principles and practices of lh use in art
TRANSCRIPT
Principles and Practices of LH administration in ART
Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT
Andrology & Human Reproduction Clinic Campinas, BRAZIL
Learning objectives At the completion of this presentation, participants should be able to: 1. Understand the role of LH in
reproductive cycles 2. Identify patient subgroups to whom LH
supplementation is beneficial 3. Appraise the differences in LH
supplementation using the available gonadotropin preparations
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015
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Principles and Practices of LH administration in ART
Kingdom of Saudi Arabia 2014
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015
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This presentation is available at http://www.slideshare.net/
sandroesteves
Is LH important in reproductive
cycles? a. True b. Maybe true c. False
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015
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0
9 Endometrium (mm)
0
5
10
15
0 5 10 15 20 Days of Stimulation
50 100
Follic
le siz
e (m
m)
and
FSH
(IU/L
)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015
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WHO type I treated with r-hFSH (150 IU) + r-hLH (75 IU) in a 2:1 ratio combination
17 patients; 27 cycles IU FSH ± SEM 1922 ± 266 IU LH ± SEM 961 ± 133 Days stimulation ± SEM 13.8 ± 1.8 % PR cycle 55.5% % PR patient 88.3% N follicles >17mm ± SEM 4.3 ± 2.4 E2 hCG day (pmol/l) 541 ± 299 Mid-luteal P4 (nmol/l) 40 ± 14 Endometrium sd10 (mm) 11 ± 3 E2/follicle (pmol/l) 152 ± 64
Carone et al. J Endocrinol Invest 2012
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015
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Early follicular phase Steroidogenesis (TC)
Late follicular phase Steroidogenesis (TC)
Up-regulates FSHr expression (GC) Sustains follicular growth and final
follicular maturation (GC)
Physiology of LH in reproductive cycles
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Balasch & Fábreques 2002
• Adequate androgen and estrogen biosynthesis
• Normal follicular development and oocyte maturation N
orm
al
• Follicular atresia • Premature luteinization • Oocyte development compromised H
igh
• Low (and estrogen) synthesis • Impaired follicular maturation • Inadequate endometrial proliferation Lo
w
LH Window
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015
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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 2001 0.7 Fleming 1998
1.2 O’Dea 2000 1.35 Mahmoud 2001
Injected rec-hLH
LH Cmax
75 IU 0.5 – 1.35 IU/L
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015
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Is LH important in reproductive cycles?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015
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a. True b. Maybe true c. False
Who need LH supplementation
during ovarian stimulation?
a. All patients b. Poor responders c. Hypo-responders d. Older women (>35) e. GnRH antagonist protocol
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015
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u Natural cycle 5.4
3.1
1.68 0.75
0
1
2
3
4
5
6
Seru
m L
H IU
/l
Sd1 Sd8 hCG OPU 0.15
GnRH agonist
Hypo-hypo GnRH antagonist
LH levels in natural and stimulated cycles
1.6
4.8
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015
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Among patients treated with FSH and GnRH analogues for IVF, is the addition of rec-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
Unselected Patient Population
Kolibianakis, et al. Hum Reprod Update 2007;13:445-452
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015
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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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015
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Impaired oocyte quality Decreased fertilization rate
Reduced embryo quality Increased miscarriage rates
Reduced ovarian
paracrine activity Hurwitz &
Santoro 2004
Androgen secretory capacity reduced
Piltonen 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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015
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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
mal
~55-70% normogonadotropic women undergoing COS1,2
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015
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LH supplementation improves clinical pregnancy in women >35 yo.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015
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Fertil Steril 2011
Impl
anta
tion
rate
(%)
p=0.03 OR: 1.56 (1.04-2.33)
p=0.84 OR: 1.03 (0.73-1.47)
27.8
18.9
28.6
26.7
<=35
36-39
r-FSH + r-hLH*
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015
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*75 IU r-hLH form Sd1
Pregnancy rates
increased by 30% in poor responders
treated with rLH+rFSH
Lehert et al Reprod Biol Endocrinol 2014, 12:17
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015
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Lehert et al 2012
Significant increase of
+0.75 oocytes in poor
responders treated with
r-hFSH + r-hLH
Lehert et al Reprod Biol Endocrinol 2014, 12:17
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0% 5%
10% 15% 20% 25% 30% 35% 40% 45%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40
Live
birt
h ra
te (%
)
Oocyte number
Observed live birth rate Predicted live birth rate
Sunkara et al. Hum. Reprod., 2011
400,135 IVF cycles
Number of Oocytes and LBR
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015
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On average, one additional embryo for transfer or cryopreservation
Air Quality Control and GMP 2,315 patients; 14,660 embryos
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015
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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
• 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)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015
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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
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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015
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Why is there a suboptimal response to exogenous FSH in
hypo-responders? LH gene polymorphism: V-LHβ Carrier frequency 0-52% in various ethnic groups
ü 13 % in Sweden ü 12-13 % in Denmark and Italy
Associated with reduced bioactivity of LH
Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015
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The cumulative FSH consumption is higher in carriers of v-beta LH
polymorphism
Alviggi et al. Reproduc0ve Biology and Endocrinology, 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015
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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)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015
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6 9 11 10 14 18 22 32
40
FSH step-up (+150 UI) LH supplementation (Sd8)
Normal Responders
Mean No. oocytes retrieved IR (%) 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)
LH supplementation in Hypo-responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015
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Who need LH supplementation
during ovarian stimulation? a. All patients
b. Poor responders c. Hypo-responders d. Older women (>35 yrs.) e. GnRH antagonist protocol
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015
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What product to use for LH
supplementation? a. hMG/HP-hMG b. rec-hLH c. Either of the above; they
are similar
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015
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Gonadotropins containing LH activity
Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.
Product LH activity (IU/vial)
LH content* Purity
hMG 75 hCG ~5% HP-hMG 75 hCG ~70% Lutroprin alfa (rec-hLH) 75 LH >99% Follitropin alfa + lutroprin alfa in a 2:1 ratio combination
75 LH >99%
*hCG concentrated or added during purification process (8IU hCG ~ 75IU LH)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015
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Fertil Steril 2012; 97(3): 561-72
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015
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Extracellular fluid
Cytoplasm
Plasma membrane
LH hCG
LH/hCG receptor
Sharing the same α subunit and 81% of AA residues of β subunit, LH and hCG bind to the same receptor
Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.
Structural characteristics, half-life in serum and downstream effects of LH and hCG following receptor binding
LH hCG Aminoacid number
Alpha subunit Beta subunit
92
121
92
145 N-linked glycosilation sites
Alpha subunit Beta subunit
2 1
2 2
O-linked glycosilation sites -- 4
Carboxyl-terminal segment non-existent present
Half-life (hours) Initial, range of mean
Terminal, range of mean Terminal (SC injection)
0.6-1.3 9-12
21-24
3.9-5.5 23-31 72-96
Response
ED50 (pM)1
Time to maximal cAMP accumulation1
ERK 1/2 activation2
AKT activation2
CYP19A1 expression in presence of ERK1/2 pathway blockade2
530.0 ± 51.2
10 min
strong
strong
increased
107.1 ± 14.3
1 h
weak
minimal
unaffected
1Effect on COS-7/LHCGR cells that constitutively express LH receptors
2Effect on human granulosa cells
Esteves & Alviggi. Principles and practices of COS in ART, Springer 2015
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015
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Divergence in receptor-mediated signaling between LH and hCG
Choi & Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015
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• ERK/PKA & AKT cell survivor regulators and apoptosis blockers
• P produc0on in preovulatory GCs mainly modulated by ERK/PKA
• In vitro ac0va0on of cAMP pathway associated with apopto0c events
ERK/PKA & AKT pathway (LH) cAMP (hCG)
ERK/PKA & AKT pathways
Casarini et al., 2012; Grzesik et al., 2014
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015
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• LH significanly more potent to induce EREG gene expression
• Epiregulin plays a key role in oocyte matura:on
Epiregulin (EREG) pathway
Chin & Abayasekara, 2004; Sekiguchi et al., 2004
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015
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0"20"40"60"80"100"120"
2PN$ Preg.$ IR$ DNA$fragmenta2on$
r4$FSH$hMG$r4FSH$+$r$LH$
*P<0.01
*
* *
Lower apoptosis rate (marker of oocyte quality) in human cumulus cells aQer administra0on of
rec-‐LH to women undergoing COS for IVF
Ruvolo et al. Fertil Steril 2007; 87:542-6
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015
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• Cross-over study (n=66) comparing rec-hFSH + rec-hLH (2:1) vs. HP-hMG
• All 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;29(5):430-5.
Type of LH supplementation and number of oocytes retrieved
7.3 9.8
No. oocytes retrieved
HP-HMG rec-FSH + rec-LH
p<0.01
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015
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19 14 14
31 26 25
0 5
10 15 20 25 30 35
Fixed 2:1 r-hFSH (150IU)/r-hLH
(75IU)
HMG rec-hFSH + HMG
Duration of Stimulation (days) Mean No. oocytes retrieved IR (%)
CPR per transfer (%)
Buhler KF, Fisher R. Gynecol Endocrinol 2011
Matched case-control study; N=4,719 IVF pts.
P=0.02
Does it matter whether hMG hCG (hMG) or rec-hLH?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015
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ü Significant differences exist between LH and hCG at boh the molecular and functional level
ü Preliminary evidence indicates that the choice of products containing LH activity impact IVF clinical outcome
What product to use for LH supplementation?
Key points
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015
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How we use LH supplementation
at Androfert
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015
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Ovarian stimulation protocol
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015
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Population Cut-off Sensitivity Specificity Accuracy
AMH*ng/mL
High-responder1 2.1 85% 79% 0.82 Poor 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 response AMH
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015
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Rec-hFSH + rec-hLH (2:1 ratio) from Sd1 Gonadotropin dose per day 450 IU: Ø rec-hFSH 300 IU + rec-hLH 150 IU)
GnRH antagonist (flexible): mean 13mm LH trigger with rec-hCG (mean 17-18 mm
Our preferred regimen in expected poor responders
(AMH≤0.82 and/or history of POR)
2 3 4 5 7 6 8 9 10 11 1
Menses
13
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015
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12
Individualized vs. conventional COS in expected poor responders (N=118)
72.0
3.5
45.0
20.0
46.6
4.8 23.3 26.8
0
20
40
60
80
Observed Poor Response (%)
Oocytes retrieved (N)
Cancellation (%) Pregnancy/cycle (%)
cCOS (Long GnRH with r-hFSH) iCOS (GnRH Antag. with r-hFSH+r-hLH)
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
*
* *
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015
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GnRH antagonist flexible protocol Rec-hFSH + rec-hLH (2:1 ratio) from Sd1
Gonadotropin dose/day 225 IU: Ø rec-hFSH 150 IU + rec-hLH 75 IU
How tse LH in Coin S Our preferred regimen in women ≥35yr. and normal ovarian reserve
(AMH>0.82)
2 3 4 5 7 6 8 9 10 1
Menses
13
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015
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11 12
GnRH antagonist flexible protocol; i. r-hFSH + r-hLH (2:1 ratio) from Sd6-7
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015
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Our preference in hypo-responders (Age <35yr.; AMH >0.82; follicular stagnation
(<10mm) Sd5-7)
Gonadotropin dose per day: 225 IU
2 3 4 5 7 6 8 9 10 11 1 Menses
14
ii. r-hFSH + r-hLH (2:1 ratio) from Sd1 2 3 4 5 7 6 8 9 10 1 13 11 12
12 13
Expected poor responders
§ AMH ≤ 0.82 ng/ml § History of previous IVF a_empt with poor response at a conven0onal s0mula0on
Hypo responders § < 35 yr. § AMH >0.82 ng/ml
§ Follicular stagna0on aQer 6-‐7 days of s0mula0on with r-‐hFSH
2
Start from Sd6-‐7 (1st cycle) Start Sd1 (subsequent
cycles) (1 vial/day)
Start from s0mula0on day 1
(2 vials/day)
Our strategy for LH supplementa0on using 2:1 combina0on of r-‐hFSH + r-‐hLH
§ Expected normo-‐responder (AMH >0.82 ng/ml and no history POR)
Age ≥ 35
Start from s0mula0on day 1
(1 vial/day)
3 1
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015
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40.4% 48.0%
ET #3 (FET) 49
ET #2 (FET) 239
ET #1 (fresh) 822
50.5% +18.8%
+25.0% Female Age ≤39 ANDROFERT
332/822 63/239 17/49
Cumulative LBR – IVF/ICSI
Year 2012
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015
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Conclusions 1. Adequate LH levels critical for
steroidogenesis, follicular development and oocyte maturation
2. 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
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015
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3. Patients most likely to benefit from 2:1
fixed FSH/LH combination during COS: Poor/hypo responders
Age >35 years; hypo-hypo 4. rec-hLH and hMG sources of LH-
acitivity LH and hCG differ at molecular and functional levels
5. iCOS with 2:1 FSH/LH combination has been one of our strategies to maximize success in IVF
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015
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Conclusions