Polycystic Ovary Syndrome

1. Complex clinical syndrome
Etiology
1. Unclear
2. Risk factors
a) Genetics
- Monozygotic twin
- First degree relatives
b) Environmental
c) Prepubertal obesity
d) Early onset menarche
e) Valproic acid user mother
f) Excess exposure of androgen in fetal life
PCOS

3. Obesity
In obesity there is hyper insulinaemia and increase insulin resistant.
Hyper insulinaemia causes androgenism by ovarian theca cell stimulation.
Reduced hepatic synthesis of SHBG.
Hyper insulinaemia
a) Mutation of insulin receptor gene in peripheral tissue so insulin cannot
work.
b) Reduce tyrosine autophosphorylation of insulin receptor.

4. Symptoms of PCOS
1. Menstrual disturbances 88%
2. Hirsutism – 66%
3. Acne 35%
4. Infertility 75%
5. Obesity
6. Acanthosis Nigrican
PCOS
From menarche to menopause.

5. PCOS
Reproductive
Anovulatory cycle
Poly cystic ovary
Hyper androgenic
Sub fertility
Pregnancy loss
Psychologics
Depression
Negative body image
Low self esteems
Psychological dysfunction
Eating disorder
Poor quality of life.
Malignancy
Endometrial
malignancies
Metabolic
Insulin resistance
Obesity
Dyslipidimia
GDM/Prediabetic/Diabetic
Cardiovascular risk
PCOS related comorbidies

6. Criteria for diagnosis
Adult
Require two of three
1. Oligomenorrhoea or anovulation
2. Clinical and /or biochemical hyper androgenism.
3. USG shows Polycystic ovaries
After exclusion of other etiologies .

7. String of Pearls

8. 3 D Picture

9. Adolescent
1. Oligomenorrhoea or anovulation
2. Clinical / or biochemical hyper adrogenism
After exclusion of other etiologies.

10. Diagnosis of PCOS by exclusion
1. Congenital adrenal hyperplasia
2. Non classical congenital adrenal hyperplasia
3. Premature ovarian failure
4. Hyper prolectineamia
5. Hypothyroridism
6. Hypothalamia amenorrhoea
7. Androgen secreting tumour
8. Pregnancy

11. Diagnosis of PCOS in adolescent is
difficult
overlap with physiological pubertal events.

12. Prevalence of PCOS
3.4-11% adolescents
18% in obese adolescent
Y barras M et al gynaecol endocrinal 2017
Growth is associated with profound metabolic changes.
Normal Adolescent
1. 85% of cycles are anovulatory is first year of menarche
2. 59% in third year
3. 25% still anovulatry in the sixth years.

13. Metabolic
1. Hyperinsulinaemia due to high growth hormone.
2. Hyperpulsatile GnRh secretion.
3. Decrease level of SHBG
4. Increase ovarian and adrenal androgen.
PCOM at USG
40% at 2 yrs.
35% at 3 yrs.
33.3% at 4 yrs after menarche.

14. PCOS during adolescent
 30% menstrual irregularity.
 60% Androgen excess.
 84% over weight
 9% Impaired glucose test or T2 DM.

15. 1st diagnostic criteria
Irregular menstrual cycles oligomenorrhoea or anovulation.
Irregular menstrual cycles and oligoamenorrhoea – 3 yrs post menarche.
By 3 yrs post menarche 90% had at least 10 cycle/yr.

16. Definition of irregular menstrual cycles in adolescents
according to time post menarche.
Period >35 days less than 6 period/year .
No period for over 6 months.
Time post menarche Definition of irregular menstrual
cycles.
Less than 1 year post menarche Irregular menstrual cycles are normal pubertal
transition
1≥ to < 3 yrs
post menarche
< 21 or
> 45 day
> 3 yrs post menarche < 21 or > 35 days
or < 8 cycles/yr
More than 1 yrs Post menarche  90 day for any one cycle.

17. 2nd criteria
Hyper adrogenism
Clinical/ biochemical
Clinical
- Acne
- Oily skin
- Hirsutism
Biochemical hyper androgenism
Type of androgen
a) Testosterone – Total (Most used)
– Free androgens index.
b) Sex hormone binding globulin.
c) Free testosterone
d) DHEAS or androslenedine – not routinely recommended.

18. Diurnal rhythm higher level in morning.
Reliable measure is not possible in women on hormonal contraception
Needs 3 months or more with drawal.
Very high level need further evaluation.

19. Investigation not required
• USG should not be used for the diagnosis of PCOS in women
< 8 years post menarche.
• AMH not included

20. Hirsutism
Ferriman Gallway score ≥ 4-6
Hyper insulinaemia (Insulin resistance)
1. Impaired GTT
2. Early development of Type II diabetes.
3. Dyslipidaenia
4. Central obesity
5. Acanthosis nigrican
6. Skin tags
Acanthosis nigrican

21. Adolescent at risk of PCOS PCOS
Does not fulfil criteria for PCOS Fulfil diagnostic criteria
a.Isolated Irregular menstrual cycles
c.Isolated hirsutism
d.Isolated severe acne

22. Adolescents at risk of PCOS
Adolescents with PCOS features who do not meet diagnostic criteria.
1. Could be considered at an increased risk.
2. Reassessment is advised at or before 8 yrs post menarche.
3. May require management of symptoms/life style.

23. Management
Obesity
Weight reduction.
An ovulation /menstrual irregularly
First line – OCP/ progesterone
Second line- Metformin
Insulin resistance
First metformin 500-850mg twice or three times daily.
Second Inositol 40mg/day
Hirsutism
1st line – OCP
2nd line – Spironolactone 100-200mg/day
- Cyproterone accetate 100 mg/day
3rd line – metformin
Acne
First – COC
2nd – Spironolactone

24. Points to be remember
1. Combination of 30mg of ethinyl oestradiol and drosperinone.
Adv: No weight gain due to diuretic effect.
Anti androgen and lipid friendly.
2. Cyproterone
anti androgen.
Normalization of LH/FSH ratio.
Negative effects on lipid profile.
Increase triglyceride level.

25. Metformin in PCOS
1. Androgen excess.
2. Restore normal menstruation.
3. Aid in weight reduction.
4. Reduce insulin resistance.
5. Excellent safety profile with few side effects.
6. Prevent or delays the progression to PCOS in high risk prepubartal girls.
7. A good option in patient with factor V leidan mutation and other risk factors for coagulation
abnormality when OCP is contraindicated.

26.  Failure of life style intervention.
Bariatric surgery in adolescent
BMI > 35
 Psychological Treatment
 Treatment of sleep apnoea.

27. Abnormal uterine bleeding (AUB) due to
PCOS
Principal goal in managing AUB in adolescent
- Diagnosis
- Correction of anaemia
- Returns to pattern of normal menstrual cycles
- Prevent recurrence
- Preventing of long term consequence of anovulation.
More than 90% respond to hormonal therapy.

28. D/D
1. Uterine pathology
2. Infection
3. Bleeding disorder
4. Pregnancy related complication
Hormone
- OCP
- Progesterone
Abnormal uterine bleeding (AUB) due to PCOS

29. Duration of therapy and follow up
 Follow up after 3 months
 Upto 5 yrs post menarche
 With holding the treatment for few months
- To allow recovery of suppression
- To ascertain : -
» Whether menstrual
› Abnormalities persist or not
› Maintain menstrual calendar
Long term follow up
- Endometrial malignancy particularly
- Obese
- F/H/O endometrial .ovarian, colon cancer.

30. Prevalence of PCOS in adult.
8-13% women
Botdag a et al human reproduction – 2016

31. Reproductive impairment in PCOS
1.Infertility
* Chronic anovulation:
The selection of dominant follicles does not occur regularly
2.Pregnancy related complications
* Abortion
* Multiple birth
* Premature labour
* PIH
* GDM

32. Causes of chronic anovulation in PCOS
1. Relative FSH deficiency (Increase LH/FSH ratio)
2. Hypersecretion of LH/Insulin/ Estrogen / Testosterone / Inhibition-B
3. Abnormalities in ovarian steroid production. Theca cell secret excessive androgen.
4. Granulose cells have increased aromatase activity.
5. Aberrant-expression of growth factor.
6. Attenuated apoptosis.
7. Increase level of AMH
a) Reduces FSH sensitivity of individual ovarian follicles
b) Block the conversion of androgen to oestrogen via the inhibition of
aromatase activity further contributing to hyper androgenism.
8. Genetic variation in FSH molecule and its receptors.

33. PCOS affecting oocyte competence
Abnormalities during folliculogensis follicular growth and oocyte meiotic maturation
process.
a) Abnormalities in mitochondrial morphology.
b) High fat diet causes reduced MT meembrane potential at both GV and M2 stages.
c)Altered mitochondria activity – poor oocytes and embryo quality.

34. Infertility Treatment
Ovulation induction
a) Time of intercourse
b) IUI
c) IVF
Unpredictable responses
1. Response may be slow
2. Hyper response – OHSS, High order birth
3. Risk of cyst formation

35. Phenotype
Group A( classic variant)
* Hyper androgenism
* An ovulation
* Polycystic ovaries
» E2, more follicle respond best to
agonist trigger.
»Higher AMH, Higher risk of OHSS.
Group B
* Hyper androgenism
* Chronic anovulation
* Normal ovaries
» Higher dose of
gonadotrophin needed.

36. Group D
* Chronic anovulation
* Polycystic ovaries
* No clinical or biochemical signs of androgen excess
» Higher AMH, AFC and E2
Group C
* Hyper androgenism
* Polycystic ovaries
* Ovulatory cycles
» Low dose of gonadotrophin

37. The management of anovulatory infertility in women with PCOS – an analysis of
evidence to support the development to global WHO guideline.
1. Life style modification in obese.
2. Life style intervention failed Bariatric surgery ≥ 35kg/m2
3. CC / letrozole first line therapy
4. Metformin alone has limited benefits in improving LBRS.
5. Gonadotrophin and LOD can be used as second line therapy.
6. Those who fail life style modification and ovulation induction therapy or have
addition infertility factor, IVF can be used with GnRh antagonist protocol.
7. If GnRh agonist protocol is used metformin as an adjuvant may reduce the risk of
OHSS.

38. 1.Weight reduction.
2. Clomiphene citrate
How acts:
a) Clomiphene competing with endogenous oestrogen receptor site
in hypothalamus that is anti oestrogen
b) Block negative feed back effect
c) Increase release of Gonadotrophin
d) Follicular development
e) Half life 60 days

39. Clomiphene treatment for PCOS in fertility
Six ovulatory cycles – recommended
given for D2 – D6 or for D5 – D9
Dose 50mg and maximum 150mg
75% of pregnancies in first 3 cycles.
When to stop CC
1. Six ovulatory cycles fail to yield pregnancy.
2. When no ovulation with 150mg/day clomiphene.
3. If endometrial thickness < 7mm at ovulation

40. How Letrozole acts
1. Inhibition of aromatase enzyme reduces the estrogen level.
2. Block negative feed back effects.
3. FSH level increases , stimulates follicular growth.
4. Rising estrogen suppress FSH release .
5. High monofollicular development.
Letrozole
1. No effect on endometrium and cervical mucus because of absence of anti oestrogen
effects.
2. Dose 2.5-5mg/day for D2-D6 or D3-D7
3. Ovulation – 85%
4. Endometrium – Implantation better.
Pregnancy rate
27.5% -Letrozole
19.1%- Clomiphene

41. 1. Extended letrozole for 10 days
High ovulation
2. Combination of letrozole and clomiphene or letrozole alone for ovulation induction in
women with PCOS.
3. 2.5mg letrozole and clomiphene – 5 days
Vs
Letrozole 2.5mg / daily
Combination group had a statistically higher ovulation compared with those who received
letrozole alone.
Pregnancy rate was higher when ovulation
induction was done using combination but
difference was not statistically significant.

42. Clomiphene/Letrozole result can be improved by
- Weight loss
- Addition of metformin
- Addition of Dexamethasone
- Addition of hCG
- Gonadotrophin
- Laparoscopic ovarian drilling.

43. Gonadotrophin
1. Presence of USG monitoring
2. Following counseling
- Cost
- Risk
› High order birth (multiple pregnancy)
› OHSS
High order birth (multiple pregnancy) are much more in non ART cycle than
ART cycle.

44. Ovarian surgery
Laparoscopic ovarian drilling ( LOD)
1. Resistant to clomiphene
2. High LH
3. High AMH
4. Unwilling to gonadotrophin
5. Laparoscopy for other indications
Long term complication of LOD
a. Adhesion formation
b. Diminished ovarian reserve

45. Trigger
Trigger is replicating the LH surge.
Ovulation occurs 36-37 hrs after the trigger injection.
1. HCG – has to be avoid
2. Recombinant HCG
3. GnRh agonist trigger
4. Dual trigger (Agonist + hCG)

46. IVF
Recommendation
» Gonadotrophin with GnRh antagonist
» GnR agonist trigger
» Vitrification of embryo
» Frozen embryo transfer
To reduced the risk of OHSS and multiple pregnancy

47. Newer Medication
1.Glucagon like peptide 1 receptor agonists
a) GPL-1 agonist enhance glucose induced insulin secretion and inhibits
glucagon secretion.
b) Delay gastric emptying
c) Reduce appetite and food intake
d) Indicated in Obese Type II DM
LIRAGLUTIDE 3mg
2. SGLT2 inhibitors

48. Obstetric Risk
1. Early pregnancy loss
2. GDM
3. PIH
4. Premature birth
5. Perinatal mortality
6. High C/S rate

49. Menstrual irregularities in reproductive age group 20-40 yrs.
PCOS causes irregular uterine bleeding in reproduction aged women affection
approximately 6% of women in this group.
Diagnosis – PCOS
Treatment targeted toward the cause.
Objective
1.Control bleeding
2.Prevent recurrences
3.Preserve fertility
4.Correct associated disorder
5.Induce ovulation in women who desire to conceive.

50. Treatment option is
» OCP or progesterone
Women who choose not to or cannot take OCPS an alternative treatment for
endometrial protection is progesterone
Either
1.Oral
2.IUD(Mirena)
Menstrual irregularities in perimenopaused women over 40 yrs.
Step wise evidence based approach to managing irregular bleeding.

51. Treatment goal stabilizing the endometrium.
1. OCP
2. Mirena
Not respond to medical
Surgical option
a)Endometrial ablation
b)Hysterectomy

52. Endometrial Hyperplasia
In premenopausal
1) Atypical –
a) Medroxy progesterone 40 mg/daily 3-6 months
b) IUD (Mirena)
Reassess by sampling
Resolution – Progesterone / Clomiphene.
Persistent – Hysterectomy
2) Cystic or adenomatous -
Progesterone
IUD( Mirena)