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
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. Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O.I
•Novel protocol
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. Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O.I
•Novel protocol
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. 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. Anovulatory cycles
•Clomiphene citrate (all doses) was
associated with an increased
pregnancy rate per treatment cycle
• Meta-analysis by Hughes et al, 2011
20. CC Resistant
• If still anovulatory after 6
months of continuous use the case is
considered “clomiphene resistant”
21. Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•Gn for O.I
•Novel protocol
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. 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. 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. Effect of letrozole on ovulation rate per cycle in PCOS (Requena
et al , 2008)
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. 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. CC resistance : what to do ?
Clomiphene Citrate
hMG or FSH
______________________________________________
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
33. Gn ?
hMG or FSH
______________________________________________
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. 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
45. •Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY
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
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. 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
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. Treatment assignment
•Couples assigned to the intervention
group received hMG/CC protocol while
couples assigned to the control group
received hMG only.
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. 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. 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. 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. 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. Conclusion
•This is a novel protocol for O.I in IUI
•The protocol is simple, safe and appears to
be very cost effective.
63. Take Home message
•Low dose Gn is the main stay in
ovulation induction to achieve the best
results