‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
Induction of
Ovulation
Hesham Al-Inany, M.D, PhD
(Amsterdam)
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
Ovulation
• Day 14?
Basic fertility work up
referral gyn
History
Physical examination
Ovulation evaluation Semen analysis
Tubal
patency:
CAT
H...
How to estimate ?
•Chance to conceive naturally (home
conception) (treatment independent
pregnancy)
http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
Clinical consequences
•Couples with prognosis <30% = IVF
•Couples with prognosis > 40% =
expectant management
•Couples wit...
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
Evaluation of
Ovulation
Diagnostic studies to confirm
Ovulation
•Basal body
temperature
 Inexpensive
 Accurate
•Endometrial biopsy
 Expensive
...
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
Anovulation
OVULATION DISORDERS
WHO Classification
• Group 1 (10%) Hypothalamic pituitary failure
low gonadotrophins - low oestrogen
•...
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
Ovulation Induction
•Monofollicular development
•Multifollicular development
Clomiphene Citrate
• Dose:
• 50-100 mg./day.
• starting day 2,3,4 or 5 for 5 days.
• Monitoring:
• ultrasound
• BBT, LH ki...
hCG vs. LH monitoring
•If normoovulatory (e.g male factor),
LH monitoring is preferred
•If ovulatory dysfunction: hCG is
p...
Anovulatory cycles
•Clomiphene citrate (all doses) was
associated with an increased
pregnancy rate per treatment cycle
• M...
CC Resistant
• If still anovulatory after 6
months of continuous use the case is
considered “clomiphene resistant”
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•Gn for O.I
•No...
Tamoxifen Citrate
• Nolvadex 10 mg
•May be used alone or
• In combination with CC to act in
synergy for better response or...
Meta-analysis
•Clomiphene citrate and tamoxifen are
equally effective in inducing ovulation.
•There does not appear to be ...
The Aromatase Inhibitors
• Letrozole (Fimara 2.5 mg)
•effective in anovulatory infertility.
•It has the following advantag...
Effect of letrozole on ovulation rate per cycle in PCOS (Requena
et al , 2008)
Metformin
•The addition of metformin in the CC-
resistant patient is highly effective in
achieving ovulation induction.
Me...
Prolactin Reducing
Medications
- For Hyperprolactinaemia associated infertility.
Causes:
• Pituitary adenoma (prolactinoma...
CC resistance : what to do ?
Clomiphene Citrate
hMG or FSH
______________________________________________
• Pregnancies and live births are achieved more effectively
and faster after OI with low-dose FSH than with CC.
• This res...
CC FSH P-value
Number of patients randomized 143 159
Number of patients per
protocol 123 132
Cycles 310 288
Clinical pregn...
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
PCOS
hMG or FSH ???
Gn ?
hMG or FSH
______________________________________________
Role of LH
 The results of ovulation induction with hMG or FSH-only
regimens did not differ in studies conducted in patie...
HMG versus Rec FSH in PCOS
Undergoing IVF
Ovarian stimulation with hMG and rFSH provides similar clinical pregnancy
rates ...
Role of LH
Role of LH
Role of LH
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O...
Standard Protocol
May fit PCOS patients
Step-Down Protocol
Step-Up Protocol
Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•Gn for O.I
•No...
Reversed hMG/CC
Protocol
•Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY
Double Benefits
•The use of hMG at start of cycle for few
days will avoid CC resistant cases
•CC will continue the growth ...
New concept has to be tested
Study
•Setting: Kasr Al-Aini hospital.
•Registered : (ACTRN12607000568415)
Sample size calculation
•if premature LH surge rate among the hMG only
group is 20%.
•Assuming CC is effective by reducing...
Drop out cases
•In order to compensate for discontinuations, we
recruited 115 women in each arm
•Each couple were included...
Randomisation
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Contro...
Outcome Parameters
Primary outcome parameters
Clinical pregnancy rate per women randomised
( i.e. fetal heart pulsations...
Treatment assignment
•Couples assigned to the intervention
group received hMG/CC protocol while
couples assigned to the co...
Novel protocol
75 IU/HMG
CD3 CD7
150 mg CC
hC
G
IUI
DF ≥ 18
mm
34-36h
Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18
mm
CD7
34-36h
Both groups
•Folliculometry
•hCG when follicle reach 18mm or more
•Serum LH on day of hCG
•IUI 34-36hs later
•Micronised p...
Assessed for eligibility (n= 245)
Excluded (n= 15)
Not meeting inclusion criteria
(n=7)
Refused to participate (n=5)
Socia...
Results
Variable Group I
(n=115)
Group II
(n=115)
P value
Age (years) 27.3 ± 4.7 28.4 ± 2.7 NS
Duration of infertility (ye...
Results (cont.)
Variable Group I
(n=110)
Group II
(n=107)
P value
Number of cancelled cycles
Inadequate response
Hyper res...
Results (cont.)
Variable HMG/CC
(n=110)
HMG
(n=107)
P value
LH on day of hCG (miu/ml) for cases with
no premature LH surge...
For whom
•This protocol is especially suitable for
young women, for those with
unexplained infertility or mild male factor...
Conclusion
•This is a novel protocol for O.I in IUI
•The protocol is simple, safe and appears to
be very cost effective.
Take Home message
•Low dose Gn is the main stay in
ovulation induction to achieve the best
results
Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com
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ovulation induction protocols update 2014

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there is a change in attitude for monofollicular ovulation induction to treat infertility: previously clomiphene citrate was the standard drug to start with : Now it is different

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ovulation induction protocols update 2014

  1. 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  2. 2. Induction of Ovulation Hesham Al-Inany, M.D, PhD (Amsterdam)
  3. 3. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  4. 4. Ovulation • Day 14?
  5. 5. Basic fertility work up referral gyn History Physical examination Ovulation evaluation Semen analysis Tubal patency: CAT HSG DLS
  6. 6. How to estimate ? •Chance to conceive naturally (home conception) (treatment independent pregnancy)
  7. 7. http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
  8. 8. Clinical consequences •Couples with prognosis <30% = IVF •Couples with prognosis > 40% = expectant management •Couples with prognosis 30-40% = IUI
  9. 9. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  10. 10. Evaluation of Ovulation
  11. 11. Diagnostic studies to confirm Ovulation •Basal body temperature  Inexpensive  Accurate •Endometrial biopsy  Expensive  Static information •Serum progesterone  After ovulation rises  Can be measured •Urinary ovulation- detection kits  Measures changes in urinary LH  Predicts ovulation but does not confirm it
  12. 12. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  13. 13. Anovulation
  14. 14. OVULATION DISORDERS WHO Classification • Group 1 (10%) Hypothalamic pituitary failure low gonadotrophins - low oestrogen • Group 2 (85%) polycystic ovaries two of the following three criteria -presence of at least 10 follicles measuring 2–9 mm in diameter and/or -clinical and/or biochemical hyperandrogenism -oligo- and/or anovulation • Group 3 (5%) Ovarian failure high gonadotrophins - low oestrogen
  15. 15. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  16. 16. Ovulation Induction •Monofollicular development •Multifollicular development
  17. 17. Clomiphene Citrate • Dose: • 50-100 mg./day. • starting day 2,3,4 or 5 for 5 days. • Monitoring: • ultrasound • BBT, LH kits • day 21 progesterone.
  18. 18. hCG vs. LH monitoring •If normoovulatory (e.g male factor), LH monitoring is preferred •If ovulatory dysfunction: hCG is preferred Meta-analysis by Kosmos et al, 2007
  19. 19. Anovulatory cycles •Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle • Meta-analysis by Hughes et al, 2011
  20. 20. CC Resistant • If still anovulatory after 6 months of continuous use the case is considered “clomiphene resistant”
  21. 21. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •Gn for O.I •Novel protocol
  22. 22. Tamoxifen Citrate • Nolvadex 10 mg •May be used alone or • In combination with CC to act in synergy for better response or in cases resistant to CC alone.
  23. 23. Meta-analysis •Clomiphene citrate and tamoxifen are equally effective in inducing ovulation. •There does not appear to be a significant benefit of one medication over the other Meta-analysis by Stiener et al, 2005
  24. 24. The Aromatase Inhibitors • Letrozole (Fimara 2.5 mg) •effective in anovulatory infertility. •It has the following advantages: • 1- It reduce E2 level. • 2- It avoids the unfavorable effects on the endometrium frequently seen with CC
  25. 25. Effect of letrozole on ovulation rate per cycle in PCOS (Requena et al , 2008)
  26. 26. Metformin •The addition of metformin in the CC- resistant patient is highly effective in achieving ovulation induction. Meta-analysis by Siebert et al, 2013
  27. 27. Prolactin Reducing Medications - For Hyperprolactinaemia associated infertility. Causes: • Pituitary adenoma (prolactinoma). • Hyperactive lactotrophs. • Medications: tranquilizers, hallucinogens, painkillers, alcohol,.. • Diseases of the kidney or thyroid gland. Dopamine agonist: - Bromocriptine. - Quinagolide. - Cabergoline
  28. 28. CC resistance : what to do ? Clomiphene Citrate hMG or FSH ______________________________________________
  29. 29. • Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. • This result has to be balanced by convenience and cost in favour of CC. • FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients. Homburg et al, 2012 CC or low-dose FSH for the first-line treatment of infertile women with PCOS: a randomized multinational study
  30. 30. CC FSH P-value Number of patients randomized 143 159 Number of patients per protocol 123 132 Cycles 310 288 Clinical pregnancies (per patient) 54 (44%) 76 (58%) 0.03 Ongoing pregnancies (per patient) 48 (39%) 68 (52%) 0.04 Clinical pregnancies (per cycle) 54 (17.4%) 76 (26.4%) 0.008 Ectopic pregnancies 1 1 Miscarriage rate per pregnancya 5 (9.2%) 7 (9.2%) Multiple pregnancies (twins only) 0 2 (3.4%) Cumulative pregnancy rate Cycle 1 12.9% 25.6% Cycle 2 29.3% 44.8% Cycle 3 41.2% 52.1% 0.02
  31. 31. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  32. 32. PCOS hMG or FSH ???
  33. 33. Gn ? hMG or FSH ______________________________________________
  34. 34. Role of LH  The results of ovulation induction with hMG or FSH-only regimens did not differ in studies conducted in patients with polycystic ovary syndrome.  hMG was clearly superior to purified FSH for the treatment of hypogonadotropic hypogonadism.  hMG was superior to FSH in women above 37 yrs old  Miscarriage rates were not affected by the use of hMG.  Thus, low but detectable LH concentrations positively influence the outcome of ovulation induction in patients with ovulatory disorders and women undergoing assisted reproductive techniques.
  35. 35. HMG versus Rec FSH in PCOS Undergoing IVF Ovarian stimulation with hMG and rFSH provides similar clinical pregnancy rates in PCOS patients treated with a long GnRH agonist protocol in IVF cycles. Turkcapar, M.D., 2013
  36. 36. Role of LH
  37. 37. Role of LH
  38. 38. Role of LH
  39. 39. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •PCOS •Gn for O.I •Novel protocol
  40. 40. Standard Protocol May fit PCOS patients
  41. 41. Step-Down Protocol
  42. 42. Step-Up Protocol
  43. 43. Outline of this talk •Ovulation : Introduction •Evaluation of Ovulation •Anovulation: causes •How To Treat •Gn for O.I •Novel protocol
  44. 44. Reversed hMG/CC Protocol
  45. 45. •Some cases are CC resistant • about 25% of IUI cycles suffer from premature LH surge cancellation. WHY
  46. 46. Double Benefits •The use of hMG at start of cycle for few days will avoid CC resistant cases •CC will continue the growth of the dominant follicle and may prevent LH surge
  47. 47. New concept has to be tested
  48. 48. Study •Setting: Kasr Al-Aini hospital. •Registered : (ACTRN12607000568415)
  49. 49. Sample size calculation •if premature LH surge rate among the hMG only group is 20%. •Assuming CC is effective by reducing it by 15% • Then hMG + CC group will be 5%, •So we will need to study 75 couples in each arm in order to reach a power of 80%.
  50. 50. Drop out cases •In order to compensate for discontinuations, we recruited 115 women in each arm •Each couple were included only once in this trial in order to prevent a possible unit-of-analysis error in interpreting the results
  51. 51. Randomisation Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group OutcomeCompared
  52. 52. Outcome Parameters Primary outcome parameters Clinical pregnancy rate per women randomised ( i.e. fetal heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation) Premature LH Secondary outcome parameters E2 levels, Number of mature follicles Endometrial thickness On day of HCG
  53. 53. Treatment assignment •Couples assigned to the intervention group received hMG/CC protocol while couples assigned to the control group received hMG only.
  54. 54. Novel protocol 75 IU/HMG CD3 CD7 150 mg CC hC G IUI DF ≥ 18 mm 34-36h
  55. 55. Control group 75 IU/HMG CD3 hCG IUI DF ≥ 18 mm CD7 34-36h
  56. 56. Both groups •Folliculometry •hCG when follicle reach 18mm or more •Serum LH on day of hCG •IUI 34-36hs later •Micronised progesterone for 18 days
  57. 57. Assessed for eligibility (n= 245) Excluded (n= 15) Not meeting inclusion criteria (n=7) Refused to participate (n=5) Social reasons (n=3) Received IUI (110) Analyzed (n=110) Cycles cancelled (n=5) Inadequate response (n=4) Hyper-response (n=1) Group I (n=115) received Merional + CC Cycles cancelled (n=8) Inadequate response (n=6) Hyper-response (n=2) Group II (n=115) received Merional alone Received IUI (107) Analyzed (n=107) Allocation Analysis Follow-Up Enrollment Randomized (n=230)
  58. 58. Results Variable Group I (n=115) Group II (n=115) P value Age (years) 27.3 ± 4.7 28.4 ± 2.7 NS Duration of infertility (years) 3.1 ± 1.9 2.4 ± 1.6 NS Cause of infertility Mild male factor Unexplained infertility 61 (53%) 54 (47%) 58 (50.4%) 57 (49.6%) NS NS BMI 28.5 ± 1.6 28.1 ± 3.1 NS
  59. 59. Results (cont.) Variable Group I (n=110) Group II (n=107) P value Number of cancelled cycles Inadequate response Hyper response 5/110 4/5 1/5 8/107 6/8 2/8 NS NS NS Basal LH (mIU/mL) 6.4 ± 2.2 5.8 ± 2.4 NS Basal FSH (mIU/mL) 6.7 ± 2.5 7.2 ± 4.8 NS Days of stimulation 7.2 ± 1.8 8.1 ± 1.3 NS E2 at time of HCG (pg/mL) 360.3 ± 162.9 280 ± 110.0 P <.05*
  60. 60. Results (cont.) Variable HMG/CC (n=110) HMG (n=107) P value LH on day of hCG (miu/ml) for cases with no premature LH surge 7.3 ± 1.8 7.8 ± 2.2 NS Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05* Number of patients with premature LH surge 6 (5.45%) 17 (15.89%) P<0.001* End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS Clinical Pregnancy 11 (10%) 9 (8.41%) NS
  61. 61. For whom •This protocol is especially suitable for young women, for those with unexplained infertility or mild male factor i.e good responders •it may also be suitable for PCOS women to avoid the risk of severe OHSS
  62. 62. Conclusion •This is a novel protocol for O.I in IUI •The protocol is simple, safe and appears to be very cost effective.
  63. 63. Take Home message •Low dose Gn is the main stay in ovulation induction to achieve the best results
  64. 64. Thank you Dr. Hesham Al-Inany MD, PhD e-mail : kaainih@yahoo.com
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