This document discusses trends in ovulation induction in patients with polycystic ovary syndrome (PCOS). It covers the hormonal mechanisms of normal ovulation and pathophysiology of PCOS. Treatment options discussed include lifestyle modification, oral ovulation induction drugs like clomiphene citrate and letrozole, insulin sensitizers, injectable gonadotropins, and ovarian drilling. The risks, benefits, and effectiveness of each approach is evaluated to determine the optimal individualized treatment strategy based on a patient's characteristics and treatment goals.

1. Greetings
from
Port City
Chittagong

2. Prof. Rokeya Begum
DIRECTOR
Surgiscope Fertility Centre
Laparoscopic & Hysteroscopic Surgeon

3. Trends of ovulation
induction in PCOS

4. The release of mature fertilizable
egg from the dominant follicle is
known as ovulation.

5. This need wonderful integrated
and synchronized succession of
hormonal action and
morphological changes involving
hypothalamus, pituitary and
ovaries.

6. Hypothalamus
AP
GnRH
Hypothalamic-
Pituitary- Gonadal
Axis (HPG): Females
TonicLH
LHsurge
Progesterone
PGF2a
Estrogens
+
FSH
Estrogen
LH

7. Major players
*GnRh
* FSH
* LH
* Oestrogen and progesterone
* Fine tuning by other factors.

8. Ovary produce vast number of
hormones and most dynamic
changing organ in female.

9. Women started life with
millions of primordial follicle
only about 400 will actually
achieve ovulation.

10. The majority of follicle never
develop beyond preantral
stage. Travelling to artesia.

11. The early stage of follicle development
in the human are independent of
gonadotrophins.
They an under control of locally acting
intra-ovarian paracrine regulators .

12. * AMH
* Growth differentiation factor
(GDF)
* Bone marrow phogenatic proteins
(BMPS)

14. Once a developing follicle reaches
the prenatal stage of development
further progression to the antral and
pre ovulary stages appears to be
absolutely dependent on the
presence of gonadotrophins.

15. Various stages of follicular development
Primordial follicle (oocyte with single
layer granulosa cell)
Primary
(Increase layer of granulosa cell)
Secondary
Antral stage (Containing follicular fluid)
Pre ovulatory follicles

16. AMH
(FSH)
E2

17. Hypothalamus secretes GnRh in
Pulsatile fashion, in follicular phase
60-90min.
Immediately proceeding the pre
ovulatory phase enormous release of
GnRh.
After ovulation frequence of pulses
gradually decreases from one in every
2-4 hrs in early luteal phase to 8-12 hrs
toward the end of the cycle.

18. With sudden demise of corpus luteum
which immediately precedes
menstruation.
The negative feedback effects of
oestradiol, progesterone and inhibin A
on FSH secretion are suddenly lost.
FSH is secreted in large quantity during
menstruation itself.

19.  Growth of antral follicle
 Granulose cell proliferation and differentiation.
 Encourage the action of enzyme aromataze in
the conversion of androstendine andandrogen
to oestrogen.
 Inhibin synthesis
 LH receptor express by FSH on grnulosa cell
>10mm follicle.
The rise in FSH
concentration leads to-

20. Mid follicular oestradiol causes rapid
suppression of FSH production by
negative feedback effect this decrease
level of FSH withdraws gonadotrophin
drive from the remainder of the growth
follicle.

21. The result is progression of
follicles to atresia but
dominant follicle leading to
ovulation.

22. The rising concentration of
FSH exceeds the threshold and
opens a window that allows
one follicle to continue grow
and develop dominant follicle.

23. Suppression of FSH close the
window prevent growth of
multiple follicle. Remainder
become atretic.

24. Only largest follicle stay above the
threshold because this has large number
of FSH receptor. It is than less affect by
declining FSH concentration and grow.
Other atretic due to lack of enough FSH
stimulation.

25. At the beginning of each cycle a group of most mature follicle 2-5mm
diameter are recruited for further growth.
These are sensitive to FSH – produce more oestrogen.
FSH level falls in response to high oestrogen.
Only few follicle or single follicle have most oestrogen and LH receptor(
Dominant)
Rest atretic
In summary

27. During the early and mid follicular phase the secretion of
LH is relatively quiet.
LH encourrage the production of androgen from theca
cells. This androgen “Passed On”.
Granulosa cell – androgen converted to oestrogen by
aromatage enzyme (CYP-19) under the influence of FSH.
LH

29. 1. Resumption of oocyte meiotic
maturation.
2. Disruption of cumulus – ocyte
complex
3.Luteinisation of granulosa cell.
4. Inhibits granulosa cell mitosis.
Pre ovulatory LH surge has number function
End result
Rupture of follicle
after 36hrs of surge

30. • Inhibin
• Activin
• Follistatin
• Growth Factor
• AMH
Other factors

31. AMH
Granulosa cell of preantral and small antral
follicle – AMH
Inhibitory effects on action of FSH
and aromatase in promoting
growth of preantral and small
antral follicles.

32. History

33. Controversies

34. Polycystic Ovary Syndrome

37. Four main disturbance
1. Hyper secretion of LH by pituitary
due to exaggerated pulses of GnRh.
Stimulates androgen production.
GnRh is preferential to LH rather than
FSH.

38. PCOS Etiology

39. 2. Hyper secretion of androgen by stromal theca cells –
follicular growth inhibited – excess immature follicles.
Hyperfunction of androgen forming enzyme (P450 C17).
Defective aromatization of androgen to oestrogen.

40. 3. Hyper insulinaemia – stimulates androgen
from theca cells and decrease production of
SHBG causing free androgen. Post receptor
defect affeting glucose transpart.
Hyper prolactinaemia – 20%

42. Effects of Hyperinsulinemia

43. 4. Abnormal ovarian morphology
- 6-8 times larger.
preantral and small antral follicle.
-  AMH
• - Arrest in growth at a size of 2-9mm.
• -Slow rate of atresia
• -Sensitive to exogenous. FSH stimulation.
• -Total ovarian volume >10ml

44. ANOVULATION

45. 1. High level of LH – more production of androgen.
2. Defective FSH induced aromatization of androgen
to oestrogen.
3. Follicular microenviroment is more androgenic
than oestrogen.
4. Huge number of atretic follicle that contribute to
increased ovarian stroma (Hyperthecosis)
5. No LH surge.
Why anovulation

46. What we really want to know in
ovulation induction
How to define the right individual treatment
for the right patient to:
• Increase pregnancy rate
• Reduce side effects
• Reduce physical,psychological and
financial burden
• Prevent poor response and OHSS

47. Central obesity and body mass index is major
determinant
hyperinsulinaemia , hyper androgenaemia.
* BMI > 30kg/m2
* BMI measuring APP

48. Anovulation
High miscarraiage
GDM
Obstetric problem

49. Loss of 5-10% of body weight
restore reproductive function
55-100% within 6 months of
weight reduction.

50. Don’t start ovulation inducing agent
in anovulatory obese women
except after weight reduction

51. Diet and exercise – Dedicated team
Bariatic surgery
BMI > 35kg/m2
Pregnancy after one year of surgery
- monitoring foetal growth during pregnancy.
Weight loss

52. Anti Oestrogen
-Clomiphene
-Letrozole

53. The competitive binding of CC to estrogen receptors
in the hypothalamus stimulates release GnRH
Gonadotropin release from the anterior pituitary
Leading to follicular development , increased
estradion production
Ovulation
CLOMIPHENE CITRATE

54. Dose - 50-250mg/day for 5 days.
Start – 2-5 day of spontaneous or
induced menstruation
Staring with lower dose and increase the
dose in increments of 50mg/day/cycle
until ovulatory cycle is achieved.

55. There is no apparent advantage of using a daily
dose of more than 150mg/day of clomiphene
citrate

56. The advantage of the cutting corner
regimen of starting with a 100mg/daily
dose rather than 50mg/day is that it will
cut down the number of superfluous
cycle of treatment until ovulation is
achieved and until those resistant to
clomiphene are identified.

57. Result
1. Ovulation in 80%
2. Pregnancy 35-40%
3. CC resistant – 20-25%
4. Multiple pregnancy 8-10%
5. Congenital abnormality and spontaneous abortion –
same as spontaneous
7. No full blown OHSS
75% pregnancy within-
First three cycle of treatment.

58. Discrepancy between ovulation and
pregnancy
* Anti oestrogenic action in peripheral tissue
cervical mucus is hostile for sperm
overcome by IUI.
* Supression of endometrium – Thin
endometrium.
* High LH

59. Pregnancy rate higher
48% - Monitoring group
30% - Non Monitoring group
Endometrial thickness And Vascularity Follicular diameter and Vascularity
Monitoring of ovulation by USG

60. Follicles ready to mature….
• Triple line Endo > 7mm,follicle >17mm
• Perifollicular and Subendometrial Hallo…oedema
• Cumulus Presence ..30-40%
• Follicular volume ..0.6 to 1.5ml
• Flow indics ..PSV:>10,RI: <0.5
• Perifollicular Vascularity..3/4th
• Sub Endo vascularity minimum 5 spiral vessels
reaching to zone 4,ant & post,RI < 0.6
• Endo peristalsis 3 to 5/min
• Uterine A.. On dominant side PI:<3.2

61. Reasons for Clomiphene Failure
Failure to Ovulate
-FAI
-BMI
-LH
-Insulin
Ovulation but no
conception
-Anti estrogen effects
.Cervical mucus
.Endometrium
-High LH

63. Clomiphene Citrate
Stopping …
• No ovulation with 150 mg/day
• 6 ovulatory cycles fail to yield
a pregnancy
• Endometrial thickness <7 mm
at ovulation

64. To increase the pregnancy rate adjuvant
can be use
1. Triggering of ovulation with HCG.
2. Intrauterine insemination when leading
follicle > 19mm.
3. Pretreatment with OCP or progesterone
to reduce the level of LH.

65. 4. Metformin or other insulin lower
agent.
5. Dexamethason 0.5mg/day along with
clomiphene- DHEA-S level greater than
2.0mcg/ml
Half life of CC – 7 days

66. Adverse effects
• 20%irritability and mood changes.
• 10%vasomotor symptoms.
• 6%abdominaldiscomfort.
• 2%breastdiscomfort.
• 2%nauseaandvomiting.
• 1%visualsymptoms.
• 1%headache.

68. Aromatase inhibitors
• The aromatase inhibitors letrozole and anastrazole are emerging as oral
alternatives to CC although they are not FDA-labeled for ovulation
induction or COS.
• Aromatase is an enzyme that converts androstenedione to estrone and
testosterone to estradiol.
Reduce systemic
estrogen levels in
the ovary
Increased
gonadotropin
secretion
Follicular
development
ovulation
Dose – 2.5-5mg /day
Free from side effect

69. No receptor action
No effect on endometrium and cervix
Half life – 2 days

70. Result
Pregnancy rate higher
27.5% in AI
19.5% - CC
Multiple pregnancy
7.4% in AI
3.2% - CC
No difference in congenital
malformation.

71. LETROZOLE can be regarded as a
possible replacement of clomiphene for
first line treatment of anovulatory
infertility like PCOS.

72. *Short half life
*Implantation rates improve with the reduction of
supra – physiologic level of estrogen, which is believed
to have deleterious effects on the endometrium.
*Reduction of estrogen levels during induction
cycles may prevent a premature surge of LH.
* High level of aromatase P450 in endometrium
suppressed causes good implantation

73. Insulin lowering agents
Insulin resistance (IR)
- 80% of women with PCOS and central obesity.
- 30-40% of lean women with PCOS

74. Features of IR
 BMI > 25kg / m2
 acanthosis migricans
 waist to hip ratio > 0.85

75. Metformin
Dose – 1500-2500mg / day
- 15-20% - suffer from gastro intestinal side effect
- Avoid or lessened by gradual starting dose.

76. Inositol stereoisomers
- Single or incombination
- Combination : M : D / 40 : 1
* Myoinositol
* D-chiroinositol

77. Insulin sensitizers should not be used
as first line agents for induction of
ovulation in women with PCOS,

78. 1. Metformin plus clomiphene citrate could be considered an
effective option in patient with CCR-PCOS. It is more applicable
when there is limited access to gonadotrophins.
2. CCR-PCOS – undergoing ovulation induction with
gonadotrophin addition of metformin reduce the chance of OHSS
and multiple birth.
Other use of metformin

79. 3. No evidence exists of increased risk of major anomalies in
women with PCOS undergoing metformin treatment during the
first trimester.
4. In patient with PCOS undergoing ART metformin co-treatment
reduce OHSS risk and increase pregnancy rate.

80. Failure with or Resistance
to Oral OI drugs

81. Injectable
gonadotropin
provides direct action
for ovarian
stimulation to
produce multiple
follicle.
Anti oestrogen – Provokes an
endogenous gonadotrophin
(FSH) to induce ovulation.
Gonadotrophin

83. Urinary – HMG (FSH : LH)
Recombinant - r FSH (only FSH)
No clear clinical superiority has been
demonstrated between urinary and
recombinant products
Preparation

84. Low dose step up
Gonadotrophin therapy is virtually the only
correct way to utilize gonadotrophin for
anovulatory patient with PCOS.

85. Complications
OHSS Multiple pregnancy

86. Criteria for hyper responder
1. Age < 30yrs
2. PCOS
3.Lean body habitus
4. Previous histroy of high response
5. AMH 
6 Antral follicle >12

87. Stein and levanthal

Bilateral wedge resection of ovaries in 1935

Active ovarian tissue can be decrease
Laparoscopic ovarian drilling

88. Abandoned
* Inducing pelvic adhesion
* Advantage of medical means of
ovulation induction

89. Wedge resection is predecessor
of laparoscopic ovarian drilling

90. By laparoscopic –
active ovarian tissue is
reduced by diathermy or
laser both have similar
result.

91. Flushing of the ovaries with normal
saline prevents over heating and
many use an antiadhesion
preparation.

92. Decrease the AMH and LH
- This procedure is viable alternative
to gonadotrophin.
- This is viable “one off” procedure.

93. PCOS Fertility Options : Surgery

94. PCOS Fertility Options :ART

95. Treating PCOS anovulatory infertility
Intervention Cost Risk of multiples
Lifestyle/Weight loss Low No increase
Clomid/Letrazole Low Modest increase
FSH injections High Marked increase (20-30
%)
Ovarian surgery High No increase but limited
efficacy
In vitro fertilization High Marked increase but
modifiable by limiting the
number of embryos
transferred.

96. Conversations are pleasant,
Discussions are interesting,
Debates are productive….

97. Pray for her departed soul
Late Prof. Syeda Nurjahan Bhuiyan

98. Thank you all
for Active
participation