lh in human reproduction
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Sandro C. EstevesDirector, ANDROFERT
Campinas, Brazil
LH in Human Reproduction
Sesiones Científicas - Sociedad Peruana de FertilidadJunio 2014 - Lima PERU
http://www.androfert.com.br/review
LH in Human Reproduction
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Sesiones Científicas - Sociedad Peruana de FertilidadJunio 2014 - Lima PERU
Learning objectivesAt the completion of this presentation, participants should be able to: 1. Understand the role of LH in
reproductive cycles2. Identify patient subgroups to whom
LH supplementation is beneficial3. Understand the differences in LH
supplementation according to gonadotropin preparations
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Is LH important in reproductive
cycles?
1a. Absolutely trueb. Maybe truec. False
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Hypogonadotropic hypogonadism treated with FSH
alone
FSH dose0
9Endometrium (mm)
0
5
10
15
0 5 10 15 20Days of Stimulation
Serum FSH
50100
Follicles
Estradiol(pg/mL)
Folli
cle
size
(mm
)an
d FS
H (IU
/L)
Estradiol levels
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Day 1 Day 5 Day 10 hCG0
50010001500200025003000
025
75
225
Day of Stimulation
Seru
m E
stra
diol
Lev
els
(pm
ol/L
)
The European Recombinant Human LH Study Group, JCEM 1998; 83:1507
Rec-hLH administration (IU):
Evidence of a LH threshold (1)
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Day 1 Day 5 Day 10 hCG0
2
4
6
8
025
75225 0 25 75 225 rLH
Day of StimulationThe European Recombinant Human LH Study Group, JCEM 1998; 83:1507
Endo
met
rial T
hick
enes
s (m
m)
Rec-hLH (IU):
Evidence of a LH threshold (2)
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Early follicular phaseSteroidogenesis (TC)
Late follicular phaseSteroidogenesis (TC)
Up-regulates FSHr expression (GC)Sustains follicular growth and final follicular
maturation (GC)
Role of LH in reproductive cycles
Physiology
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Balasch & Fábreques 2002
•Adequate androgen and estrogen biosynthesis, normal follicular development and oocyte maturationN
orm
al•Follicular atresia•Premature luteinization•Oocyte development compromisedH
igh
•Low (and estrogen) synthesis• Impaired follicular maturation• Inadequate endometrial proliferationLow
LH Window
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What is the minimum needed LH level?
Seru
m L
H U
I/L
1.5
1.0
0.5 0.5 Westergaard 20010.7 Fleming 1998
1.2 O’Dea 20001.35 Mahmoud 2001
Injected rec-hLH
LH Cmax
75 UI 0.5 – 1.35 UI/L
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Is LH important in reproductive
cycles?1
a. Absolutely true
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Who need LH supplementation
during ovarian stimulation?
2a. All patientsb. Poor respondersc. Hypo-respondersd. Older women (>35)e. GnRH antagonist protocol
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Natural cycle5.4
3.1
1.68 0.7
50
1
2
3
4
5
6
Seru
m L
H IU
/l
Sd1 Sd8 hCG OPU0.15
GnRH agonistHypo-hypoGnRH antagonist
LH levels in natural and stimulated cycles
1.6
4.8
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threshold
Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant
LH associated with the probability of live birth?
0.01 0.1 10 100
Study FSH + LH FSH OR (fixed) Weight OR (fixed) n/N n/N 95% CI % 95% CI
Agonist Sills 1999 3/13 10/17 10.00 0.21 [0.04, 1.05] Balasch 2001 0/16 1/14 2.32 0.27 [0.01, 7.25] Humaidan 2004 39/116 31/115 31.00 1.37 [0.78, 2.41] Fabregues 2006 24/60 25/60 22.50 0.93 [0.45, 1.93] Tarlatzis 2006 6/55 10/59 12.90 0.60 [0.20, 1.78]
Subtotal (95% CI) 72/260 77/265 78.72 0.94 [0.64,1.39] Antagonist Sauer 2004 9/25 10/24 9.80 0.79 [0.25, 2.49] Griesinger 2005 8/62 9/65 11.48 0.92 [0.33, 2.56]
Subtotal (95% CI) 17/87 19/89 21.28 0.86 [0.40,1.85]
Total (95% CI) 89/347 96/354 100.00
]
advantage r-hFSH Advantage r-hFSH + r-hLH
No patient preselection
Kolibianakis, et al. Hum Reprod Update 2007;13:445-452
No, for unselected
pts.
Is LH needed in unselected women treated with FSH and
GnRH antagonists in IVF?Mochtar et al.3 RCT (N=216)
Baruffi et al.5 RCT (N= 434)
Estradiol on hCG day (pg/ml)
WMD 571(95% CI 259; 882)
WMD 514 (95% CI 368; 660)
No. retrieved oocytes
WMD 0.50 (95% CI -0.68;
1.68) WMD 0.41
(95% CI -0.44; 1.3)
CPR†/LBR*†OR 0.79
(95% CI: 0.26; 2.43)†OR 0.89
(95% CI: 0.57; 1.39)
Mochtar et al. Cochrane Database Syst Rev. 2007;2:CD005070; Baruffi et al, Reprod Biomed Online. 2007;14:14-25.
WMD weight mean difference
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No, it is not.
Total Dose per Live Birth (IU)*
0
3,000
7,000
10,000
21.6%
Rec-FSHHP-hMG
6,3247,739
hMG
9,69052.2%
*Mean total dose per cycle/Live birth rate (≤35
years)Esteves SC et al. Reprod Biol Endocrinol 2009
N=865; GnRH agonist cycles
rec-F
SH
HP-HMG
HMG
30.1 32.4 24.4LBR (%)
p=NS
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Who need LH supplementation during
ovarian stimulation?Key points (1)
2Mandatory in the
hypogonadotrophic hypogonadal (HH) patients
(FSH and LH<1.2 IU/l)For most women in IVF,
endogenous LH levels, irrespective of the GnRH analogue, is sufficient to support follicular development and steroidogenic activity, so «FSH-only« stimulation is enough
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Bioactive LH Levels
30-45% have less sensitive ovaries
Older patients (≥35 years)3
Poor responders4
Slow/Hypo-responders5
Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)6
Low
1Tarlatzis et al. Hum Reprod 2006; 2Esteves et al. Reprod Biol Endocrinol 2009; 3Marrs et al. Reprod Biomed Online 2004;4Mochtar MH, Cochrane Database, 2007; 5Alviggi, et al. RBMOnline 2009;
6De Placido et al. Clin Endocrinol (Oxf) 2004
Nor
ma
l~55-70% normogonadotropic women undergoing COS1,2
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Impaired oocyte qualityDecreased fertilization
rateReduced embryo qualityIncreased miscarriage
rates Reduced ovarian
paracrine activity
Hurwitz & Santoro 2004
Androgen
secretory
capacity reducedPiltonen et al.,
2003
Decreased number of functional
LH receptors
Vihko et al. 1996
Reduced LH
bioactivity
Mitchell et al. 1995; Marama et al 1984
3-5 in every 10 treated women have “aged” ovaries
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LH supplementation improves outcome in women
>35 yo
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Fertil Steril 2011Im
plan
tati
on r
ate
(%)
p=0.03OR: 1.56 (1.04-2.33)
p=0.84OR: 1.03 (0.73-1.47)
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Bologna Criteria for Poor Responders Ferraretti et al. ESHRE Consensus, Hum Reprod 2011
At least 2 of the following:1. Advanced maternal age
≥40 years or risk factor for POR2. Previous POR
≤3 oocytes with conventional stimulation
3. Abnormal ovarian reserve biomarker
AFC<5-7; AMH <0.5-1.1ng/mLOr Two episodes of POR after
maximal stimulation
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Pregnancy rates
increase by 30% in
poor responders
treated with rec-
hLH
Lehert et al 2012
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rec-hLH improves oocyte yield in Poor Responders
Significant increase of 0.75 oocytes per 1,000 UI gonadotropin administered
Lehert et al 2012
Lehert et al 2012
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Why is LH beneficial in aged women and poor responders?
Total Testosterone
55%
DHEAS 77%
Free Testosterone
49%
Androstenedione 64%
n = 1423
Davison SL et al JCEM 2005;90:3847
It seems to be in part a matter of androgens
• Action of LH at the follicular level in a dose dependent manner increases androgen production
• Androgens are then aromatized to estrogens and help restore the follicular milieu
Rationale of LH supplementation (1)
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Rationale of LH supplementation (2)
Anti-apoptotic effect on
granulosa cells
Up-regulate growth factors
Increase FSH receptor
responsiveness
Act synergistically with IGF-
1
Rimon E et al., 2004; Robinson RS et al., 2007; Tilly JL et al., 1992; Peluso JJ et al., 2001, Ben-Ami I et al., 2009
2Evidence of a beneficial effect in
older women (≥35 yrs.) and poor responders
Benefit related to increased androgen production and direct efect on the ovary
better follicular recruitment higher number of oocytesbetter implantation rate
Who need LH supplementation during
ovarian stimulation?Key points (2)
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Definition of hypo-responders (initial poor responders) Alviggi et al. RBM online 2006; 2009
• Normal ovarian reserve • May present follicular growth
plateau on D7-D10• Achieve ‘adequate’ number of
oocytes retrieved and estradiol production
• But at the expense of an increased cumulative rFSH dose (i.e. >3000 IU) and duration of stimulation
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Why is there a suboptimal response to exogenous FSH
in hypo-responders? LH gene polymorphism: V-LHbCarrier frequency 0-52% in various ethnic groups
13 % in Sweden12-13 % in Denmark and Italy
Associated with reduced bioactivity of LH
Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999
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The cumulative FSH consumption is higher in carriers of v-beta LH
polymorphism
Alviggi et al. Reproductive Biology and Endocrinology, 2013
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Hypo-responders benefit from LH
Cochrane review 2007
Mochtar MH, Cochrane Database, 2007 issue 2
Favours r-hFSH Favours r-hFSH + r-hLH
Ongoing PR per woman randomized(COS in a GnRH-agonist dow-regulated IVF/ICSI cycle)
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6 9 1110 14 1822 32 40
Mean No. oocytes retrievedIR (%)OPR (%)
De Placido et al. Hum Reprod. 2004; 20: 390-6.
RCT 260 pts. with “steady” response on stimulation D8 (E2 <180pg/mL; >6 follicles
<10mm)
P<0.05
LH supplementation in Hypo-responders
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2Evidence of a beneficial effect of
LH supplementation in hypo-responders (initial poor responders)
Dose-related increased LH bioactivity with a positive effect on androgen production and ovarian function
Who need LH supplementation during
ovarian stimulation?Key points (3)
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Who need LH supplementation
during ovarian stimulation?
2a. All patientsb. Poor respondersc. Hypo-respondersd. Older women (>35 yrs.)e. GnRH antagonist protocol
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTIONS ESTEVES, 352014 June
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What product to use for LH
supplementation?
3a. hMG/HP-hMGb. rec-hLHc. Either of the above; they
are similar
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Products containing LH Activity
Leao & Esteves. Clinics 2014; 69(4): 279–293.
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Fertil Steril 2012; 97(3): 561-72
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Beta unit Carboxyl terminal segment
Longer in hCG Higher
receptor affinity in
hCG
Absent in LH and
present in hCG
Longer half-life in hCG
Sources of LH ActivitySources of LH
LHLeao & Esteves. Clinics 2014; 69(4): 279–293.LH
hCG
Although they attach to the same receptor (LHCG-
R)…
Courtesy of Xuliang Jiang, EMD Serono Research Institute, Inc
Sharing the same α subunit and 81% of the aminoacid residues of the β subunit, LH and hCG bind to the same receptor: LH/hCG receptor (Kessler et al., 1979)
Constitutively expressed on
theca cells
Expressed on granulosa cells at a follicle size
of 8-12 mm
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…LH and hCG downstreamcascade pathways are
differentLH hC
GLHR and FSHR expression (Trafficking of retinoic acid : RXRB, TTR, ALDH8A1)Meiosis and follicular maturation (TRA : RXRB, TTR, ALDH8A1; IL11; AKT3)
Follicular development (IL11; AKT3)Cellular growth (RXRB, TTR, ALDH8A1; IL11;AKT3)Ovarian steroidogenesis (TRA : RXRB, TTR, ALDH8A1)Embryo development & survival (AKT3)
Aromatase inhibition (PPARS)
Apoptosis enhanceme
nt (DNAsi)
LH hCG
Grondal ML et al. Fertil Steril 2009; Menon KM et al. Biol Reprod 2004;; Ruvolo et al. Fertil Steril 2007
Fixed 2:1 r-hFSH (150IU)/r-
hLH (75IU)
HMG rec-hFSH + HMG
0
5
10
15
20
25
30
35
19
14 14
3126 25
Duration of Stimulation (days)
Mean No. oocytes re-trieved
IR (%)
CPR per trans-fer (%)
Buhler KF, Fisher R. Gynecol Endocrinol 2011
Matched case-control study; N=4,719 IVF pts.P=0.0
2
Does it matter whether hMG hCG (hMG) or rec-hLH?
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• RCT comparing rec-hFSH + rec-hLH (2:1) vs. HP-hMG
• Higher No. oocytes retrieved in the rFSH + rLH (2:1) group (9.8 vs 7.3; p<0.01)
• 2/3 of the patients in rFSH+rLH group (vs. 1/3 hMG group) had frozen embryos to transfer if fresh transfer failed
Fábregues F et al. Gynecol Endocrinol. 2013 May;29(5):430-5.
Does it matter whether hMG hCG (hMG) or rec-hLH?
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3Significant differences exist
between LH and hCG at boh the molecular and functional level
Limited evidence indicates that the choice of products containing LH activity impact IVF clinical outcome
What product to use for LH supplementation?
Key points
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What product to use for LH
supplementation?
3a. hMG/HP-hMGb. rec-hLHc. Either of the above; they
are similar
ANDROFERTandrofert.com.br
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How we use LH supplementati
on at Androfert
4
Ovarian stimulation protocol
• Clinical features• Age• Ovarian volume• AMH/AFC
Identify who is who
• Patient friendly• Efficacy• Effectiveness• Efficiency • Safety
Protocol
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Population Cut-off Sensitivity
Specificity
Accuracy
AMH*ng/mL
High-responder1
2.1 85% 79% 0.82Poor responder2
0.82 76% 86% 0.88*Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved
Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16
Biomarkers of ovarian responseAMH
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Rec-hFSH + rec-hLH (2:1 ratio) from stimulation D1
Total dose: 300 IU FSH + 150 IU LHGnRH antagonist (flexible): mean diameter 13mmLH trigger with rec-hCG (mean diameter 17-18 mm)
Our Preferred Stimulation Regimen in Expected Poor
Responders
2 3 4 5 76 8 9 10 111
Menses
Rec-hCG 250mcg
12
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Individualized vs. Conventional COSin Expected Poor
Responders (N=118)
020406080 72.0
3.5
45.020.0
46.6
4.823.3 26.8
cCOS (Long GnRH with recFSH)
Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved;
Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16.
*p<0.05
*
**
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GnRH antagonist flexible protocolRec-hFSH + rec-hLH (2:1 or 3:1 ratio) from D1
Total dose: 150-225 IU FSH + 75 IU LH
How tse LH in Coin SLH supplementation in women ≥35 years and hypo-responders
(normal ovarian biomarkers)
2 3 4 5 76 8 9 10 111
Menses
Rec-hCG 250mcg
12
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LH in Human Reproduction Conclusions
Adequate LH levels critical for steroidogenesis, follicular development and oocyte maturation
Androgen secretory capacity decreases with ovarian aging
Mechanisms include decreased number of functional LH receptors and ovarian paracrine activity. LHr polymorphisms involved in hypo-responders
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Patients that could benefit from LH supplementation during COS:
Poor/hypo respondersAge >35 years; hypo-hypo
Sources are rec-hLH and hMGLH and hCG differ at molecular, functional and clinical levels
iCOS with rec-hLH is one of our strategies to maximize pregnancy in IVF
LH in Human Reproduction Conclusions
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Than
k Yo
u
grac
ias