LH IN ASSISTED REPRODUCTION

Dr G A RAMA RAJU.

KRISHNAIVF

VISAKHAPATNAM.

Dr.Subhas mukherjee

http://drsubhasmukhopadhyay.blogspot.com/

I dedicate this lecture

LH IS BAD Controlled Important Harmful

Replacement useful in some

only

LH

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• Is there a need for recombinant luteinizing hormone?

• Has the appropriate patient population been defined?

• Has a safe and effective dose been identified?

75 IU/day

• Is the composite primary endpoint of follicular development an appropriate endpoint to assess efficacy in this patient population?

Luveris® (lutropin alfa for injection)

Luteinizing hormone produced

by recombinant DNA technology

Common names

• Recombinant human luteinizing hormone

• r-hLH

Lyophilized powder in 75 IU vials

Self-administered by subcutaneous

injection

Agenda

Therapeutic window

Potential indication

Current scientific evidence

Clinical Perspective and

Risk/Benefit Assessment

Summary and Conclusions

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LH and FSH Action on the Follicle

Theca externa cells

Theca interna cells

Capillary network Basement membrane

CumulusOophoruscells

OocyteZona pellucida

Granulosacells Follicular

antrum

LH receptorson theca cells

FSH receptors on granulosa cells

E2

FSH

LHA

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The LH Therapeutic Window Concept

• Follicular growth impaired

• Inadequate androgen (and estrogen) synthesis

• No full oocyte maturation

LH threshold

Normal follicular growth and development

Normal androgen and estrogen biosynthesis

Normal oocyte maturation

Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265-274

• Suppression of granulosa cell proliferation

• Follicular atresia (nondominant follicles)

• Premature luteinization (preovulatory follicle)

• Oocyte development compromisedLH ceiling

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CNS Influence

Steroidal and

Nonsteroidal

Feedback

GnRH

LH FSH

HH Can Be Caused by Hypothalamic Disorders, Pituitary Disease or Both

Hypothalamus

Pituitary

Ovary

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HH Treated with r-hFSH Alone

Shoham Z et al. Fertil Steril 1993; 59:738

0

5

10

15

0 5 10 15 20Days

Serum FSH

50

100

Follicle

Estradiol

r-hFSH

Estradiol(pg/ml)

Follicle Size(mm)

and FSH(IU/L)

0

9EndometrialThickness

(mm)

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HH Treated with r-hFSH and r-hLH

Estradiol(pg/ml)

Serono data Study 6253

Follicle Size(mm)

and FSH(IU/L)

r-hFSHr-hLH

0

5

10

15

0 5 10 15 20Days

50

100

20

Serum FSH

Follicle

Estradiol

150

200

250

300

350

400

0

0

9EndometrialThickness

(mm)

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Follicular Development in HH

•Give back what’s missing

LH

HMG

GNRH

Beneficial effect of LH supplementation in ART

> 5

< .5

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Precise

Purity

Consistency

Half life 24 hrs

Modest accumulation 1.2 miudl

Higher binding HCG

>30 hrs hal life

Accumulation after 7 day 10.7 miu/dl

LH

Beneficial effect of LH supplementation in ART

Age• Marrs et

al;Humaidanet al 2004

Initial poor responder

Follicular stagnation

• Ferrarettti et al; 2004

Low poor responders• Ruvolo et al. 2007

LH POLYMORPHISIM

Women > 35 years:

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The number of functional LH receptors decreases with age

•

Vihko et al,1996

Endogenous LH may become less potent or biologically active

•Mitchell et al, 1995

The only group to benefit from LH supplementation with an increase in thenumber of mature eggs collected, improved implantation and pregnancy rates

• Marrs et al, 2003; Humaidan et al, 2004

Poor responders:10-15% of IVF patients have an inadequate response to FSH stimulation by day 8

De Placido et al, 2001, 2004

Women showing a hypo-responsive response in IVF down regulated cycles had asignificant increase in pregnancy and implantation rates with the addition ofrecombinant LH (40.7% vs. 22%)

Ferraretti et al, 2004Prospective randomised controlled

trial

Beneficial effect of LH supplementation in ART

• >3000 units Fsh

• Less than 4 oocyte

• >800 pg /ml

poor responder in previous

cycle

• No follicle > 10 mm by day 6

• , 200 pg /ML ON DAY 6

• Poor progression or slow follicular growth

• < 2mm in 3 days

Suboptimal responder in the current cycle

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How did an optimal dose found.

Dose Finding Studies LH

Controlled ovarian stimulation and HH

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Percentage of Patients with Follicular Development

63.6%

70.0%

25.0%

11.1%

0 IU LH 25 IU LH 75 IU LH 225 IU LH

1/9 2/8 7/11 7/10

p = 0.467 p = 0.020 p = 0.012p-values vs 0 IU LH

Trend Test*

p = 0.004

* Statistically significant and robust

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Risks• Known complications of gonadotropins in infertility treatment–Ovarian Hyperstimulation Syndrome (OHSS)–Multiple births

• Other minimal/transient treatment-related adverse events (minor)

• Risks mitigated with proper diagnosis, dosing and observation

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Risks vs. Benefits

Optimal folliculogenesisand endocrine

profile based on individualized

treatment

Convenience (subcutaneous, self-administered)

Safety profile comparable to

currently marketed

gonadotropins

High pregnancy rate in this profoundly

LH-deficient patient

population

ASIA PACIFIC LH ADBOARD.

ASIA PACIFIC LH ADBOARD.

Indian study :krishnaivf LH study submitted for publicationGrhn triptolein

protocol adding lh lesser dosage

Slight improvement in pregnancy rate

Significant on going

pregnancy rate

More frozen embryo

Adding Lh

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More frozen embryo

Significant on going pregnancy

rate

Slight improvement in pregnancy rate

Grhn triptoleinprotocol adding lh

decreased total fshdosage

Thank u

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