Polycystic ovarian Syndrome - Dr Tejal Vaidya Resident obstetrics and gynaecology

1. POLYCYSTIC OVARIAN
SYNDROME
- DR. TEJAL VAIDYA

2. PREVALENCE -
Polycystic ovarian syndrome (PCOS) affects 4% to 9% of women of
reproductive age.
It is the leading cause of infertility and 20 % anovulation in infertile
women is due to PCOS.

3. DEFINITION -
It is a heterogenous ,multisystem
endocrinopathy in women of reproductive age
group with ovarian expression of various
metabolic disturbances and wide spectrum of
clinical features like- obesity ,menstrual
abnormalities and hyperandrogenism.
STEIN AND LEVENTHAL SYNDROME
It was originally described by Stein and
Leventhal (1935) as a syndrome manifested by
amenorrhoea ,hirsuitism, and obesity associated
with enlarged ovaries.

4. NICHD guidelines(1990)-
1) Clinical and /or biochemical signs of
hyperandrogenism
2) Oligo or chronic anovulation
Exclusion of other etiologies of androgen excess
and anovulatory infertility is necessary.

5. ESHRE/ASRM / ROTTERDAM REVISED (2003)
CRITERIA (2 OUT OF 3) FROM BELOW
MENTIONED LIST MUST BE PRESENT TO
DIAGNOSE PCOS.
1. Oligo-ovulation and/or anovulation
2. Clinical and/or biochemical signs of
hyperandrogenism.
3. Polycystic ovaries

6. AES ( ANDROGEN EXCESS SOCIETY) GUIDELINES
(2006)
Patient demonstrates both –
1) hirsutism and /or hyperandrogenism
2) oligo / anovulation and /or polycystic ovaries

7. ETIOLOGY
Change in lifestyle, stress, diet
Familial occurrence
Environmental and Genetic factors- autosomal
dominant inheritance. 50 % first degree
relatives have pcos

8. Genetic causes are undetermined, but may
include genes related to insulin secretion,
insulin receptor function, ovarian
steroidogenesis and paracrine regulators of
ovarian function
Hypothalamic –pituitary compartment
abnormality
Androgen excess
Anovulation

9. Insulin Resistance (key role) – Insulin resistance
with resultant hyperinsulinaemia initiates PCOS in
50 – 70 % cases.
Mutation of insulin receptor gene in peripheral
target tissues
Autoantibodies
Receptor defect
Reduced tyrosine autophosphorylation of insulin
receptor
Tyrosine serine phosphorylation
Post receptor insulin signaling defect

10.  Selective insulin resistance , skeletal muscles continue to remain resistant other tissues like
hypothalamus ,ovary,adrenals remain sensitive compensatory hyperinsulinemia
decreased levels of SHBG ADRENALS/OVARIES/HYPOTHALAMUS increased levels
of GnRH

11. PATHOPHYSIOLOGY

12. TWO CELL TWO GONADOTROPIN
THEORY

13. In the ovary, estradiol is formed from the conversion of
testosterone into estradiol by the enzyme cytochrome P450
aromatase. This occurs in granulosa cells.
However, granulosa cells do not have the enzyme 17a-
hydroxylase/lyase, and thus cannot convert progesterone into
androgens.
CYP17 gene encoding 17-hydroxylase/C17-20-lyase activity
crucial to androgen synthesis, is expressed exclusively in thecal
cells.
The FSH receptor gene is expressed exclusively in granulosa
cells, where FSH acts directly to induce cytoproliferation and
differentiation via cyclic AMP/protein kinase-A mediated post-

15. CHRONIC ANOVULATION
high estrogen
positive feedback negative feedback
on LH. on FSH.
inadequate LH surge stimulates maturation
of follicles.
no rupture of
follicle. Polycystic ovaries.

18. HYPERANDROGENISM
Hyperandrogenism in the ovarian microenvironment is
a cardinal feature of PCOS.
Types: 1) Ovarian 2) Adrenal
Ovarian: Increased LH
stimulates theca cells of follicle
androgens

19. Adrenal:
Adrenal androgenism coexists with ovarian
androgenism in PCOS. The causes of this
adrenal androgen excess are due to..
1)Selective activation of the androgenic
pathway
2) Estrogen induced stimulation of adrenal
androgenesis.

20. HISTOLOGICAL FEATURES
• Thickening of tunica albugenia
• Cysts are follicles at varying stages of
maturation and atresia.
• Theca cell hypertrophy(STROMAL
HYPERTHECOSIS)
• Increased collagenization of tunica
• Increased cortical stroma thickness
• Increased subcortical stroma

21. CLINICAL FEATURES
1) Clinical hyperandrogenism
male type alopecia
acne
hirsutism
2) Clinical feature of insulin resistance
acanthosis nigrans
3) Obesity
4) Menstrual abnormalities- Oligomenorrhoea/ amenorrhoea/ DUB
5) Infertility / first trimester abortions

22. SKIN MANIFESTATIONS –
Hirsutism:
Appearance of hairs in androgen dependent sites in which hair
normally are not present in women.
Target areas are midline facial, moustache, beard, chest and
intermammary hairs and on inner thighs.
F-G SCORE FOR HIRSUTISM

24. Alopecia:
Progressive non scarring patterned loss of scalp
terminal hairs.
Acanthosis nigricans:
Mucocutaneous eruptions characterised by
hyperkeratosis, papillomatosis, and increased
pigmentation. Sites are axillae, nape of the neck,
under breasts and flexures.
Acanthosis nigricans is a reliable marker of insulin
resistance in hirsute women.
The HAIR-AN syndrome consists of
hyperandrogenism, insulin resistance and acanthosis
nigricans.
acne:

25. CLINICAL D/D-
1. HYPOTHYROIDISM- dry skin, cold
intolerance,goiter, increased fatigue
2. HYPERPROLACTINAEMIA – galactorrhoea
3. VIRILIZATION – ovarian tumours , adrenal
tumours
4. CUSHING’S SYNDROME- hypertention , buffalo
hump, pad of fat in the nape of neck, purple
striae ,plethoric face

26. DIFFERENTIAL DIAGNOSIS AND
SCREENING TESTS
Diagnosis Laboratory test
Pregnancy Pregnancy test
Hypothyroidism TSH
Hyperprolactinemia Prolactin
Late-onset CAH 17-hydroxyprogesterone
a
Ovarian tumor Total testosterone
b
Hyperthecosis Total testosterone
Adrenal tumor DHEA-S
b
Cushingís syndrome 24-hour urine free
cortisol
Differential diagnoses and screening tests.

27. ON EXAMINATION
Obesity- waist over hip ratio > 0.72 is abnormal
Body mass index between 25-30 is overweight and
above 30 is obesity
Hirsutism, acne is looked for
 Acanthosis nigra over nape, axilla, below the breast ,
thigh is looked for
Blood pressure is raised in most cases
Pelvic findings are normal , pelvic pain may be
present in few cases, it is not common to palpate
enlarged ovaries .

28. INVESTIGATIONS
1) Blood glucose levels – 2 hrs After 75 g oral glucose
•Normal - <140 mg/dl
•Impaired – 140-199 mg/dl
•Diabetes - > 200 mg/dl
OGTT IMPAIRED
2 hour glucose tolerance test:
glucose levels.
fasting 64 – 128 mg/dl
1 hr 120 – 170 mg/dl
2 hr 70 – 140 mg/dl

29. Diagnostic criteria for the insulin resistance syndrome in women.
Any three or more of the following:
Waist circumference >88 cm
Triglycerides ≥ 150 mg/dL
HDL-cholesterol <50 mg/dL
Blood pressure ≥130/85 mmhg
Fasting glucose ≥110 mg/dL

30. 2) Serum FSH and LH – LH increases , FSH level
decreases
LH : FSH = 2:1
3) TOTAL TESTOSTERONE - A total testosterone is
likely to be more reliable than a free testosterone. Most
testosterone values in PCOS will be ≤150 ng/dL (≤5.2
nmol/L).Testosterone values of ≥200 ng/dL (≥6.9
nmol/L) warrant consideration of an ovarian or adrenal
tumor.

31. 4) DIHYDROEPIANDROSTERONE –SULPHATE - DHEA-S
values may be normal or slightly elevated in
PCOS.DHEA-S values ≥800 µg/dL (21.7 µmol/L)
warrant consideration of an adrenal tumor.
5) PROLACTIN - Mild hyperprolactinemia has been
reported in 5% to 30% of patients with PCOS. Patients
with prolactinomas may have polycystic ovaries on
ultrasound
6) 17 – HYDROXYPROGESTERONE- A morning, fasting,
unstimulated level of <200 ng/dL (<6 nmol/L) in the
follicular phase reliably excludes late-onset 21-
hydroxylase deficiency.

32. 7) 24 HR URINE FREE CORTISOL - Mild elevations
can be seen in PCOS with values ≥2 times the
upper limit of normal more consistent with
Cushing's syndrome.
8) Lipid profile
Full fasting cholesterol panel
Elevated total cholesterol
Elevated LDL cholesterol
Decreased HDL cholesterol
Elevated triglycerides

33. 9) PELVIC USG-( STRING OF PEARLS /NECKLACE)
The criteria for PCOS put forth by Adams et al. are the
most often cited: the presence of ≥12 cysts measuring
2–9mm around a dense core of stroma or scattered
within an increased amount of stroma.

35. 10) LAPROSCOPY - “Oyster ovaries”
- Thick sclerotic capsule is noted in chronic
cases. No evidence of corpus luteum or stigma
of ovulation are noted.
- Both diagnostic and therapeutic value.

36. 11) ENDOMETRIAL BIOPSY-
Helpful to rule out endometrial hyperplasia in
those with prolonged amenorrhea (more than 5
months).

37. MANAGEMENT OF PCOS
Treatment depends on the patients goal.
Some patients require hormonal contraception, whereas others desire
ovulation induction.
But, in all cases in which there is significant ovulatory dysfunction,
progestational interruption of unopposed estrogen effects on the
endometrium is required.
Interruption of the steady state of hyperandrogenism and control of
hirsutism usually can be accomplished simultaneously.

38. WEIGHT REDUCTION
Initial recommendation.
It promotes health, reduces insulin,androgen
levels,increase SHBG and may restore ovulation
either used alone or in combination with
ovulation induction agents.
The weight loss of as little as 5 to 7% over a 6
months period can reduce the bioavailable or
calculated free testosterone level significantly
and restore ovulation and fertility in more than
75% of the women.

40. UNMARRIED/ ADOLESCENT GIRLS
WITH PCOS1) LIFESTYLE MODIFICATIONS-
•Weight reduction ,diet ,exercise
2) REGULATION OF MENSTRUATION -
•Combined oral contraceptive pill – low dose /ultralow dose
•Cyproterone acetate + EE
3) HYPERANDROGENISM-
•Antiandrogens
• cyproterone acetate
4)INSULIN RESISTANCE
•Metformin

41. Combined ocps with aldosterone derivative – (drosperinone)
It has antimineralocorticoid activity and mild antiandrogenic
Yasmin,jasmine,yarina
Drosperinone 3 mg and EE 30 microgm
Myo-inositol derivatives
Decrease serum testosterone
increases insulin sensitivity
Improves ovulatory function

42. MARRIED WOMEN WITH
INFERTILITY1) Lifestyle modifications
2) Metformin
3) Clomiphene citrate
4) CC +dexamethasone
5) Metformin+ clomiphene citrate
6) FSH ,LH , GNRH analogues
7) low doses glucocorticoids benefit women with androgenic
anovulation
8) Clomiphene resistant cases – laproscopic ovarian drilling

43. MARRIED BUT FAMILY COMPLETED
1) lifestyle modifications
2) menstrual regulation – ocp
3) hyperandrogenism / hirsutism
perimenopausal woman
Hyperandrogenism

45. HIRSUTISM
70 % Of women with pcos have hirsutism
Combined Oral Contraceptive Pills
The progestin component suppresses LH, resulting in
diminished ovarian androgen production.
The estrogen increases hepatic production of SHBG,
resulting in decreased free testosterone
concentration.
Estrogen decreases conversion of testosterone to DHT
in skin by inhibition of 5-alpha reductase
OC pill alone may be relatively ineffective ( less than
10% success rate) in the treatment of hirsutism in
patients with PCOS. So management includes co
administration of agent that impede androgen action

46. CYPROTERONE ACETATE –
Steroid derivative of 17 – hydroxyprogesterone
Progestational, antigonadotrophic, antiandrogenic
activity
The mechanism of action:
1. Compititive inhibition of testosterone and DHT at
the level of androgen receptors.
2. Induces hepatic enzymes and may increase the
metabolic clearance rate of plasma androgens.

47. Administered in the reverse sequential regimen
(cyproterone acetate 100 mg/day on days 5 to
15, and ethinyl estradiol 30 to 50 mg/day on
cycle days 5 to 26). This cycle schedule allows
regular menstrual bleeding, provides excellent
contraception and is effective in treatment of
even severe hirsutism and acne.
Side effects includes fatigue, weight gain,
decreased libido, irregular bleeding, nausea and
headaches.

48. SPIRONOLACTONE
Aldosterone antagonist , also a potent antiandrogen
Competitively binds to androgen receptor in hair follicle
Suppression of testosterone biosynthesis by the decrease in the
CYP450 enzymes.
Inhibition of skin 5-alpha reductase activity
Increase in androgen catabolism with increased peripheral conversion
of testosterone to estrone.
dose- 50 to 100 mg twice daily.

49. The common side effects are menstrual
irregularity, nausea ,vomiting
Other side effects are mastodynia, urticaria,
scalp hair loss.
Periodic electrolyte and blood pressure
monitoring

50. FLUTAMIDE
It is a pure non steroidal antiandrogen, and is
approved for the treatment of prostate cancer.
Mechanism of action is inhibition of nuclear binding of
androgen in the target tissue.
When combined with OC pills there is a significant
improvement in hirsutism and drop in
androstenedione, DHT, LH and FSH levels.
Dose- 250 mg / day

51. The side effects of this treatment includes
fatigue, headache, nausea, dizziness,
decreased libido, liver toxicity ,cholestatic
jaundice ,hepatic necrosis ,vomiting

52. FINESTERIDE
It is specific inhibitor of type 2 5-alpha
reductase enzyme activity.
It causes improvement in hirsutism when given
as 5 mg/day

53. KETOKONAZOLE
An antifungal agent, inhibits the key steroidogenic
cytochromes. (CY P 450)
When administered at low doses (200 – 400 mg/day)
significantly reduces the levels of androstenedione,
testosterone and calculated free testosterone.
Side effects- nausea ,vomiting, pruritis, hepatic
dysfunction

54. METFORMIN
Insulin sensitizers improve
Hyperinsulinaemia and Hyperandrogenism
,hence Metformin is now the most widely
used insulin sensitizer.
Biguanide family
Improves the sensitivity of peripheral
tissues to insulin resulting in reduction of
circulating levels .

55. METFORMIN
Inhibits hepatic uptake and gluconeogenesis
Increases the glucose uptake by peripheral
tissues and reduce fatty acid oxidation .
Supports ovarian function and return to normal
ovulation.
Inhibits human theca cell androgen synthesis .
increases levels of SHBG .
Used for induction of ovulation and also
prevents ovarian Hyperstimulation

57. Side effects Gastrointestinal intolerance in 30%
(nausea, abdominal pain and/or diarrhea)
Precautions Hold for 48 hours prior to and after
surgery and/or administration of radiocontrast
materials
Contraindications Creatinine ≥1.4 mg/dL (for
women)
Liver disease (or risk thereof: alcohol abuse/binge
drinking)
Other risks for lactic acidosis: pulmonary disease,
congestive heart failure
Tab metformin 500 mg bd/tds dose

58. GNRH AGONISTS AND
ANTAGONISTS
Gnrh agonists- nafarelin/leuprorelin/busirelin
Decreased LH AND FSH
s/e- due to reduced levels of estrogen therefore, estrogen add back
therapy should be started
Gnrh antagonists –cetrorelix,ganerelix
Inhibits LH AND FSH
Advantages over gnrh agonists-
1)no flare up due to no intrinsic activity
2)competitive receptor binding hence dose dependent action
3) resumes ovulatory function in 6 weeks of stoppage of drug

59. PREGNANCY COMPLICATIONS
Gestational diabetes
 Obesity
 Insulin resistance
 Birth defects
Pregnancy-induced hypertension
 Women over 40
 Obese
 Insulin resistance
Premature delivery
Miscarriage.

60. SEQUELAE
Type 2 Diabetes mellitus (15%)
Cardiovascular diseases
Lipidaemias
Hypertension
Endometrial cancer
Breast cancer
Premature ovarian failure following surgery