حمن الر الله بسمحيم الر

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.I•Novel protocol

Ovulation

• Day 14?

Basic fertility work up

referral gyn

HistoryPhysical examination

Ovulation evaluation Semen analysisTubal

patency:CATHSGDLS

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 with prognosis 30-40% = IUI

Outline of this talk

•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol

Evaluation of Ovulation

Diagnostic studies to confirm Ovulation

•Basal body temperature Inexpensive Accurate

•Endometrial biopsyExpensiveStatic information

•Serum progesteroneAfter ovulation

risesCan be measured

•Urinary ovulation-detection kitsMeasures changes

in urinary LHPredicts ovulation

but does not confirm it

Outline of this talk

•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol

Anovulation

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

Outline of this talk

•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol

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 kits• day 21 progesterone.

hCG vs. LH monitoring

• If normoovulatory (e.g male factor), LH monitoring is preferred

• If ovulatory dysfunction: hCG is preferredMeta-analysis by Kosmos et al, 2007

Anovulatory cycles

•Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle

• Meta-analysis by Hughes et al, 2011

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•Novel protocol

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.

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

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

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.

Meta-analysis by Siebert et al, 2013

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

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 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

CC FSH P-value

Number of patients randomized 143 159

Number of patients per protocol 123 132

Cycles 310 288Clinical 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

Outline of this talk

•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol

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 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.

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

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.I•Novel protocol

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•Novel protocol

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 of the

dominant follicle and may prevent LH

surge

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 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%.

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

Randomisation

ParticipantsR

a n

d o

m l

y

A s

s i

g n

e d

Intervention Group

Control Group

Follow-up

Follow-up

Intervention Group

Control Group

O u

t c

o m

e

C

o m

p a

r e

d

Outcome Parameters

Primary outcome parametersClinical pregnancy rate per women randomised ( i.e.

fetal heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation)

Premature LH

Secondary outcome parametersE2 levels, Number of mature follicles Endometrial thickness

On day of HCG

Treatment assignment

•Couples assigned to the intervention

group received hMG/CC protocol while

couples assigned to the control group

received hMG only.

Novel protocol

75 IU/HMG

CD3 CD7

150 mg CC

hCG 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 progesterone for 18 days

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)

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%)

NSNS

BMI 28.5 ± 1.6 28.1 ± 3.1 NS

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*

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

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

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 youDr. Hesham Al-Inany MD, PhD

e-mail : kaainih@yahoo.com