Unexplained infertility: oral fertility drugs

1. Unexplained
infertility:
oral fertility drugs
Aboubakr Elnashar
Benha University Hospital
Aboubakr Elnashar

2. CONTENTS
I. DEFINITION
II. TREATMENT
III. ORAL FERTILITY DRUGS ALONE
IV. ORAL FERTILITY DRUGS WITH IUI
V. RECOMMENDATION
 CONCLUSION
5Aboubakr Elnashar

3. I. DEFINITION
Inability to conceive
after one year
with routine (standard, basic) investigations of
infertility showing no abnormality.
(RCOG guidelines,1998; Randolph,2000)
Aboubakr Elnashar

4. ESHRE (2000)
Tests that have an established association with
pregnancy:
Conventional semen analysis
Tubal patency tests
Mid luteal P
Aboubakr Elnashar

5. II. TREATMENT
 By definition: empiric
{does not address a specific defect or functional
impairment }
(Soules,2000 , Balen,2003; ASRM, 2006)
 AIM:
To increase the monthly PR above the natural rate of
1.5-3%
 How?:
1. improve gamete quality
2. increase gamete number
3. facilitate gamete interaction.
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6.  Dependent on:
 Availability of resources
 Patients’ age
 Duration of infertility.
 The standard protocol is to:
 Progress from simple to complex
 Balance the effectiveness against the cost
and side effects.
(Ray et al,2012)

7. The Fast Track Treatment
3 cycles of (CC/IUI)
IVF
Standard Treatment
3 cycles of CC/IUI
3 cycles of FSH/IUI
IVF
RCT: FSH/IUI tt was of no added value.
(Reindollar et al, 2010)
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8. Overtreatment in couples with UI.
(Kersten et al, 2015)
Netherlands
Fertility tt started too early, in couples with UI who
were eligible for tailored Expectant Management
36%
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9.  STRATEGY
1. ≤35
≤2y: Expectant for 2y
≥2Y: Active
2. 35-39
≥ 1 y: Active
3. ≥40 y:
Active
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10. Prediction of success of superovulation-IUI
1. D3 FSH: 10-15 mIU/mL and E2≥40 pg/mL:
: low chance of pregnancy
(Kasser et al, 2014)
2. Endometrial thickness
11.60 mm: low chance of pregnancy.
5.5-8.25 mm and triple line: high chance of
pregnancy in UI induced with CC.
(Shahin, 2008)
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11.  Lines
I. Expectant management (EM)
II. Antioxidants
II. Tubal flushing or perturbation
III. Ovulation-inducing agents
1. CC:
2. Aromatase inhibitors (AI)
3. Gonadotropins
IV. IUI
V. Fallopian tube sperm perfusion
VI. ICSI
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12. III. ORAL FERTILITY DRUGS ALONE
1. CC
Enhances fertility by:
1.Correcting subtle defect in ovarian function-either
follicular development or LPD
2. Increasing the number of follicles that develop &
consequently oocyte that are released
(Balen,2003).
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13. Results:
 No better (and even inferior) LBR than EM (14% vs
17%).
(Bhattacharya et al., 2008)
Number of cycles needed under CC for one additional
pregnancy was 40 compared with placebo
(ASRM, 2006).
No evidence that CC was more effective than no tt or
placebo
(SR by Hughes et al.;2010, Cochrane SR)
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14. Nacetyl cysteine
1,200 mg/d orally for 5d starting on D2
ineffective in inducing or augmenting ovulation in UI
and cannot be recommended as an adjuvant to CC
(Badawy et al, 2006)
Vit E
improve the endometrial response in UI
{antioxidant
anticoagulant effects
modulate antiestrogenic effect of CC and the
problem of a thin endometrium}
(Cicek et al, 2012)
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15. 2. Aromatase inhibitors (AI)
 Mechanism
Release of the estrogen negative feedback, increase
GnTR, stimulate ovarian follicle development
(Casper and Mitwally, 2006).
2. Increase sensitivity of follicles to FSH. increasing
follicle recruitment in UI (Mitwally & Casper,2000)
 Advantages over CC:
{short half life: 45h)
absence of ER depletion
No effect on the endometrial thickness or cervical
mucous Aboubakr Elnashar

16.  Dose:
 2.5 mg/d from day 3-7
 No advantage of increasing dose over 2.5 mg
(Badawy et al, 2007)
5 mg/d: CC Failure
better follicular phase parameters, endometrial
development, serum E2 and LH levels in UI
(Samani et al, 2009)
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17. Let Vs CC
Comparable effectiveness
(Bayar et al, 2006; Badawy et al., 2009; Polyzos et al. ,2008. MA)
Comparable impact on uterine blood flow and PR
(sakhavar et al, 2014)
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18. CPR: significantly higher (23.07 Vs 10.68%).
{statistically significant increase in endometrial
receptivity as assessed by endometrial thickness and Doppler
flow indices of uterine and subendometrial vessels}.
(Ibrahim et al, 2012)
Statistically significant higher CPR
(Liu et al, 2014, SR and MA)
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19. Let Vs GNT
No statistically significant difference in CPR/ cycle:
18.4 vs15.7%.
Less cost
 No injections: simple and convenient
(Baysoy et al, 2006)
PR/cycle: 8.9% vs14% in GnT/IUI.
(Gregorio et al, 2007)
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20. IV. ORAL FERTILITY DRUGS WITH IUI
Mechanism
increasing the density of the motile spermatozoa
available to these eggs: increase the monthly
probability of pregnancy.
1. CC/IUI
 5–7% PR/cycle even after 7 cycles
( ESHRE, 2009)
Not proved to be effective
(Hughes et al, 2010)
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21. CC/IUI Vs rFSH/IUI
Inferior.
(Berker et al, 2011)
Adding vaginal E to CC
: significant increase in ET.
not reflected in the pregnancy.
(Cetinkaya K , Kadanalı S , 2012)
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22. Luteal phase support
Progesterone supplementation in CC/UI
intravaginal micronized progesterone 100 mg twice
daily beginning 3 days after CC/UI:
improved CPR
{improve endometrial receptivity}
(Elguro et al, 2014)
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23. 2. LET/IUI
Can replace CC
(Sammour,2001).
Extended let regimen
(2.5 mg/d from D1 to 9) Vs CC (100 mg/d from D3
to 7)/IUI
superior efficacy
(Fouda UM , Sayed AM., 2011)
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24. V. RECOMMENDATIONS
NICE, 2013
 Do not offer oral ovarian stimulation agents (CC, or
anastrozole or letrozole).
{No increase the chances of CPR or LBR}
 Offer IVF after 2 years
 IUI (with or without stimulation) should not be
routinely offered for couple with UI
 Exceptions: when people have social, cultural or
religious objections to IVF

25. Limitations of systematic review.
1. Correct question was not raised
2. Objective was monofollicular not multi follicular
development
3. Patients with more than two follicles were cancelled
4. Sample size was inadequate
5. Fixed dose of oral fertility drugs was used
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26. Canadian UI Study group [Fisch et al, 1989].
CC Vs placebo for 4 cycles:
CC group: CPR 19%
Control group: No pregnancy
[Deaton et al.,1990]
CC/IUI Vs TI:
1 follicle: CPR: 6.4%
2 or more follicles: CPR: 14.5%
No multiple pregnancy
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27. Oral ovulation induction drugs can be of value in
the tt of UI if employed properly.
1. Goal of tt: multiple ovulation
2. tt should be monitored via US
 to insure more than one large follicle has
developed
 endometrium should be evaluated to determine if
supplemental estradiol is needed
3. if the tt goal is not met: increase the dosage of
medication in the next cycle
Aboubakr Elnashar

28. CONCLUSION
Oral ovulation induction drugs
 First-line therapy of UI
Simple
inexpensive
Even in the absence of IUI, are of value in tt of UI
(Olive 2014).
Aboubakr Elnashar

29. Thank you
Aboubakr Elnashar