A comparison of outcomes from in vitro fertilization cycles stimulated with either recombinant luteinizing hormone (LH) or human chorionic gonadotropin acting as an LH analogue delivered as human menopausal gonadotropins, in subjects with good or poor ovarian reserve: A retrospective analysisMichael H. Dahan *, Mohammed Agdi, Fady Shehata, WeonYoung Son, Seang Lin TanMcGill Reproductive Center, McGill University, Royal Victoria Hospital, Montreal, Canada

European Journal of Obstetrics & Gynecology and Reproductive Biology 172 (2014) 70–73

Anna HnugProduct ManagerFeb 17th, 2014

Background information- Addition of LH may benefit certain patients

有些特性的病人加入 LH 後可以促進濾泡發育(folliculargenesis) 及增加懷孕率• 年齡較大 (>35 yr)• Poor responder• Very low serum LH level

在幾個 meta-analysis 中可看到， LH+FSH 的 protocol 比FSH alone 的 protocol

• 懷孕率較高• 臨床懷孕率較高• 活產率較高• 著床率較高 (r-hLH)• 使用 FSH 的劑量較少

(agonist long protocol)• 取得較多的卵 (antagonist

protocol)

LH & follicle maturation

雖然 LH level 在 late follicular phase 才昇高，但在 early & mid follicular phase 時 LH 有助於濾泡成熟 ( &selection of dominant follicle)

Background information: r-hLH vs. hMG

探討問題

需要 LH 的 IVF 病人- 包括卵巢庫存量較少且使用 microdose

flair protocol 的 IVF 病人族群

r-hLH hMG

何者效果較佳？

Materials & Methods - medications

單一中心回溯性研究Patients undergoing IVF•Including:- Received FSH and either r-hLH or HMG (not both)•Excluding:-Thyroid abnormalities-Hyperprolactinemia-Hypothalamic pituitary dysfunction-Ovarian failure

r-FSH (Gonal-f) + r-hLH (Luveris)

r-FSH (Gonal-f/Puregon)/urofollitropin + hMG (Repronex*)

Indicators include:Total FSH dose Oocytes obtained Pregnancy rateTotal LH dose Embryos obtained Clinical pregnancy

rate

n=105

n=962-year period

Total n=201

* Repronex: Ferring Inc. North York , Canada)

Materials & Methods - protocols

Good ovarian reservebaseline FSH <10 IU/Landbaseline AFC 6≧Poor ovarian reservebaseline FSH 10 IU/L≧orbaseline AFC < 6

n=122

n=79

GnRH agonist long protocol

*Microdose flair protocol

• Trigger: 10,000IU or 5,000IU hCG• Retrieval & ET: 17 gauge single lumen needle or 16 gauge double lumen flushing needle

r-FSH (Gonal-f) + r-hLH (Luveris)

r-FSH/urofollitropin + hMG (Repronex)

n=105

n=96

*Microdose flair protocol

112.5~225 IU/daily

300~600 IU/daily

Results (Table 1)Patient demographics 兩組相當

Recombinant h-LH hMG p-value

Number of cycles 105 96 –

Age (years) 36.2 ± 4.1 36.7 ± 4.4 0.39

Day 3 serum FSH (IU/L) 9.3 ± 7.4 8.9 ± 3.3 0.57

Day 3 serum estradiol (pmol/L) 180 ± 98 200 ± 118 0.22

Antral follicle count 14 ± 10 12 ± 7 0.11

Previous pregnancies 0.8 ± 1.1 1.0 ± 1.1 0.18

Previous full term pregnancies 0.2 ± 0.5 0.26 ± 0.7 0.22

Previous miscarriages 0.6 ± 0.9 0.7 ± 0.8 0.40

Results (Table 2)Infertility 原因僅 tubal disease 有顯著差異Infertility diagnosis r-hLH group hMG group p-value

Number of cycles 105 96 –

Male factor 50% 42% 0.24

Endometriosis 8% 13% 0.24

Genetic disease carrier 5% 9% 0.30

PCOS 7% 1% 0.10

Tubal disease 7% 17% 0.02*

Unexplained 28% 23% 0.38

*Since patients may have more that one infertility diagnosis, the diagnostic rates total >100%.

Results (Table 3)IVF treatment outcomes 比較

r-hLH hMG p-valueComments (r-hLH組 )

Number of cycles 105 96 –

Total FSH dose (IU) 3944 ± 1820 4783 ± 2100 0.003* 使用較少的 FSH

Total LH dose (IU) 1601 ± 952 2354 ± 1784 0.0001* 使用較少的 LH

Oocytes obtained 12 ± 7 10 ± 6 0.008* 得到較多的卵Embryos obtained 7 ± 5 5 ± 3 0.009* 得到較多的胚胎Percent of ICSI cases per group 75% 82% 0.23

Pregnancy rate per cycle start 42% 26% 0.03* 較高的懷孕率Clinical pregnancy rate, per cycle start 36% 20% 0.02* 較高的臨床懷孕率

Results (Table 4)依照卵巢庫存量指標比較 r-hLH vs. hMG 有無顯著差異 (p-value)

Baseline FSH <10 IU/L

Baseline AFC ≥ 6

Baseline FSH ≥10 IU/L

Baseline AFC <6

r-hLH (n) 78 88 27 17hMG (n) 68 82 28 14

Total FSH dose (IU) 較少 0.003* 0.002* 0.35 0.15

Total LH dose (IU) 較少 0.001* 0.001* 0.09 0.21

Oocytes obtained 較多 0.01* 0.002* 0.33 0.44

Embryos obtained 較多 0.03* 0.007* 0.16 0.63

Pregnancy 較高 0.12 0.01* 0.15 1.0

Clinical pregnancy 較高 0.18 0.02* 0.04* 1.0

good good poorpoor

•在 good ovarian reserve (FSH < 10IU/L ; AFC ≥ 6) 的病人 , r-hLH gr. 的表現顯著優於 HMG( 取得較多卵、較高懷孕率 )

Recombinant human LH supplementation versus supplementation with urinary hCG-based LH activity during controlled ovarian stimulation in the long GnRH-agonist protocol: a matched case–control study

Klaus F. Bühler1 & Robert Fischer2

1Kinderwunschzentrum Hanover-Langenhagen & Wolfsburg, GMP Müseler-Albers/Arendt/Bühler/Schill, Langenhagen, Germany and2Fertility Center Hamburg, Hamburg, GermanyEuropean Journal of Obstetrics & Gynecology and Reproductive Biology 172 (2014) 70–73

r-hFSH + r-hLH (2:1)(n=1573)

hMG alone(n=1573)

hMG + r-hFSH(n=1573)

long GnRH-agonist protocol(n=4719)

與另兩組相比： • r-hFSH 使用量較少• 懷孕率較高• 胚胎植入著床率較高

Materials & Methods - medications

• 2007 Oct.~2009 Jun.• Data collected using RecDate electronic database

Results (Table 1)Patient demographics 兩組相當

Results (Table 2)r-hLH+r-hFSH gr. FSH 使用劑量顯著較低

Results (Table 3)r-hLH+r-hFSH , 35 yr sub gr. ≦ 的implantation rate per ET 顯著較高 (24.8% vs. 17.2% & 17.5%)

Discussion

The pts population analysed can be regarded as representative for routine ART treatment in Germany r-hLH (in combination with r-hFSH) 比 u-hMG 的懷孕率顯著較高 (per cycle and per ET); 著床率顯著較高 (per ET) Age subgroup analysis: r-hLH 對於小於 35 歲的 pts, 有較明顯的效益

Information sharing:Current standard luteal phase support in NTUH

TNUH current standard luteal phase support

• For fresh IVF cycle, Estrade (2 mg) 3 bid and Crinone 1 bid for follicle number > 10 or for all cases• For fresh IVF cycle, Utrogestan (100 mg) 1 tid or Crinone 1 qd, plus Pregnyl (hCG 1500 IU) q3d, 3 doses, for follicle number < 10• For frozen ET with natural cycle, Crinone 1 qd• For frozen ET with HRT* cycle, Crinone 1 bid

* HRT: Hormone Replacement Treatment

Starting time and duration of the luteal phase support• For the fresh IVF cycle, start since 2 days after OPU (2-4 cell stage) - After pregnancy test, if the corpus lutein is rescued, stop the LPS gradually. - If the corpus lutein is not rescued, continue to GA 12 weeks.• For frozen ET with natural cycle, start since 2 days after ovulation (2-4 cell stage). - Stop LPS after pregnancy test or continue to GA 7-9 weeks. • For HRT cycle, the day of LPS is defined as ovulation day, - continue to GA 12 weeks.

Early pregnancy / Extend the luteal support

• For the fresh IVF cycle, - If the corpus lutein is rescued, taper and then stop the LPS at GA 5 weeks. -If the corpus lutein is not rescued, continue to GA 12 weeks.• For frozen ET with natural cycle, - stop LPS after pregnancy test or continue to GA 7-9 weeks. • For HRT cycle, continue to GA 12 weeks.

Feedback on Crinone

• Good results• No pain, No dizziness• Reduce OHSS• Some with itching, not common