Ovulation induction

1. Induction of ovulation
By
Mohamed Elmahdy

2. Induction of ovulation Super ovulation

5. DOPPLER
when PI was > 3.0. the uterine Doppler flow
indices have a high negative predictive value and
sensitivity (in the ranges of 88 to 100% and 96 to
100% respectively)
Donald School Journal of Ultrasound in Obstetrics and Gynecology,
April-June 2010

7. Hypothalamus
AP
GnRH
Hypothalamic-Pituitary-
Gonadal Axis (HPG):
Females
LH surge
Tonic LH
Progesterone
PGF2a
Estrogens
+
FSH
Estrogen
LH

8. FEMALE REPRODUCTIVE SYSTEM
• HORMONAL REGULATION OF OOGENSIS AND OVULATION
OVULATION:
sharp surge in LH
with simulataneous
increase in FSH
Meiosis I resumes;
oocyte and surrounding
cumulus break away
and are extruded
oocyte passes into
oviduct
ECTOPIC
IMPLANTATIONS

9. FSHwindow
Period of time that is crucial for
selection of single dominant follicle
from cyclically recruited cohort. After
that the dominant follicle continue
growing as its sensitivity to FSH is
increased.

10. In stimulated cycles
Increase the length of FSH window
that increase the number of
selected follicles.

14. Anovulation

15. WHO classification
• Group I: hypogonadotrophic
hypogonadism.
• Group II: predominately polycystic ovary
syndrome.
• Group III: ovarian failure.

16. WEIGHTREDUCTION
• Spontaneous pregnancy after weight
reduction even less than 5 % of the body
weight.
• Reduction of the CC or FSH dose
NICE 2013, SOGC

18. Clomiphene Citrate
• exhibits both estrogen agonist and
antagonist properties, i.e. selective
estrogen receptor modulating activity.
• Estrogenic agonist properties are
manifest only when endogenous
estrogen levels are extremely low.

19. Pharmacology
• CC is a mixture, in approximately a 3:2 ratio, of 2
geometric isomers, enclomiphene and
zuclomiphene
• Enclomiphene is the more potent isomer ,rises
rapidly after administration and fall to
undetectable concentrations soon thereafter.
• Half life : 5 days.
• The inactive Isomer present in blood for 6- 8
weeks.

20. • During CC treatment, levels of both LH and
FSH undergo a prolonged rise, compared
with a natural cycle because of the
prolonged ER depletion in the brain.
• FSH window is extended, leading to multiple
follicle growth and a higher multiple
pregnancy rate with CC than occurs in natural
cycles.

21. Mechanism of action of CC
• CC binds to estrogen receptors (ERs) throughout
the for an extended period of time, i.e.weeks
rather than hours as with natural estrogen.
• Depletes ER concentrations by interfering with the
normal process of ER replenishment.
• The antiestrogenic effect on the hypothalamus.
estrogen concentrations are falsely perceived as
low leading to increased GnRH production
• Actions at the pituitary level may also be involved.

22. x
Hypothalamus
AP
GnRH CC
LH surge
Tonic LH
Progesterone
PGF2a
Estrogens
+
FSH
Estrogen
LH
x
x
x
x
X

23. • In ovulatory women, CC treatment
increases GnRH pulse frequency .
• In anovulatory women with PCOS in
whom the GnRH pulse frequency is
already abnormally high, CC treatment
increases pulse amplitude but not
frequency

24. Contraindications
Negative progesterone challenge
test

26. HCG
• A meta-analysis of 7 studies comparing triggering
ovulation with hCG (1,461 patients) with urinary LH testing
to identify the endogenous LH surge (1,162 patients) for
timing IUI for women with unexplained infertility treated
with CC reported:
That there were lower odds of pregnancy when an hCG
trigger was used (139 of 1,461) compared with LH surge
monitoring (138 of 1,162; odds ratio [OR] 0.74; 95%
confidence interval [CI] 0.57–0.96) (80, 81).

27. Outcome of CC treatment
• induce ovulation in 60–80% of properly
selected candidates.
• cycle fecundity is approximately 15% in
women who ovulate in response to
treatment, with higher chance of pregnancy
in the first cycles .
• Amenorrheic women are more likely to
conceive than oligomenorrheic women.

28. pregnancy is most likely to occur in
the first 3 to 6 cycles, and therapy
beyond 6 cycles is generally not
recommended.

29. Routine supplementation of the luteal
phase with vaginal progesterone does not
seem to improve pregnancy rates in normo-
ovulatory women stimulated
with clomiphene citrate for IUI.
Hum Reprod. 2010 Oct;25(10):2501-6

30. CC failure
failure to conceive within six CC-induced
ovulatory cycles should be regarded as
• clear indication to expand the diagnostic
evaluation to exclude other factors .
• change the overall treatment strategy when
evaluation is already complete

31. Adverse effects
• 20% irritability and mood changes.
• 10% vasomotor symptoms.
• 6% abdominal discomfort.
• 2% breast discomfort.
• 2% nausea and vomiting.
• 1% visual symptoms.
• 1% headache.

32. Cervical mucus
Affect the quality or quantity of cervical
mucus.

33. Endometrium
• reduction in endometrial thickness in 30 % of
cases.
• Reduction in glandular density and an
increase in the number of vacuolated cells.
• Decreased uterine blood flow during the
early luteal phase and the peri implantation
stage may also explain, at least in part, the
poor outcome of CC treatment.

35. Follow up
(Good-practice points) used in the RCOG
and NICE guidelines, recommend the use
of US to monitor the ovaries during
stimulation with CC. (NICE 2013)
J Obstet Gynaecol 2011 Oct;31(7):566-71.

36. 1. Weight loss, exercise, and lifestyle modifications. (II-3A) (NICE
2013)
2. Clomiphene citrate has been proven effective in ovulation induction
for women with PCOS and should be considered the first-line therapy.
(I-A)
3. Metformin combined with clomiphene citrate may increase
ovulation rates and pregnancy rates but does not significantly
improve the live birth rate over that of clomiphene citrate alone.(I-A)

37. 4. Metformin may be added to clomiphene citrate in
women with clomiphene resistance who are older and
who have visceral obesity. (I-A)
5. Gonadotropin should be considered second-line
therapy for fertility in anovulatory women with PCOS.
The treatment requires ultrasound and laboratory
monitoring. High costs and the risk of multiple
pregnancy and ovarian hyperstimulation syndrome are
drawbacks of the treatment. (II-2A)

38. 6. For women who are taking clomifene citrate,
do not continue treatment for longer than
6 months.
7. Do not offer oral ovarian stimulation agents
(such as clomifene citrate, anastrozole or
letrozole) to women with unexplained
infertility

39. Cochrane Database Syst Rev. 2009 Oct 7;
(4):CD002249.
• clomiphene plus dexamethasone treatment was effective (OR
9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone.
• A significant improvement in the pregnancy rate was reported
for clomiphene plus combined oral contraceptives versus
clomiphene alone.

40. No improvement in pregnancy rate if
combined with
• Tamoxifen 20 mg
• Dopamine agonists
• Estradiol.

41. Tamoxifen
• Similar structure to clomiphene .
• Studies showed no difference as regards
ovulation , pregnancy, abortion or adverse
effects rates.
• 20- 40 mg daily for 5 days.

42. N acetyl cysteine
NAC as a safe and well-tolerated adjuvant to
CC for induction of ovulation can improve the
ovulation and pregnancy rates in PCOS
patients. It may also have some beneficial
impacts on endometrial thickness.
J Obstet Gynaecol Res. 2012 Sep;38(9):1182-6

43. Metformin
Anovulatory women with polycystic ovary
syndrome who have not responded to
clomifene citrate and who have a body mass
index of more than 25 should be offered
metformin combined with clomifene citrate
because this increases ovulation and pregnancy
rates. ( A )

44. Aromatase activity
• conversion of androstenedione and testosterone
to estrone and estradiol, respectively.
• ovaries, brain, adipose tissue, muscle, liver,
breast tissue, and malignant breast tumors.
• The main sources of circulating estrogens are
the ovaries in premenopausal women and
adipose tissue in postmenopausal women

46. Pharmacology
• AIs are completely absorbed after oral
administration with mean terminal half-life
of approximately 45 h with clearance mainly
by the liver.
• Mild gastrointestinal disturbances account
for most of the adverse events.

47. Indications forAIs in induction of ovulation.
• AI when used alone results in the
development of one or two mature follicles
and a significantly reduced risk for OHSS and
multiple gestation.
• To achieve multiple ovulation, the addition
of FSH to the AI is likely necessary. (augmet
FSH response due to increase intrafollicular
androgens)

49. CC (d 5).
Casper R F , and Mitwally M F M JCEM 2006;91:760-771
©2006 by Endocrine Society

50. On endometrium
Decreasing E2 levels lead to up-regulation of
ERs in the endometrium, leading to rapid
endometrial growth once estrogen secretion is
restored.

51. AIS Induction of ovulation after CC failure.
• failed ovulation induction or ovulation with a
very thin midcycle endometrium (≤0.5 cm)
• 75% ovulation
• 25% cumulative pregnancy rate after 3 cycles.

52. Optimal dose of AIs
• 5-d course of treatment is between 2.5 and
5.0 mg.
• Higher doses resulting in persistence of
aromatase inhibition and estrogen levels too
low for normal endometrial development by
the time of ovulation.
• If combined with FSH give sequential not
overlapping protocol.

53. Adverse effects
• Fewer than CC .
• Hot flashes .

54. Pregnancy outcome
Less incidence of multiple pregnancy.
Less miscarriage rate .
Congenital anomaly?????

55. In 2005, however, Health Canada and the
manufacturing company of letrozole issued a “Physician
Warning Letter” on the off-label use of letrozole for
fertility and the possibility of embryotoxicity,
fetotoxicity, and teratogenicity found in rats.
Health Canada Endorsed Important Safety Information on
Femara (letrozole). Published November 17, 2005.

56. • Tulandi et al. retrospectively evaluated 911
newborns from letrozole and CC pregnancies.
They found a 2.4% incidence of congenital
malformations and chromosomal
abnormalities in the letrozole group versus
4.8% in the CC group.
Fertil Steril 2006;85:1761–5.

57. Letrozole vs CC
From the available data there is no convincing
evidence that letrozole is superior to
clomiphene citrate and therefore the cost
should be taken into account when using anti-
oestrogens.
Cochrane 2011

58. GONADOTROPHINS

59. Fixed dose regimen
In the fixed dose regimen, the gonadotropin
dose is kept constant throughout the
stimulation. If the optimal staring dose has
been determined, this protocol is simple to
follow and results in good outcomes.

60. Step up
• Start with 150 IU for 7 days
• Increase by 75 IU if no response every 6 days
• Till response occur continue till the criteria of
HCG

61. 150 IU
225 IU
Day 3
6 days US 6 days or HCG

62. Low dose step up
• start with one 75 IU of HMG from day 3 for 6
days.
• The HMG dose was increased by half an ampoule
(37.5 IU) every 6 days until the leading follicle
reached 10 mm in diameter.
• Thus the same dose (i.e. the threshold dose) was
maintained until the criteria for triggering
ovulanon (at least one follicle >18 mm in
diameter) were achieved.

63. RB&E, 2014

64. Step down
High starting dose of gonadotropins (300-450
IU) is used for the first 2 days, followed by a
dose reduction (150-225 IU/day).

65. Urinary orrecombinant
• Whether or not urinary gonadotrophins
should be used as first choice compared with
recombinant products is more a discussion
of purity, trace ability and costs. There is no
convincing evidence of a significant difference in
the probability of conception.
Cochrane 2011

66. Sequential CC Gonadotrophins

67. Sequential CC/gonadotropin therapy
• Standard CC treatment regimen, followed by
low-dose (hMG) or (FSH) (75–150 IU/day for
3 days).
• Treatment is individualized thereafter in the
same way as with traditional gonadotropin
therapy, on the basis of transvaginal
ultrasound examinations .

69. • The sequential CC/hMG regimen is as
effective as hMG regimen for ovulation
induction, produces satisfactory pregnancy
results and reduces the treatment cost.
Arch Gynecol Obstet. 2013 Mar;287(3):591-7.

70. Cycle fecundity
Similar to that achieved by treatment
with gonadotropins alone .

71. Advantages
• Reduction in the dose of Gonadotropin .
• Reduction in the associated costs of
monitoring.
• Clomiphene citrate–resistant anovulatory
women often are very sensitive to low doses
of gonadotropins.

72. The number of oocytes retrieved being higher
in letrozole group might indicate that letrozole might
contribute to successful ovarian stimulation with a
lower dosage of gonadotropins. Despite the lower
peak estradiol levels, pregnancy rates being similar to
other group also support the idea that letrozole can
contribute to normal potential of implantation.

73. Glob J Health Sci. 2015 Sep 1;8(4):45762

74. Conclusions

75. 7days
75 IU 150 IU
37.5-75 IU
7 days