – Polymenorrhoea – Menorrhagia –

47% 19.2% 29.7% 2.7% 1.4%

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Clinical Manifestations
Features of hyperandrogenism  Hirsutism  Acne  Alopecia  Clitoromegaly Infertility Recurrent pregnancy loss
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Clinical Manifestations
Long term consequences  HTN  Type 2 DM  Cardiovascular disease  Dyslipidemia

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Diagnostic evaluation
FSH USG LH Prolactin

FBS PCOS Insulin cortisol SHBG TSH

Testosterone DHEAS Lipid profile

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Differential diagnosis
• • • • • • • • • •
Hypogonadotropic hypogonadism Hyperprolactinemia Hypothyroidism Hyperadrenalism - Cushing syndrome - Non classic congenital adrenal hyperplasia Androgen secreting tumors - Ovarian - Adrenal Androgenic alopecia

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Approach
History  Menstrual history  H/o androgenic symptoms  Body weight changes  Life style – eating and exercise, alcohol, smoking  History of infertility, recurrent miscarriages  Family history of PCOS, diabetes, obesity, hypertension, hyperandrogenism
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Approach…
Examination • General Examination
- B.P - Breast examination – galactorrhea - Thyroid examination

• • •

Assessment of obesity
BMI Waist hip ratio - > 0.85 Waist circumference > 88 cm

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Approach…
 Assessment
 

of acne:

Mild - < 10 papules on one side of the face Moderate - > 10 papules and pustules on one side or spread to shoulders Severe – above plus deep infiltrates

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Assessment of hirsutism
Ferryman – Gallwey score - >8

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Approach…
Examination • General Examination - Abdominal striae – Cushing’s syndrome - Virilization : Frontal balding, deepening of voice broadening of shoulders, ↓ breast size • Pelvic examination - Clitoral inspection - Loss of vaginal rugae - Bimanual examination : ovarian enlargement
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Investigations
Baseline investigation Ultrasonography - Rotterdam criteria
      

Follicles > 12 in number, size: 2 – 9 mm Ovarian volume > 10 cm3 Stromal hyperechogenicity Presence of findings in single ovary sufficient Endometrial thickness Done in early follicular phase ( D1 – D3) TVS – better resolution ~100% detection, TAS – 30% detection

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Baseline investigations…
Assessment of pituitary and ovarian hormones
LH (D1-3 ) FSH (D1-3 ) Prolactin Normal 2-10 IU/L 2-8 IU/L 5.4 – 22.5 ng/dl PCOS ↑ N/↓ N/↑

TSH – 0.5 – 5 IU/L
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Investigations…
Assessment of metabolic function
 

Fasting glucose / insulin - < 4.5 – insulin resistance Glucose tolerance test: BMI > 30, ( > 25 in south asian women) Lipid profile
RCOG guidelines (2003)

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PCOS over the life span
Prepubertal Adolescence Reproductive age Postmenopausal
Premature pubarche Menstrual problems Acne, hirsutism Infertility Obesity Insulin resistance Type II diabetes Hypertension Cardiovascular disease Endometrial cancer

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Management
Obesity
 Weight

reduction  Life style modifications  Dietary modification
 

High protein, low carbohydrate Small frequent meals

 Education

and counseling

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Management…
Menstrual disturbances and hirsutism
  -

Weight reduction Combined oral contraceptive pills: Estrogen - ↑SHBG Progestins * Inhibit 5 α reductase * Androgen receptor antagonist * ↑ Clearance of androgen

Ethinyl estradiol (30 mcg) with desogestrel (.15 mg) low androgenic potential progestins (norgestimate, gestodene)

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Management…
Menstrual disturbances Progestins with anti-androgenic activity:  Cyproterone acetate  Drosperinone - 17α spironolactone derivative  Mechanism:
    

↑ SHBG Androgen receptor antagonist Reduced androgen production Inhibits 5 α reductase activity Antidiuretic action
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Management …
Menstrual disturbances
Ethinyl estradiol 35 mcg + cyproterone acetate 2mg Ethinyl estradiol 35 mcg + drosperinone 5mg

Progestin only therapy
  

Cyclical progesterone therapy Depot progesterone injections Progesterone releasing IUCD (Mirena)
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Management …
Hirsutism
Antiandrogens Spironolactone - 25 - 100 mg/day Flutamide - 500 mg/day Finasteride - 5 mg/day

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Management…
Insulin sensitizing agents
Metformin

Oral biguanide  ↑ peripheral glucose uptake, ↓ hepatic glucose production and ↑ insulin sensitivity  ↓ androgen production

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Management of infertility
Directed towards establishing ovulation Weight loss :
-

Loss of 5-10% - restores reproductive function in 55100%. ↓ Insulin and androgen ↑ SHBG First line of treatment in obese women with anovulatory infertility
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-

Management of infertility…
Clomiphene citrate

• First line drug therapy for ovulation induction • Ovulation rate – 80%, pregnancy rate – 40% • 75% of pregnancies achieved within three
cycles

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Management of infertility…
Metformin  Indications:
  

No response to clomiphene citrate Obese patients who fail to lose weight Lean patients with hyperinsulinemia

 Dose:

1500 – 2250 mg / day (incremental doses)  Side effects – GI disturbances, lactic acidosis

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Management of infertility…
Metformin  Advantages
  

Regularizes cycles in 96% women Reduces hyperandrogenism Ovulation rate – 87%

 Metformin

+ clomiphene citrate

Improved ovulation and pregnancy rates (76% vs. 46%)

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Management of infertility…
Gonadotropin therapy

Following clomiphene failure

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Management of infertility…
Aromatase inhibitors (letrozole)  Suppress estrogen production  Does not have anti-estrogenic action on endometrium  Useful in
 

Clomifene resistant cases Adjunct to FSH in poor responders

 Possible

teratogenicity

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Infertility
Step-wise approach  Weight loss  Ovulation induction with clomiphene citrate  Metformin as single agent  Metformin with clomiphene citrate  Gonadotropin therapy  Insulin sensitizers with gonadotropin therapy  IVF
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Laparoscopic ovarian drilling
Indications  Clomiphene resistant women with no consistent ovulation.  Side effects with clomiphene  Failed gonadotropin treatment  Women with OHSS with clomiphene citrate or gonadotropins

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Pregnancy and PCOS
∀ ↑ risk of miscarriage due to hypersecretion of LH • Risk of recurrent miscarriage 36 – 56% (24% in
general population) ∀ ↑ risk of GDM – GTT to be done • Metformin therapy to lower serum insulin may have beneficial effect on miscarriage rate and risk of GDM • Increased risk of preeclampsia

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Tender loving care

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Summary
The cause of PCOS is not known  Multifactorial and polygenic  Rotterdam's criteria

  

Oligovulation and / or anovulation Clinical and / biochemical evidence of Polycystic ovary on USG

hyperandrogenism

Defect
  

Central Ovary Feedback axis

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Summary…
 

 

Insulin: co-gonadotropin Hyperinsulinemia and obesity – synergetic effect → hyperandrogenemia and anovulation PCOS – most common cause of anovulatory infertility ( 75%) Long term sequelae
   

Hypertension Type 2 diabetes mellitus Cardiovascular disease Endometrial cancer

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Summary …
 Meticulous

history and examination  Appropriate selection of investigations  PCOS – different problems in different age groups  Symptomatic approach of management  Weight loss and life style modification – first line management for menstrual problems, infertility and to prevent long term sequelae

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Summary …
 Combined

OCPs – first line drugs for menstrual problems and hirsutism  Step wise approach to infertility  Increased risk of miscarriage, GDM and preeclampsia  Long term sequelae – chance to detect them at a younger age group

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