1. Management
of
INFERTILITY in PCOD
Difficulties & Solutions
Made Easy
Dr. Sharda Jain
Dr. Jyoti Agarwal
Dr. Jyoti Bhaskar
Dr. Abhishek Parihar

2. Management of
INFERTILITY in PCOD
Difficulties & Solutions Made Easy
Review this Lecture at:
Slideshare.net

3. In Reproductive Age Group
Type of Patients Which We See
Anovulatory infertility
Obesity
Menstrual irregularity &
Heavy Menstrual Bleeding
For Prevention of
METABOLIC SYNDROME

4. Challenges of PCOD
In 20 - 40 yrs Age Group
WOMEN WORRY
• Infertility
• Early pregnancy
Loss
• During pregnancy
- PIH
- GDM
Dr’s Worry
• Poor Ovarian
Function
• Poor Oocyte quality
& maturation
• High Insuline
• High Androgen

5. Treatment
Her concerns are
- INFERTILITY
- Early pregnancy loss
- She wants
Baby
Baby
Baby …

6. Not concerned about
Other Symptoms & Signs
in Adult Group
Anovulation & Menstrual
irregularities
- Acne Hirsutism
- Metabolic Syndrome
• Central obesity
• Insulin resistance
• Glucose intolerance
- Ca Endometrium
Obesity

7. PCOD & Infertility
Is our focus here
As Lately it is confusing
The Gynaecologists !!

8. Learning Objectives
• Update on controlled ovarian induction.
• Update on follicle / cycle monitoring
• LOD
• Challenges of obesity / OHSS & multiple
pregnancy.
• Newer Drugs in PCOD
• Tailor Made Therapy

9. INCIDENCE :
Commonest endocrinal gynecologic disorder:
- Minimum 10% based on clinical
biochemical and u/s criteria in india
- 30% of infertility.
- 50-70% of Hirsutism.
- 80 - 90% of case of oligomenorrhea.
- great contribution to kitty of recurrent
miscarriage.

10. DIAGNOSIS
Uploaded On slideshare.net
Ref.http://www.slideshare.net/LifecareCentre/polycystic-ovarian-disease-hyperandrogenism-evidence-based-
update-on-diagnosis-consequences

11. Clinical Manifestation of PCOD
Acne
Obesity
Acantosis Hirsutism
HAIR LOSS IRREGULAR
MENSES

12. Bio chemical and Diagnostic
Markers of PCOD
Accepted everywhere
– Elevated androgen (i.e. testosterone > 60 or free
testosterone >0.75) levels
– Elevated LH:FSH ratio > 2:1
– Increased Insulin levels
– Insulin resistance , (Clinical / Lab)
Lab diagnosis of insulin resistance is not needed
– Ultrasound appearance of PCO

13. Exclusion of Related Disorders
• Thyroid disorders
Sr.TSH,Sr.Prl
• Hyperprolactinemia
• Cushing’s syndrome
Dexa supression test
• Late onset congenital adrenal hyperplasia (CAH)
• Basal morning 17-OHP,(2-3 ng/ml)
• Ovarian and adrenal tumors DHEAS
• WHO I &III –FSH,LH,E2
• Syndromes of severe insulin resistance(HAIRAN
syn)

14. TREATMENT OF PCOS in Adult Women
THIS CAN BE DIVIDED INTO TWO CATEGORIES
Women desirous
of pregnancy
Women not
desirous
pregnancy but
wants symptom
cure

15. Minimal Infertility Workup
• Semen Analysis
• Tube testing
•AMH
•R/O TB

16. Pre Treatment Considerations
• Weight loss
• Insulin Resistance
• Exclude Endometrial hyperplasia
• Exclude Metabolic Syndrome

17. It is good to RULE OUT
Diagnosis of following before
start of Treatment
Diagnostic criteria for various conditions are
not discussed here
BMI
Pre-Diabetes
Hypertension
Fatty Liver
Diabetes type II Hyperlipidemia
Insulin Resistance Hypo-Thyroidism
Metabolic Syndrome Vitamin-D Deficiency

18. Phenotypes of PCOS
1. PCOS with PCO :
• PCO + hyperandogenism + anovulation.
• PCO + anovulation.
2. PCOS without PCO :
hyperandogenism + anovulation.
3. PCO without PCOS.
( Isolated PCO = Asymptomatic PCO ).
(Azziz et al.,2006)

19. WHO
Classification
• I - Hypothalamic pituitary failure
(Hypogonadotrophic hypogonadism)
Kallman’s, Sheehan’s, anorexia
• II - Hypothalamic pituitary dysfunction
(PCOS)
• III – Ovulatory Failure –
Hypergonadotrophic hypogonadism,
Turner’s, autoimmune, mumps, RT, CT

20. THESSALONIKI CONSENSUS ON INFERTILITY
TREATMENT IN PCOS, GREECE 2007
FIRST LINE
CLOMIPHENE CITRATE
SECOND LINE
LOD/GONADOTROPINS
THIRD LINE
IVF
The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March
2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008
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21. THESSALONIKI CONSENSUS ON INFERTILITY
TREATMENT IN PCOS, GREECE 2007

22. Management in General
for PCOD Obese Patients
• Obese patients are advised to lose
weight which may
be accomplished by one or a
combination of following
methods -
– Diet
– Diet & Exercise
– Anti-obesity Medicines ???

23. Even 5% Weight loss improves
fertility outcome
Impacts Fertility Outcomes

24. Exercise
Daily exercise improves body's
use of insulin and can help
relieve symptoms of PCOS
A 30 minutes daily exercise can
improve many symptoms

25. COUNSELLING
• PCOS patients are often high
responders to medications
• Explain risk of
– Ovarian hyperstimulation syndrome
(OHSS)
– High risk of multiple pregnancy
– Possibility of fetal reduction

26. PCOD: Various treatment modalities for
infertility Treatment
Pharmacological Treatment Surgical Treatment
CC /Tomoxifen
Gonadotropins
hMG
uFSH
HP-FSH
rec-FSH
Hyperinsulinemia?
Insulin sensitizer
GnRH-analogs
Wedge
resection
LOD

27. Drugs for Ovarian Stimulation
in PCOS
• Clomiphene Citrate,
•Tamoxifen
• Gonadotrophins:
• HMG
• highly purified ur FSH
• Rec. FSH
• GnRH antagonist
•Metformin

28. CLOMIPHENE CITRATE
• Most widely
• Simple to use,
 Minimal side effects,
 Cost effective

29. CLOMIPHENE CITRATE ( SERM)
Binds
HYPOTHALAMUS ER
GnRH
Pituitary
FSH
OVARY
Folliculogenesis
Blocks ER
Cervi
x
Vagina
Endometrium

30. DOSAGE
Starting Dose 100mg day 2 onwards for 5 days
• Single dose -- together
• Monitor Cycle with USG
• If ovulation confirmed – maintain same
dose
• Max to 150 mg

31. Anovulatory infertility in PCOS
 50-80% will ovulate on CC
 Only 40-50% will conceive

32. CC FAILURE ( 40%)
No Pregnancy
3 CYCLES OF CC
WITH OVULATION AND TIMED INTERCOURSE
2 CYCLES OF CC WITH IUI

33. CC RESISTANCE (20%)
3 CYCLES OF CC
NO OVULATION
CC +
GONADOTROPHINS
COST , PT’S CHOICE
COUNSELLING
GONADOTROPHINS

34. Antioestrogenic Effect
• Thin Endometrium
• Poor Cervical Mucus
Start early in cycle – Day 2 or Day 1
Add oestradiol valearate from day 8/9
Use all gonadotrophin cycle

35. BIGGEST
Breakthrough
Enclomiphene citrate versus clomiphene citrate
as a primary ovulation induction drug in Type -2
anovulatory infertility cases (PCOD) as per WHO
Results
Better Ovulation Induction
Better Endometrial thickness and
An edge in pregnancy rate
Indian market is flooded with such preparations

36. TAMOXIFEN
• 20-40 mg/day D2- D7,max 60 mg/day
• Off label use for OI
• Ovulation rates- 65 to 75%
• Pregnancy rates- 30 to 35%.
• Advantage-
– No anti-estrogenic effect on endometrium.
– Improve bone density & lipid profile
• 2-3 times increased risk of endometrial Ca & DVT
• No evidence of a difference in effect between CC
and tamoxifen (Cochrane library, 2009)

37. INDICATIONS FOR METFORMIN
IN PCOS
• Weight loss with lifestyle changes
• Menstrual disorders
• Anovulation resistant to CC
• IGT /Type II DM
• Metabolic syndrome

38. METFORMIN—PRESENT ROLE
• Use of metformin in PCOS should be restricted to
those patients with glucose intolerance
ESHRE/ASRM-Sponsored PCOS Consensus
Workshop *,2007, Thessaloniki, Greece
• Metformin may be added to CC in women with
clomiphene resistance who are older and have
visceral obesity (I-A)
SOGC guidelines, 2010

39. OCTOBER 2010

40. IS METFORMIN INDICATED AS PRIMARY OVULATION
INDUCTION AGENT IN WOMEN WITH PCOS? A SYSTEMATIC
REVIEW AND META-ANALYSIS
Siebert T.I. Viola M.I Steyn D.W. Kruger T.F 2012
Tygerberg Hospital
• CC alone is superior to M alone regarding
live birth rate and Ovulation.
• An increase in ovulation and pregnancy
rate with CC+M when compared with CC
alone , but no difference was found when
live birth rate

41. INSULIN-SENSITISING DRUGS (METFORMIN, ROSIGLITAZONE,
PIOGLITAZONE, D-CHIRO-INOSITOL) FOR WOMEN WITH POLYCYSTIC
OVARY SYNDROME, OLIGO AMENORRHOEA AND SUBFERTILITY
• Metformin was associated with improved clinical
pregnancy but there was no evidence that metformin
improves live birth rates whether it is used alone (or in
combination with clomiphene when compared with
clomiphene.
• Therefore, the role of metformin in improving
reproductive outcomes in women with PCOS appears to
be limited.
• Metformin was also associated with a significantly higher
incidence of gastrointestinal disturbances than placebo (
Cochrane library:16 may 2012(up-to-date: 2 oct 2011)

42. METFORMIN TREATMENT BEFORE AND DURING IVF OR
ICSI IN WOMEN WITH PCOS
• No evidence that metformin treatment before or
during ART cycles improved live birth or clinical
pregnancy rates. The pooled OR for live birth rate (3
RCTs) was 0.77 and for clinical pregnancy rate (5
RCTS) was 0.71.
• The risk of OHSS in women with PCOS and
undergoing IVF or ICSI cycles was reduced with
metformin
Cochrane library: 2009

43. PCOS Patients with
Anovulation & Ovulation disorder
RESISTANT TO CLOMIFENE CITRATE:
SECOND – LINE TREATMENT, depending
on clinical circumstances and the women’s
preference
• Gonadotrophines
• Laparoscopic Ovarian drilling or
(NICE 2013)

44. Gonadotrophins - Indications
CC Resistance
CC Failure

45. Choice of Gonadotrophins
• HMG
• Highly purified Urinary HMG/FSH
• Recombinant. FSH
Day 2 LH/FSH
FSH
LH
PCOS
FSH
WHO group1
HMG

46. DOSE
• BMI
• Ovarian reserve
• Age
• Cause of Infertility
• Dose needed in previous cycle

47. Complications
 Multifetal pregnancy
• OHSS - Life threatening
Monitoring
Experience
Strict protocols

48. Protocols
1. CC only with TI or IUI
2. CC ± FSH or ± HMG with IUI
3. Gonadotrophin only
n Conventional regime
n Gn. Low dose step-up protocol
n Gn. step-down protocol
4. Gonadotrophin with GnRH antag

49. DAYS OF CYCLE
2
3
4
5
6
7
8
9
10
11
12
13
14
15
21
CC ONLY PROTOCOL -- +/- IUI
TVS – ET AND AFC
CC
100 MG
DAILY
Day 2-6
TVS – FOLLICLE SIZE, ET
IF ET< 5MM OV 2MG BD DAILY
TVS – FOLLICLE , ET , CERVICAL MUCUS
STUDY, POST COITAL TEST
FOLLICLE >20MM -- LH SURGE
+ VE -VE
Inj HCG 5000 U i/m
Timed Intercourse
stat 8pm
B LONG F ONCE DAILY ALL
THROUGH OUT THE CYCLE
24hrs later at 8am 36 hrs later at 8am at Lifecare
IUI
Sexual relation at same night and for 2 days
Luteal support – ETV ES/ Susten vaginally at night
Serum Progesterone 7 days after IUI/Ovulation
UPT 18 days after IUI/Ovulation

50. Unripe
follicle
Ripening
follicle
Ovulation Corpus
luteum
Regression of
Corpus luteum
Clomiphene
100 mg day2
for 5 days
Gonadotrophin
stimulation
Oocyte mature
38 hrs
HCG Leading follicle > 18mm

51. FSH Administration Regimens
75 IU 75 IU 112.5 IU 150 IU
Days 7 14 21 28
hCG
Chronic Low Dose (CLD): S. Franks et al.
Step Down (SD): B. Fauser et al.
150 IU 112.5 IU 75 IU hCG
Foll.  10 mm
Sequential (SE): J.N. Hugues et al.
½
112.5 IU 75 IU 150 IU
75 IU hCG
6 12
Foll.  14 mm

52. LAPAROSCOPIC
OVARIAN DRILLING

53. Laparoscopic Ovarian Drilling
• Main Indications
1. CC Resistance
2. Pts. who persistantly hypersecrete LH
• Methods – Monopolar cautery or Laser
• Efficacy
50% of LOS treated Pts. adjuvant therapy will be reqd.
Addition of CC after 12 weeks if no ovulation detected
Addition of FSH should be considered after 6 months.
• Complications
Haemorrhage, bowel injury, adhesions, premature menopause

54. MECHANISM OF ACTION
A.) Drilling of follicles releases androgen rich follicular fluid and
decreases androgen producing stroma.
B.) There is transient reduction in inhibin and precipitous fall in
LH, which increases secretion and expression of FSH.
C.) Crowding of cortex decreases which allows progress of
normal follicles to the surface resulting in resumption of normal
ovulation.
LOD appears to be as effective as routine gonadotropin therapy
in the treatment of clomiphene-insensitive PCOS.

55. LAPAROSCOPIC OVARIAN DRILLING (LOD)
Technique: 4 puncture/ovary,4-5 mm depth,40 watt
coagulation for 4 sec
Advantages
• High success rate
• Prolonged response
• ↓Multiple births
• ↓ OHSS
Disadvantages
• Adhesion formation
• Requires surgery
• 1/3 require ovulation
medications
• POF risk
• Less successful in
smokers 25% vs 95%

56. PATIENTS RESISTANT FOR LOS
• Increased duration of infertility (>3yr)
• Women with marked obesity,
BMI>35kg/m2
• Increased free testosterone and free
androgen index

57. Practical tips for monitoring for
ovulation induction in PCOS

58. Who Should Monitor?
Why Add to The Burden ?
Do it yourself

59. Five Reasons To Monitor
To evaluate if the dose being used is optimal
To adjust the dose of the drug as some patients
are hyper responsive and some are poor
responders.
To find the optimal time for inducing ovulation
To time IUI
To avoid excessive stimulation , to prevent OHSS
and multiple pregnancy
All patients to be monitored

60. How to Monitor ?
• BY E 2 ALONE
• BY ULTRASOUND ALONE
• BY BOTH
• BY COLOR POWER DOPPLER
• BY OTHER HORMONES
MINIMUM MONITORING

61. Monitoring
Ultrasound states the morphological
growth of the follicles
Hormones indicates the functional
activity of the follicles

62. Monitoring Should Be
• Easy
• Reliable
• Patient friendly
• Not expensive
• Can be done by self

63. Importance of D - 2 Scan
TVS is performed on day 2 of the cycle to see for
• Antral follicle count
• To rule out any cyst.( > 3 cm)
• Endometrial shedding
• Or any other pelvic pathology
We expect normal sized ovaries with very small follicles
(3—5 mm in diameter)
Follicles are of clinical importance only when their size is
10 mm
Follicular size is measured by taking mean of 2 or 3
largest perpendicular diameters of each follicle .

64. Ultrasound Follicular Monitoring
Serial USG follicular monitoring is started from
day 7 or 8 of the cycle
But in case of gonadotrophins we start scanning from 6th day of
stimulation.

65. Assessing the Follicular Maturity
• The follicles normally grow at a rate of
2- 3 mm / day in a stimulated cycle.
• Definitive size of the follicle which confirms
the maturity of oocytes is still controversial.
• A follicle measuring 18—20 mm has been
found to contain a mature oocyte.

66. Correlation with serum
oestradiol levels
• Plasma estradiol levels correlates closely
with the stage of development of the
dominant follicle
• Serum estradiol levels >200 pg / ml on day 8
of stimulation indicates adequate dose of
gonadotropins.
Ultrasound monitoring has totally
replaced estradiol monitoring in most
centers.

67. Follicular Doppler
Flow Studies
• A mature follicle shows
vascularity in atleast ¾
th of the follicular
circumference &
• PSV is 10 cm/sec.
• At this time LH surge
starts and
• This is the right time to
give hCG trigger

68. Interpretation of Ovarian Indices
• Rising PSV & steady low RI suggests follicle is close
to rupture
• Decreasing PSV & rising RI suggests follicle is likely
to become LUF.
• Fertilisation of a follicle with PSV of less than 10 cm
/sec may result in an embryo with chromosomal
abnormality.

69. Perifollicular vascularisation
Grade 1 : < 10% Grade 2 : 10-25%
Grade 3 : 25-50% Grade 4 : > 50%

70. hCG timing
ALWAYS TIME HCG WITH FOLLICLE SIZE

71. Ovulation Trigger
The end point of any ovulation induction
protocol is to indentify the best time for
triggering ovulation.
most crucial step
In a gonadotrophin In clomiphene
Leading follicle is Leading follicle is
18 – 20 mm in diameter. 20 – 22 mm in size

72. Ovulation to Be Confirmed By
• Disappearance of the follicle
• Presence of free fluid in the cul-de-sac.
• Presence of hyperechoic , smooth
secretary endometrium.

73. Timing of insemination
IUI is done 24 hrs. after LH
surge is detected
IUI is done 36 - 38 hrs. after
hCG injection

74. Serum Progesterone and
Implantation
• Periovulatory progesterone levels are used
as a predictor of outcome.
• Elevated levels of serum progesterone in the
late follicular phase is associated with
diminshed chances of conception.

75. Premature LH surge
• Premature LH surge is known to occur in
approx 25 % of patients once the leading
follicle is 16 mm.
• Urinary LH kits are available to detect LH
surge.
A blood level of >10 IU /L correlates with the LH surge

76. Premature LH surge
• If an LH surge is detected , injection hCG is
given immediately.
• The hCG injection is required to supplement
the LH secreted by the body as it is not
adequate enough to induce the final
maturational changes in all the follicles .
• IUI is done 24 hrs after the LH surge

77. Chances of Conception in
PCOD in IUI cycles
• Over 50 % of women under 40 years
will conceive within 6 cycles of IUI
• Of those who do not conceive within 6
cycles of IUI about half will do so in next
6 cycles
Cumulative pregnancy rate is
over 75 %
NICE guidelines 2013

78. Important !!!!
Clinics providing ovarian
stimulation with
gonadotrophins should have
protocols in place for
-Preventing
-Diagnosing OHSS
-Managing
NICE guidelines 2013

79. Challenges in PCOD & Infertility
OBESITY
OHSS

80. Obesity
And
Female Infertility
UPLOAD ON SLIDESHARE.NET
Ref : http://www.slideshare.net/LifecareCentre/obesity-in-female-
infertility-by-dr-sharda-jain-dr-jyoti-agarwal-dr-jyoti-bhaskar-
dr-abhishek-parihar-dr-yogesh-agarwal

81. Ovarian Hyperstimulation Syndrome(OHSS)
Practical Management
In 1500 IUI Cycles
Uploaded on slideshare.net
http://www.slideshare.net/LifecareCentre/medical-management-of-ovarian-
hyperstimulation-syndrome-ohss-in-1500-iui-cycles-practical-
tips

82. PCOS
Treatment Guidelines
&
Review of
Newer Medical Treatment in Infertility
Uploaded on slideshare.net
Ref. http://www.slideshare.net/LifecareCentre/pcos-treatment-guidelines-review-
of-newer-medical-treatment-in-infertility-dr-sharda-jain

83. Newer concepts of managing
With Myo-Inositol
Uploaded on
slideshar.net
Ref: http://www.slideshare.net/LifecareCentre/newer-concepts-of-
managing-pcod-with-myoinositol

84. Summary of
Uses of Newer Drugs

85. TAKE HOME MESSAGE
• Preconceptional counselling
• Recommended first line treatment-Clomiphene
• Metformin in CC resistant & BMI>30 kg/m2
• Second line: Gonadotropins or LOD
• LOD pregnancy occurs in about 50% cases, it
also decreases Dose of additional ovulation
drugs required
• Third line: IVF our challenges & experiences will be uploaded shortly

86. ADDRESS
11 Gagan Vihar , Near Karkari Morh
Flyover Delhi -51
CONTACT US
9650511339
011-22414049,
WEBSITE :
www.lifecarecentre.in
www.drshardajain.com
www.lifecareivf.com
E-MAIL ID
Sharda.lifecare@gmail.com
Lifecarecentre21@gmail.com
info@lifecareivf.com