RECOMBINANT VS. URINARY FSH IN IUI

J. Serna MD PhD

QUESTIONS

Is it necessary multiple follicle development for IUI?

IUI vs. TI? Best medication?

QUESTIONS

Is it necessary multiple follicle development for IUI?– Balance risk/benefits– Difficult to draw clear conclusions from

studies in subfertile couples

PRs IN IUI

Etiology Non Stimulated

Clomiphene hMG

Male Factor 4.6 5.9 11.2

Unexplained 6.0 17.3 21.6

Endometriosis

- - 10.4

Anovulation - 18.2 15.6

Cervical - - 12.1PR: Natural cycle: 4.6%

CC: 11.8%Gonadotropins 17.7%

IUI: Ovarian Stimulation

Drug DiagnosisPregnancy

RateP

Martinez 90

CC MaleNCMFD

3/305/35

NS

OR0.78Arici 94 CC

Unexplained

NCMFD

1/206/23

<.05

MaleNCMFD

1/261/26

NS

Cohlen 98Gonadotropins

MaleNCMFD

13/15321/153

NS

OR2Nulsen 93

Gonadotropins

Unexplained

NCMFD

1/4111/57

<.05

MaleNCMFD

1/417/54

<.05

Duran HE Hum Reprod Update 2002

Male factor: CC do not PR, but gonadotropins doesUnexplained: CC and gonadotropinas PR vs. NC

IUI-D: Ovarian Stimulation

Remohí 1996

Ovarian Stimulation Natural Cycle

Number of cycles 1009 420

Number of pregnancies 205 (20.3) 48 (11.4)

Cumulative PR 77.1 ± 3.3 51.0 ± 3.5

IUI-D: Ovarian Stimulation

Lashen 1999

PR/Cycle PR/Patient

Natural cycle 13% 32%

CC 10% 18%

Gonadotropins 21% 53%

QUESTIONS

Is it necessary multiple follicle development for IUI?

IUI vs. TI? Best medication?

Metaanalysis: MFD + TI vs. MFD + IUI

PR/cycle > double vs. NC

and > 5 times FSH + IUI vs. NC

OR 2.37 FSH + IUI

Hughes E, Hum Reprod 1997; 12(9): 865-72

In most cases it is better MFD vs. natural cycle

Gonadotropins are better than CC in most non-PCO patients

TI yields worst results than IUI

QUESTIONS

Is it necessary multiple follicle development for IUI?

IUI vs. TI? Best medication?

Drugs for ovarian stimulation

- Clomiphene citrate

- Gonadotropins

- hMG

- FSH ( uFSH vs rFSH)

Gonadotropins

Menotropin Urofollitropin

– Almost no LH rFSH

– Highest purity– Batch to batch consistency– Potentially allergenic urinary proteins

Urinary Highly Purified Human FSH (uhpFSH)

Active FSH Immunoselection (anti-FSH Ab) Metrodin® HP:

95 % purity LH activity 0,1 UI/mg FSH activity 9000 UI/mg < 5 % other proteins Less batch to batch variability

Better control intersubject variability

Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17

Evidence of urinary prion excretion in asymptomatics animals and humans

Not able to develop the disease after CNS injection Shaked GM. J Biol Chem 2001; 276: 31479-82

Theoretical risks: Urinary products: infected donors Recombinant products: hamster cells, bovine serum

Reichl H. Hum Reprod 2002; 17: 2501-8

Debate: Absence of data do not exclude the risk of CJD transmission.

Matorras R. Hum Reprod 2002; 7: 1675

Main problem: price, activity Crosignani PG. Hum Reprod 2002; 7: 1676.

There is no demonstrated infective reason to interrupt urinary products, nor absolute security with recombinant counterparts.

Balen A. Hum Reprod 2002; 7: 167-9

Prionic risk

Constantly Looking for Quality and Consistincy

1930 1950 1980 1995 2004

Purity Specific activityConsistency

SafetyEfficacy

EfficiencySide Effects

PMSG

Porcine FSH

hCG

Pituitary FSH

hMG uFSHrFSH

rLH rHCG

rFSH-fbm

Modified Gn

Immunereactions Side EffectsCreutzfeld-Jacob

Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17

AIM

To compare the results of ovulation induction in couples undergoing IUI with uhpFSH vs. rFSH

Isaza V, Requena A, García-Velasco J, Martínez-Salazar J, Remohí J, Pellicer A, Simón C.

Recombinant vs. Urinary Follicle-Stimulating Hormone in Couples Undergoing Intrauterine Insemination: A Randomized Study

Journal of Reproductive Medicine, 2002

IVI MADRID

Material and Methods

Prospective Randomized June 1999 to May 2000 108 women 224 cycles

Inclusion criteria

Infertility more than 1 year 18 and 38 y.o. At least one normal patent tube MSC > 5 Mill/mL after swim-up No previous OI, TI or IUI No PCOs

Institutional review board approval + IC

Pretreatment work-up

HSG and/or laparoscopy TVU scan D3 Serum FSH, LH, E2, PRL and TSH D22 Progesterone Semen analysis WHO + MSC

Diagnostic groups

Endometriosis Ovulatory Dysfunction Male Factor Unexplained infertility

Distribution of etiologies

Male Factor

39%

Ovulatory dysfunction

20%

Endometriosis

6%

Unexplained infertility

35%

Stimulation Protocol

TVUS on 1st to 3rd cycle day Ovulation induction started on D3 with

– rFSH 100 IU– uFSH 150 IU

Randomly assigned by even/odd file record number

Patients with several cycles received the same medication

5000 UI hCG

100 UI rFSH

150 UI uFSH

MENS

rFSH

uFSH

1 2 3 4 5 6

TVS IATVS

Stimulation Protocol

TVUS Ovarian monitoring started on D5

No dose adjustment 5,000 IU hCG with a 18 mm leading

follicle + E2 +12 & +36 h IUIs

Cancellations No ovarian response 5 or more follicles

Luteal phase support 400 mg bid micronized vaginal progesterone Serum hCG 12 days after 2nd IUI Clinical pregnancy defined as HB 22-25 days after

the positive result

Outcomes measures

Main– Total number of follicles > 12 mm

Secondary– Follicles >17mm and 12-16– Number of cycles with 2- 4 follicles

>17mm– Duration of gonadotropin treatment– Total FSH dose– Serum E2 on hCG– Ration E2/follicle > 17mm– E2/units of FSH

RESULTSCharacteristics

rFSH (n =118 cycles, 55 couples)

uFSH (n =106 cycles, 53 couples) P

Age (yr) 33.1 ± 0.3 32.4 ± 0.2 NS

BMI (Kg/m2) 22.3 ± 2.6 23.7 ± 2.3 NS

Duration of infertility (mo) 40.5 ± 3.56 36.4 ± 1.9 NS

Infertility diagnosis

Male Factor 22 (40%) 23 (43.4%) NS

Ovulatory dysfunction 11 (20%) 10 (18.9%) NS

Endometriosis 3 (5.5%) 3 (5.7%) NS

Unexplained infertility 19 (34.5%) 17 (23.1%) NS

Hormone levels on day 3

FSH (mIU/mL) 6.2 ± 0.3 6.0 ± 0.2 NS

LH (mIU/mL) 6.2 ± 0.5 6.2 ± 0.4 NS

E2 (pg/mL) 42.3 ± 2.9 52.0 ± 4.4 NS

rFSH group uFSH group

IUI cycle118 Cycles (55 couples

Cumulative pregnancy rate (%)

106 cycles (53 couples)

Cumulative pregnancy rate (%)

1st 11/55 20.0 11/53 20.7

2nd 8/39 36.4 7/37 35.7

3rd 4/18 50.6 3/11 53.2

4th 2/6 67.1 1/5 62.6

P > 0.05 in each group

RESULTS

ParameterrFSH (n = 118

cycles)uFSH (n = 106

cycles) P

No. of days of stimulation

7.4 ± 0.1 8.1 ± 0.02 <.005

FSH dose (IU) 799.1 ± 20.7 1293.0 ± 148.0 <.001

Total no. of follicles (>12 mm)

2.9 ± 0.1 3.7 ± 0.1 <.001

No. of follicles > 17mm 2.2 ± 0.1 2.0 ± 0.1 NS

No. of follicles 12-16 mm 0.7 ± 0.1 1.7 ± 0.1 <.001

E2 at hCG (pg/mL) 679.6 ± 52.4 813.0 ± 54.1 NS

E2/IU of FSH 0.9 ± 0.02 0.6 ± 0.01 <.001

E2/follicle > 17 mm 308.9 ± 15.1 406.5 ± 24.1 <.001

RESULTS

RESULTS

7

7,2

7,4

7,6

7,8

8

8,2

rFSH uFSH

DAYS OF STIMULATION

0

200

400

600

800

1000

1200

1400

rFSH uFSH

FSH dose (IU)

0

0,5

1

1,5

2

2,5

3

3,5

4

rFSH uFSH

Total no. of follicles (>12 mm)

1,9

1,95

2

2,05

2,1

2,15

2,2

rFSH uFSH

No. of follicles > 17mm

RESULTS

0

0,5

1

1,5

2

rFSH uFHS

No. of follicles 12-16 mm

600

650

700

750

800

850

rFSH uFSH

E2 at hCG (pg/mL)

0

0,2

0,4

0,6

0,8

1

rFSH uFSH

E2/IU of FSH

0

100

200

300

400

500

rFSH uFSH

E2/follicle > 17 mm

Outcome rFSH (n = 118 cycles, 55 couples)

uFSH (n = 106 cycles, 53 couples)

P

PR/cycle (%) 25/118 (21.2%) 22/106 (20.8%) NS

PR/couple (%) 25/55 45.5% 22/53 (41.5%) NS

Cumulative PR 4 cycles (%) 66.7% 65.8% NS

Miscarriage rate (%) 2/25 (8.0%) 3/22 (26.3%) NS

Multiple PR (%) 5/23 (21.7%) 5/19 (26.3%) NS

Cancellation rate (%) 2/118 (1.7%) 2/106 (1.9%) NS

RESULTS

Shorter duration of stimulation Less total FSH doses Less total number of follicles

More follicles >17 mmLess follicles 12-16

Better optimization of the results

CONCLUSION

Similar Pregnancy Rates, Miscarriage Rates

There was a trend towards a less Multiple Rate

CONCLUSION