SlideShare a Scribd company logo

Principles and Practices of Individualization in ART

Sandro Esteves, profile picture
Sandro Esteves

This document discusses principles and practices of individualization in ART (assisted reproductive technology). It begins by explaining why individualization is important to maximize benefits, minimize risks and complications, and improve the three key dimensions of infertility care: effectiveness, safety, and patient-centeredness. It describes how stimulation protocols can be individualized based on clinical characteristics and ovarian biomarkers like AMH and AFC. For example, high responders may use an antagonist protocol to minimize OHSS risk, while poor responders' main goal is improved patient-centeredness through strategies to boost compliance. The document advocates tailoring treatment to individual patient subgroups defined by biomarkers to enhance quality and outcomes in ART.

Health & Medicine
1 of 64
Downloaded 69 times
1
2
3
4
5
Most read
6
7
8
Most read
9
Most read
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
        Principles  and  Prac-ces  of   Individualiza-on  in  ART   Sandro  C.  Esteves,  MD.,  PhD.   Medical  Director,  ANDROFERT   Andrology  &  Human  Reproduc=on  Clinic    Campinas,  BRAZIL  
Learning  Objec-ves   1.  Individualiza-on:  a  quality  concept   2.  How  to  individualize  COS  to  different   pa-ent  subgroups   3.  How  to  individualize  triggering     4.  How  to  individualize  luteal  support   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
Why  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT
Maximize  beneficial   effects  of  treatment   Minimize  complica-ons  and  risks   Why  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015 ANDROFERT
Top  3  clinical  dimensions  for  quality   improvement  in  infer-lity  care   •  Effec-veness:      Technical  aspects  to  deliver  the  best  possible  outcome    (e.g.  pregnancy,  live  birth,  cumula=ve  LBR)   •  Safety:    Complica=ons  (OHSS),  adverse  effects,  risks  (pa=ent  &    offspring),  errors/mistakes   •  Pa-ent-­‐centeredness:      Informa=on  and  pa=ent  involvement,  competence  and    aPen=on  of  clinic  and  staff,  accessibility,  coordina=on    and  integra=on,  emo=onal  support   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT Dancet  et  al.  Hum  Reprod  2011;  Mainz  Int  J  Qual  Health  Care  2013    
How  stakeholders  value  the  top  3  quality   dimensions  of  infer-lity  care   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT 0% 50% 100% Doctors  &   embryologists   Nurses   Pa-ents   Safety   Effec-veness   Pa-ent-­‐ centeredness   Dancet  et  al.     Hum  Reprod  2013  
Lack  of  psychological  support  and  poor  quality   of  service  ~60%  treatment  discon-nua-on     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT 22  studies     21,453  pa=ents   8  countries  
Individualiza-on  is  a  quality  concept   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT Safety   Pa-ent-­‐   centeredness   Effec-veness  
How  to  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
Individualizing  S-mula-on  Protocols   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT • Clinical   characteris-cs   • Ovarian  biomarkers   Iden-fy     who  is  who     • Pa-ent-­‐centered   • Effec-ve   • Safe   Protocol  
What biomarker do you value more? a. Basal FSH b. AMH c. AFC d. Age
AMH  ~  AFC  >  FSH  >  Age   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
Popula-on   Cutoff   Sensi-vity   Specificity   Accuracy   AMH  ng/mL     High-­‐ responder1   2.1   85%   79%   0.82   Poor   responder2   0.82   76%   86%   0.88   *Beckman-­‐Couter  genera-on  II  assay;  1>20  oocytes  retrieved;  2≤4  oocytes  retrieved   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16       AMH  &  AFC  should  be  internally  validated   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
Quality-­‐based  individualiza-on  in  COS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT High   responders*   Normal     responders*   Low   responders*   Biomarkers   Safety   Pa-ent-­‐   centeredness   Effec-veness   *expected  
High  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT •  Main  goal:  Safety   •  Clinical  quality  indicator:  OHSS   •  Protocol  of  choice*:      Antagonist  (flexible;  cetrorelix)    Tailored  recFSH  (112.5-­‐150  IU/d;  follitropin                        alfa;  pen  injector)       *Androfert,  Brazil  
GnRH  antagonists  in  high  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT 9  RCT;  966  PCO  women   Rela-ve  Risk   Dura-on  of  ovarian  s-mula-on   -­‐0.74  (95%  CI  -­‐1.12;  -­‐0.36)   Gonadotropin  dose   -­‐0.28  (95%  CI  -­‐0.43;  -­‐0.13)   Oocytes  retrieved   0.01  (95%  CI  -­‐0.24-­‐0.26)   Risk  of  OHSS   Mild   Moderate  and  Severe   20%  vs  32%     1.23  (95%  CI  0.67-­‐2.26)   0.59  (95%  CI  0.45-­‐0.76)   Clinical  PR   1.01  (95%  CI  0.88;  1.15)   Miscarriage  rate   0.79  (95%  CI  0.49;  1.28)   Pundir J et al. RBM Online 2012; 24:6-22
iCOS  (n=118):  rec-­‐hFSH  112.5-­‐150  IU  +  GnRH  antagonist  (flexible)   cCOS  (n=131):  rec-­‐FSH  150-­‐225  IU  +  GnRH  agonist  (nafarelin)     39.3   18.5   14.0   57.0   14.3   14.7   4.8   56.0   0   10   20   30   40   50   60   Observed   Excessive   Response  (%)   Oocytes  retrieved   (N)   OHSS  (%)   Pregnancy  (%)   cCOS   iCOS  *p<0.05   *   *   Individualized  vs  conven-onal  COS  in   high  responders   Excessive  response  >20  oocytes  retrieved;  Mild/severe  OHSS  reported;   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT *  
Poor  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT •  Main  goal:  pa-ent-­‐centeredness     •  Clinical  quality  indicators:   – Compliance  (drop-­‐out  rate)   – Pa-ent  burden  (cancela-on  rate)   •  Protocol  of  choice*:      Antagonist  (flexible;  cetrorelix)    recFSH  +  recLH  (follitropin  alfa  +  lutropin  alfa          2:1  ra=o:  300  IU  recFSH  +  150  IU  recLH);          from  s=mula=on  D1       *Androfert,  Brazil  
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, 19 2015 ANDROFERT
Lehert et al 2012 Increase  of  ≈1   oocyte  per  1,000   UI  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, 20 2015 ANDROFERT
Individualized  vs.  Conven-onal  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)   Cancella=on  (%)   Pregnancy/cycle   (%)   cCOS  (Long  GnRHa  +  300-­‐450  IU  recFSH  alone)   iCOS  (GnRH  antagonist  +  rFSH  (225-­‐300  IU)  +rLH  (75-­‐150  IU))   Expected  poor  response:  AMH<0.82  ng/dL;  Observed  poor  response  <5  oocytes  retrieved;   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16     *p<0.05   * * * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
Normal  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT •  Main  goal:  effec-veness   •  Clinical  quality  indicators:  number  oocytes   •  Protocol  of  choice*:      <35yr:  Antagonist  +  recFSH      cetrorelix  (flexible);  187.5-­‐262.5  IU/d  follitropin     alfa  pen  injector      >35yr:  Antagonist  +  recFSH/recLH      cetrorelix  (flexible);  follitropin  alfa  +  lutropin  alfa   2:1  ra=o;  225-­‐300  IU/d;  from  s=mula=on  D1       *Androfert,  Brazil  
Nega-ve   predictor   Posi-ve   predictor   van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589 Female  Age   (OR=0.95;  CI:  0.94-­‐0.96)     Number  of  oocytes  retrieved   (OR=1.04;  CI:  1.02-­‐1.07)     Level 1a   Predictors  of  pregnancy  in  IVF   14  studies     >30,000  pa=ents   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
What is the optimum number of retrieved oocytes to increase pregnancy rates ? a.  4 to 8 b.  9-12 c.  13-17 d.  The higher the better
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 Livebirthrate(%) Oocyte number Observed live birth rate Predicted live birth rate Sunkara  et  al.  Hum  Reprod  2011   450,135 IVF cycles Best  chance  of  live  birth  is  associated   with  ~15  oocytes   number of oocytes that best optimized LBR was 15 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT ...irrespec-ve  of  age  group  
The  higher  the  cohort  size,  the  higher  the   chance  of  having  euploid  embryos   Ata  et  al.  RBM  Online  (2012)  24,  614–620       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
Do you take into account the severity of male factor infertility when planning COS? a.  Yes b.  No c.  Never though about it
41.4 47 43.3 20 100 64 61 34.2 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) Live Birth (%) Non-obstructive (N=365) Obstructive (N=146) P<0.01   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
 3,412  cycles   Oocyte  number  and  LBR  at  Androfert   (ICSI  cycles  involving  severe  male  factor)     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT 0%   10%   20%   30%   40%   50%   60%   1   2   3   4   5   6   7   8   9   10   11   12   13   14   15   20   25   Number  of  oocytes   Clinical  pregnancy   Live  birth  
Each  addi-onal  warming  cycle  increases   the  chance  of  achieving  a  live  birth 40.4% 48.0% ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0% Female Age ≤38 332/822 63/239 17/49 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
Oocyte yield by gonadotropin      ↑  1.5  oocytes  (GnRH  antagonist  cycles)   Devroey  et  al.,  2012      ↑  3.1  oocytes  (GnRH  antagonist)     Bosch  et  al.,  2008      ↑  1.8  oocytes  (GnRH  agonist  cycles)   MERIT  Study,  2006        ↑  2.8  oocytes  (GnRH  agonist  cycles)   Hompes  et  al.,  2008        ↑  2.1  oocytes  (16  RCT;  different  protocols)   Lehert  et  al.,  2010   Higher  with   rec-­‐FSH  vs.     hMG,     HP-­‐hMG,  and   uFSH   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
LH  supplementa-on  improves  clinical   pregnancy  in  women  >35  yr   Hill    et  al.  Fer5l  Steril    2012   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
LH  ac-vity  by  rec-­‐LH  vs  hMG   Adapted  from:  Leao  &  Esteves.  Clinics  2014;  69(4):  279–293.   Product   LH  ac-vity   (IU/vial)   LH   content*   Purity   hMG   75   hCG   ~5%   HP-­‐hMG   75   hCG   ~70%   Lutroprin  alfa  (rec-­‐hLH)   75   LH   >99%   2:1  Follitropin  alfa  +   Lutroprin  alfa     (rec-­‐hFSH  +  rec-­‐hLH)   75   LH   >99%   *hCG  concentrated  or  added  during  purifica-on  process  (8IU  hCG  ~  75IU  LH)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
LH  and  hCG  elicit  different  gene   expression     LH   hCG   LHR  and  FSHR  expression                                                               (Trafficking  of  re=noic  acid  :  RXRB,  TTR,  ALDH8A1)   Meiosis  and  follicular  matura-on                                                                             (TRA  :  RXRB,  TTR,  ALDH8A1;  IL11;  AKT3)   Follicular  development  (IL11;  AKT3)   Cellular  growth  (RXRB,  TTR,  ALDH8A1;  IL11;AKT3)   Ovarian  stereodogenesis    (TRA  :  RXRB,  TTR,  ALDH8A1)   Embryo  development  &  survival  (AKT3)   Aromatase   inhibi-on   (PPARS)   Apoptosis   enhancement     (DNAsi)   LH   hCG   Grondal  ML  et  al.  FerFl  Steril  2009;  Menon  KM  et  al.  Biol  Reprod  2004;  Ruvolo  et  al.  Fer=l  Steril  2007     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
COS  with  LH  ac-vity  delivered  by  rec-­‐ LH  vs  hMG  in  IVF   Authors,  yr.   Design   N   Main  findings   Buhler  &   Fisher,  2011   Matched  case-­‐ control   4719   Higher  CPR  in  fixed  2:1  rec-­‐ FSH  +  rec-­‐LH  (31%)  vs  hMG   (26%)  and  vs  combo  (rec-­‐FSH   +  hMG,  25%);  p=0.02   Fábregues  et   al,  2013   Cross-­‐over   study   66   Higher  N  oocytes  in  fixed  2:1   rec-­‐FSH  +  rec-­‐LH  (9.8)  vs  HP-­‐ hMG  (7.3);  p<0.01.  Higher  N   frozen  embryos  in  recLH   Dahan  et  al,   2014   Observa=onal     201   Higher  N  oocytes  in  rec-­‐LH   (12)  vs  hMG  (10);  p=0.008.   Higher  CPR  rec-­‐LH  (36%  vs   20%;  p=0.02)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
Individualizing  trigger  and  LPS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT High   responders   Normal     responders   Low   responders   Safety   Pa-ent-­‐   centeredness   Effec-veness  
14h 14h 20h 48h  0   20  h   Natural  LH   surge   hCG   Adapted  from  Chan  et  al.  Hum  Reprod.  2003;18:2294-­‐7   Day  6   hCG  and  GnRHa  elicit  final  follicular  matura-on   as  surrogates  for  the  mid-­‐cycle  LH  surge   GnRHa   36-48 h ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT Day  8  
GnRH-­‐agonist  vs  hCG    trigger   Fresh  autologous  cycles   Moderate/   severe  OHSS   OR  0.10     0.01-­‐0.82   Live  birth   OR  0.44   0.29-­‐0.68   Youssef et al. Cochrane Database Syst Rev. 2011 High  responders   Fresh  ET   Freeze  all   GnRH-­‐a  trigger   One  size  trigger  does  not  fit  all   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
Freeze-­‐all  embryo  policy:  is  it  for  all?     •  Non-­‐inferior  in  effec-veness  in  high-­‐ quality  vitrifica-on  programs,  but…   •  Safety     – Increase  ART  unit  workload   – Perinatal  outcome     •  Higher  rate  of  large  for  gesta-onal  age  (Wennerholm HR 2013)   •  Pa-ent-­‐centeredness   – Psychological  &  cost  burden     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
    Modified  LPS  for  fresh  ET  in   GnRH-­‐a  trigger   No.  follicles  day  OPU   1,500  IU  hCG  at  OPU  &  1,000   OPU+5  &  standard  LPS  ≤  14   1,500  IU  hCG  at  OPU  +   standard  LPS  15-­‐25   1,000  IU  hCG  at  OPU  +   standard  LPS  or  Freeze  all  26-­‐30   Freeze  all  >30   Humaidan  et  al.  Hum  Reprod.  2013;28(9):2511-­‐21   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT 14h   14h   20h   48h  0   20  h   4h   GnRHa   Natural   LH  surge   Luteal  phase   defect  
Individualizing  trigger   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT Normal  &  poor   responders   rec-­‐hCG   u-­‐hCG   hCG  trigger  
RCT   N   Effect   Oocytes   retrieved   9   1409   MD:  -­‐0.04     95%  CI:  -­‐0.69  to  0.61   Live  birth   6   1,019   OR:  1.04   95%  CI:  0.79  to  1.37   Miscarriage   7   1,106   OR:  0.69   95%  CI:  0.41  to  1.18   Severe  OHSS   3   549   OR:  1.49     95%  CI:  0.54  to  4.1   Youssef  et  al.  Cochrane  Database  Syst  Rev.  2011;  13(4):CD003719   Databases  searched  up  to  January  2010   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015 ANDROFERT
Farrag et al. JARG 2008; 25:461-6 8.4 7.3 7.1 4.7 0 2 4 6 8 10 No. Retrieved oocytes No. MII with mature cytoplasm rec-hCG (250 mcg; n=42) u-hCG (10,000 IU; n=47) *p<0.01 * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
Effec-veness     RCT  comparing  trigger  with  rec-­‐hCG  (250  mcg)  vs   u-­‐hCG  (10,000  IU)  on  delivery  rates  in  eSET   antagonist  cycles   26.7% 44.1% Delivery rate (%) u-hCG rec-hCG N=119   aged<32   OR:  2.16  (95%  CI:  1.01-­‐4.67;  p=0.04)   Papanikolaou  EG  et  al.  Fer5l  Steril  2010;  94:2902-­‐4   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
RCT   N   Odds-­‐ra-o   Local  site  reac-ons*   rec-­‐hCG  vs.  u-­‐hCG   3   374   0.39    95%  CI:  0.25  to  0.61   Driscoll  et  al.  2000:  27%  vs  42%   ERHCG  group  2000:  23%  vs  45%   Abdelmassih  et  al.  2005:  23%  vs  45%   Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719 * Pain and/or inflammation   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015 ANDROFERT
hCG  preferences  in  treatment-­‐ experienced  pa-ents  at  Androfert       Total (n=76) 60% 29% 3% 8% prefer new pen prefer pre-filled syringe prefer lyophilized powder to reconstitute Not matter ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
Why  immature  oocytes?     1.  Follicles  <13mm   2.  LH  receptor  deficiency   3.  Blood/intrafollicular  level   barely  achieved     4.  Not  enough  -me  for   intrafollicular  hCG  ac-on   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT Trigger  is  the  most  important  injec-on   of  the  cycle  
Weight (kgs) 55 64 90 Blood volume (lts) (7% of weight) 3.8 4.4 14 Fat (kgs) (essential 13.5% of weight) 7.4 8.6 27 hCG Blood Threshold hCG Intrafollicular Threshold Blood represents about 7% of the body mass or about 4.5 kg (volume ~ 4.4 liters) in a 64 kg (141 lb) person." Cameron, J.. Physics of the Body. 2nd Edition. Madison, WI:, 1999: 182. Injecting hCG: Size and BMI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
What is the optimum interval between trigger and oocyte retrieval? a.  34 to 35h b.  35 to 36h c.  36-38h d.  >38h e.  Doesn’t matter much
  63 73 76 79 82 Oocyte  maturity  %   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
Individualizing  LPS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT Normal  &  poor   responders   Fresh  ET   FET  
In  FET  cycles,  all  of  the  current  methods  of   endometrial  prepara-on  appear  to  be  equally   effec-ve  in  terms  of  ongoing  pregnancy  rate*   •  Meta-­‐analysis  of  20  compara=ve  studies     •  ~13,000  cycles   •  Natural  and  ar=ficial  cycles  with  and  w/o   GnRH  agonist   •  Safety  &  pa-ent-­‐centeredness  not  addressed       Groenewoud  ER  et  al.  Hum  Reprod  Update.  2013;19:458-­‐70   *in  eumenorrhoic  pa-ents   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT
Luteal  phase  abnormal  in  s-mulated   cycles   •  Corpus  luteum  func-on   dependent  on  pulsa-le  LH   release  from  pituitary   •  Supraphysiologic  steroid  levels   (by  mul-follicular  development)   inhibits  LH  secre-on   •  Low  LH  levels  causes  luteolysis,   implanta-on  failure  and   shortened  luteal  phase   Jones 1996; Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Fauser & Devroey 2003; Trinchard-Lugan et al 2002; Sherbahn 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT
LPS  mandatory  in  s-mulated  cycles •  hCG  vs.  Placebo  or  No  treatment:   Higher  ongoing  PR  (OR=1.75; 95% CI: 1.09-2.81) •  Progesterone  vs.  Placebo  or  No  treatment:   Higher  clinical  PR  (OR=1.83; 95% CI: 1.29-2.61) Higher  ongoing  PR  (OR=1.87; 95% CI: 1.19-2.94) Higher  live  birth  rates  (OR=2.95; 95% CI: 1.02-8.56) Level   1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015 ANDROFERT
Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011 High-­‐quality  evidence  on  LPS  in   s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
P routes & types Evidence Effect Conclusion Vaginal as effective as IM/oral 13 RCT; 2 MA; >2,000 cycles Similar CPR, LBR & miscarriage True Vaginal safer and more patient- friendly than IM/oral 3 RCT; 1 MA; >2,000 cycles Lower side effects; Increased patient satisfaction True Among vaginal P, patients prefer gel 7 RCT; 1 MA; >2,400 cycles Easier to use; better adherence; lower discharge True Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010; van der Linden et al Cochrane 2011 High-­‐quality  evidence  on  LPS  in   s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
1  hour   3  hours   2  hours   4  hours   Time   Bioadhesion of vaginal P is essential because it takes ~4h to reach steady state in the uterus (first-pass effect) Bulletti C et al. Hum Reprod 1997 aqueous   lipid   -ssue   micronized  progesterone  in  an  ‘oil-­‐in-­‐water’   emulsion  (Crinone®  8%)     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT
Similar  outcome  in  low  vs.  high  dosage   Crinone  8%  (90  mg/d)  vs.  200-­‐800  mg/d  (capsules;  tablets;   pressaries) No.  studies   No.     OR;  95%  CI   Live  birth   2   1485   1.01;  0.81-­‐1.26   Clinical  PR   12   4973   1.04;  0.92-­‐1.17   Miscarriage  rate   8   2350   1.27;  0.85-­‐1.89   Mul-ple  PR   4   905   0.95;  0.57-­‐1.58   Van der Linden et al Cochrane 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015 ANDROFERT
Vaginal  P  started  at  the  -me  of  OPU  reduces   uterine  contrac-ons  at  the  -me  of  ET 4.6 2.8 4.5 4.2 UC on day of hCG UC on day of ET Crinone started on the day of OPU (n=43) Crinone started on the evening of ET (n=41) P<0.001 Fanchin et al. Fertil Steril 1999 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015 ANDROFERT
Luteal-­‐placental  shiw  on  P  produc-on   occurs  around  7-­‐12th  gesta-onal  week 0 100 200 300 400 500 600 700 800 900 0 10 20 30 40 50 60 70 80 4 5 6 7 8 9 10 E2(pg/mL) P(ng/mL) Gestational age in weeks P E2 Scott et al. Fertil Steril 1991; 56:481 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 61 2015 ANDROFERT
Principles  and  Prac-ces  of  Individualized   ART  at  Androfert   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 62 2015 ANDROFERT High   responders   Normal     responders   Low   responders   Clinical  features  +  AMH   Antagonist  protocol;  tailored  COS  rec-­‐FSH   (112.5-­‐150  IU)  +  tailored  trigger  (GnRHa  or   rec-­‐hCG);  tailored  LPS  (modified  LPS  or   vaginal  P  gel  OPU)   Antagonist  protocol;  tailored  COS  w/rec-­‐ FSH  (<35yr)  or  rec-­‐FSH+rec-­‐LH  2:1  ra-o   (>35  yr);  rec-­‐hCG  trigger;  LPS  vaginal  P  gel   Antagonist    protocol;  recFSH  +  recLH  2:1   ra-o  +  rec-­‐hCG  trigger;  LPS  vaginal  P  gel    
Principles  and  Prac-ces  of   Individualiza-on  in  ART   Conclusions •  Individualiza-on  is  a  quality  concept   •  Safety,  effec-veness  and  pa-ent-­‐centeredness   are  important  principles  in  a  quality-­‐based   individualized  infer-lity  care     •  Novel  biomarkers  combined  with  new  devices   &  drug  regimens  can  be  used  to  deliver  a  high   quality  evidence-­‐based  individualized  ART   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 63 2015 ANDROFERT
Thank  you        ‫ا‬‫شكر‬ Obrigado   This  presenta-on  is  available  at   hxp://www.slideshare.net/ sandroesteves  

More Related Content

PDF
Principles and Practices of LH Use in ART
Sandro Esteves
 
PDF
Principles and practices of LH administration in COS
Sandro Esteves
 
PDF
Management of Male fertility and gonodotropin role
Sandro Esteves
 
PDF
Role of LH in Controlled Ovarian Stimulation
Sandro Esteves
 
PDF
The Role of Recombinant hCG in IVF
Sandro Esteves
 
PDF
Recombinant hCG: state-of -art formulation for a patient-centered management ...
Sandro Esteves
 
PDF
Anabolic Steroids and Male Infertility
Sandro Esteves
 
PDF
Subclinical Infections and Male Infertility
Sandro Esteves
 
Principles and Practices of LH Use in ART
Sandro Esteves
 
Principles and practices of LH administration in COS
Sandro Esteves
 
Management of Male fertility and gonodotropin role
Sandro Esteves
 
Role of LH in Controlled Ovarian Stimulation
Sandro Esteves
 
The Role of Recombinant hCG in IVF
Sandro Esteves
 
Recombinant hCG: state-of -art formulation for a patient-centered management ...
Sandro Esteves
 
Anabolic Steroids and Male Infertility
Sandro Esteves
 
Subclinical Infections and Male Infertility
Sandro Esteves
 

What's hot (20)

PPTX
LH in Human Reproduction (Updated)
Sandro Esteves
 
PDF
Progesterone rise and IVF success
Sandro Esteves
 
PDF
Principles and practices in individualizing in ART
Sandro Esteves
 
PDF
Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy R...
Sandro Esteves
 
PDF
Management of nonobstructive azoospermia
Sandro Esteves
 
PDF
Principles and Practices of LH Administration in Controlled Ovarian Stimulation
Sandro Esteves
 
PDF
Semen analysis as per WHO and clinical implications
Sandro Esteves
 
PDF
Principles and Practices of Individualized OI and IUI
Sandro Esteves
 
PDF
Testicular Sperm Retrieval and Poor Sperm Yield: How do we manage?
Sandro Esteves
 
PDF
Abnormal Semen Parameters: What doctors should know
Sandro Esteves
 
PDF
Medical Management of Male Factor Infertility
Sandro Esteves
 
PDF
Maximizing Outcomes in Assisted Reproductive Technology by Individualization
Sandro Esteves
 
PPTX
LH in Human Reproduction
Sandro Esteves
 
PDF
Management of Nonobstructive Azoospermia Before Surgical Sperm Retrieval
Sandro Esteves
 
PDF
Novel treatments to trigger final follicular maturation and luteal phase support
Sandro Esteves
 
PDF
Role of microsurgery in male infertility
Sandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Sperm Retrieval ...
Sandro Esteves
 
PDF
Obesity and Male Infertility
Sandro Esteves
 
PDF
Mobile Phones and Male Infertility
Sandro Esteves
 
PDF
Management of poor responders
Sandro Esteves
 
LH in Human Reproduction (Updated)
Sandro Esteves
 
Progesterone rise and IVF success
Sandro Esteves
 
Principles and practices in individualizing in ART
Sandro Esteves
 
Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy R...
Sandro Esteves
 
Management of nonobstructive azoospermia
Sandro Esteves
 
Principles and Practices of LH Administration in Controlled Ovarian Stimulation
Sandro Esteves
 
Semen analysis as per WHO and clinical implications
Sandro Esteves
 
Principles and Practices of Individualized OI and IUI
Sandro Esteves
 
Testicular Sperm Retrieval and Poor Sperm Yield: How do we manage?
Sandro Esteves
 
Abnormal Semen Parameters: What doctors should know
Sandro Esteves
 
Medical Management of Male Factor Infertility
Sandro Esteves
 
Maximizing Outcomes in Assisted Reproductive Technology by Individualization
Sandro Esteves
 
LH in Human Reproduction
Sandro Esteves
 
Management of Nonobstructive Azoospermia Before Surgical Sperm Retrieval
Sandro Esteves
 
Novel treatments to trigger final follicular maturation and luteal phase support
Sandro Esteves
 
Role of microsurgery in male infertility
Sandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Sperm Retrieval ...
Sandro Esteves
 
Obesity and Male Infertility
Sandro Esteves
 
Mobile Phones and Male Infertility
Sandro Esteves
 
Management of poor responders
Sandro Esteves
 
Ad

Viewers also liked (20)

PPTX
INDIVIDUALISED OVARIAN STIMULATION PROTOCOLS
G K hospital Indore
 
PDF
The Istanbul Consensus Workshop on Embryo Assessment: Proceedings of an Exper...
Sandro Esteves
 
PDF
Benefícios do prontuário eletrônico na clínica de reprodução humana
Sandro Esteves
 
PDF
O que é importante avaliar na ERA ICSI E IMSI
Sandro Esteves
 
PDF
Evolution of ovarian stimulation for ART - towards an individualized approach
Sandro Esteves
 
PDF
Cuaderno valoración morfología asebir 3ª edición
Asebir
 
PPTX
Videos Comentados em Infertilidade Masculina
Sandro Esteves
 
PPTX
Gestão da Qualidade em Clínicas de Reprodução Assistida - 2013
Fabiola Bento
 
PPTX
Avaliação genética do homem infértil
Sandro Esteves
 
PPT
Letrozole Final
Shannon DeGrote
 
PDF
Aromatase inhibitors or gonadotropin-releasing hormone agonists for the manag...
Aboubakr Elnashar
 
PPTX
Eficácia Clínica da Gonadotrofina Coriônica Humana Recombinante (hCG-rec) pa...
Sandro Esteves
 
PPTX
Ovarian stimulation oral agents
Ahmad Saber
 
PPT
Ovulation induction
nermine amin
 
PPT
Letrozole in assisted reproduction , Prof. Usama M. Fouda
umfrfouda
 
PPTX
Como preparar sua publicação para ser aceita em uma boa revista?
Sandro Esteves
 
PPTX
ovulation induction protocols update 2014
Hesham Al-Inany
 
PPTX
UNEXPLAINED INFERTILITY & INTRAUTERINE INSEMINATION Dr. Sharda jain Lifecare...
Lifecare Centre
 
PPT
Ovarian Stimulation in IUI- Overview Sr. Jyoti Bhaskar
Lifecare Centre
 
PDF
Clomiphene citrate or aromatase inhibitors for superovulation in women with u...
Aboubakr Elnashar
 
INDIVIDUALISED OVARIAN STIMULATION PROTOCOLS
G K hospital Indore
 
The Istanbul Consensus Workshop on Embryo Assessment: Proceedings of an Exper...
Sandro Esteves
 
Benefícios do prontuário eletrônico na clínica de reprodução humana
Sandro Esteves
 
O que é importante avaliar na ERA ICSI E IMSI
Sandro Esteves
 
Evolution of ovarian stimulation for ART - towards an individualized approach
Sandro Esteves
 
Cuaderno valoración morfología asebir 3ª edición
Asebir
 
Videos Comentados em Infertilidade Masculina
Sandro Esteves
 
Gestão da Qualidade em Clínicas de Reprodução Assistida - 2013
Fabiola Bento
 
Avaliação genética do homem infértil
Sandro Esteves
 
Letrozole Final
Shannon DeGrote
 
Aromatase inhibitors or gonadotropin-releasing hormone agonists for the manag...
Aboubakr Elnashar
 
Eficácia Clínica da Gonadotrofina Coriônica Humana Recombinante (hCG-rec) pa...
Sandro Esteves
 
Ovarian stimulation oral agents
Ahmad Saber
 
Ovulation induction
nermine amin
 
Letrozole in assisted reproduction , Prof. Usama M. Fouda
umfrfouda
 
Como preparar sua publicação para ser aceita em uma boa revista?
Sandro Esteves
 
ovulation induction protocols update 2014
Hesham Al-Inany
 
UNEXPLAINED INFERTILITY & INTRAUTERINE INSEMINATION Dr. Sharda jain Lifecare...
Lifecare Centre
 
Ovarian Stimulation in IUI- Overview Sr. Jyoti Bhaskar
Lifecare Centre
 
Clomiphene citrate or aromatase inhibitors for superovulation in women with u...
Aboubakr Elnashar
 
Ad

Similar to Principles and Practices of Individualization in ART (20)

PDF
Optimizing Treatment Outcome in ART
Sandro Esteves
 
PDF
Management of Poor Responders
Sandro Esteves
 
PDF
Ovarian Biomarkers in OI
Sandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Role of IVF Labo...
Sandro Esteves
 
PDF
GnRH agonist versus antagonist and impact on cycle outcome
Sandro Esteves
 
PDF
Improving Success by Tailoring Infertility Treatments - We are all individuals
Sandro Esteves
 
PPTX
Strategies for Improving Success Rates in ART PART
Lifecare Centre
 
PDF
Tailoring Ovarian Stimulation
Sandro Esteves
 
PPT
COH IN ART
Dr. Mamta Vernekar Dighe
 
PPTX
Infertility up to date2
RihabAbbasAli
 
PPTX
Infertility up to date2
RihabAbbasAli
 
PPTX
Infertility up to date2
RihabAbbasAli
 
PDF
Improving Success by Tailoring Infertility Treatments - We are all individuals
Sandro Esteves
 
PDF
Estevesevolutionofovarianstimulationforart towardsanindividualizedapproach-fi...
鋒博 蔡
 
PPTX
Poor response in IVF : How to manage : 2018
Hesham Al-Inany
 
PDF
On invividualization of ovarian stimulation: the arguments in favor
Sandro Esteves
 
PDF
#Individualization of #cos to #optimize #success
Dr. Abha Majumdar
 
PPTX
MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI
DR SHASHWAT JANI
 
PDF
MATCHING OVARIAN RESERVE, OVARIAN RESPONSE AND EMBRYO IMPLANTATION – FROM THE...
Sandro Esteves
 
PPTX
Workshop on Management of poor prognosis patients
Matheus Roque
 
Optimizing Treatment Outcome in ART
Sandro Esteves
 
Management of Poor Responders
Sandro Esteves
 
Ovarian Biomarkers in OI
Sandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Role of IVF Labo...
Sandro Esteves
 
GnRH agonist versus antagonist and impact on cycle outcome
Sandro Esteves
 
Improving Success by Tailoring Infertility Treatments - We are all individuals
Sandro Esteves
 
Strategies for Improving Success Rates in ART PART
Lifecare Centre
 
Tailoring Ovarian Stimulation
Sandro Esteves
 
COH IN ART
Dr. Mamta Vernekar Dighe
 
Infertility up to date2
RihabAbbasAli
 
Infertility up to date2
RihabAbbasAli
 
Infertility up to date2
RihabAbbasAli
 
Improving Success by Tailoring Infertility Treatments - We are all individuals
Sandro Esteves
 
Estevesevolutionofovarianstimulationforart towardsanindividualizedapproach-fi...
鋒博 蔡
 
Poor response in IVF : How to manage : 2018
Hesham Al-Inany
 
On invividualization of ovarian stimulation: the arguments in favor
Sandro Esteves
 
#Individualization of #cos to #optimize #success
Dr. Abha Majumdar
 
MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI
DR SHASHWAT JANI
 
MATCHING OVARIAN RESERVE, OVARIAN RESPONSE AND EMBRYO IMPLANTATION – FROM THE...
Sandro Esteves
 
Workshop on Management of poor prognosis patients
Matheus Roque
 

More from Sandro Esteves (20)

PDF
MODERN REQUIREMENTS OF AN ASSISTED REPRODUCTIVE CENTER OF EXCELLENCE
Sandro Esteves
 
PPTX
Optimize oocyte yield to maximize live birth in ART
Sandro Esteves
 
PDF
Clinical Utility of Sperm DNA Fragmentation Testing: is the jury still out?
Sandro Esteves
 
PDF
Oocyte number, female and male age, and ART outcomes
Sandro Esteves
 
PDF
Impact of Sperm DNA Fragmentation and Dyszoospermia on Recurrent Implantation...
Sandro Esteves
 
PDF
Management of Infertile Men with Non-obstructive Azoospermia: clinical and IV...
Sandro Esteves
 
PDF
Fragmentação do DNA Espermático - Que Aplicações Clínicas?
Sandro Esteves
 
PDF
Luteal Phase Support: Key Variables to Achieve Success in ART
Sandro Esteves
 
PDF
Understanding Strategies to Maximize Cumulative Live Birth Rate
Sandro Esteves
 
PDF
Air quality: is it that important? And if so, how to measure and control it?
Sandro Esteves
 
PDF
Técnicas de Obtencão de Espermatozóides na Azoospermia - Como fazer?
Sandro Esteves
 
PDF
Varicocele e Infertilidade
Sandro Esteves
 
PDF
Como Revisar um Artigo Científico
Sandro Esteves
 
PDF
Poder Amostral e Estatística
Sandro Esteves
 
PDF
Novel concepts in male factor infertility: clinical and laboratory perspectives
Sandro Esteves
 
PDF
Public lecture - Stem Cell and Male Infertility
Sandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Steps Before Spe...
Sandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Chances of Harve...
Sandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Azoospermia Diff...
Sandro Esteves
 
PDF
Clinical Utility of Sperm DNA Fragmentation Testing in Male Infertility Treat...
Sandro Esteves
 
MODERN REQUIREMENTS OF AN ASSISTED REPRODUCTIVE CENTER OF EXCELLENCE
Sandro Esteves
 
Optimize oocyte yield to maximize live birth in ART
Sandro Esteves
 
Clinical Utility of Sperm DNA Fragmentation Testing: is the jury still out?
Sandro Esteves
 
Oocyte number, female and male age, and ART outcomes
Sandro Esteves
 
Impact of Sperm DNA Fragmentation and Dyszoospermia on Recurrent Implantation...
Sandro Esteves
 
Management of Infertile Men with Non-obstructive Azoospermia: clinical and IV...
Sandro Esteves
 
Fragmentação do DNA Espermático - Que Aplicações Clínicas?
Sandro Esteves
 
Luteal Phase Support: Key Variables to Achieve Success in ART
Sandro Esteves
 
Understanding Strategies to Maximize Cumulative Live Birth Rate
Sandro Esteves
 
Air quality: is it that important? And if so, how to measure and control it?
Sandro Esteves
 
Técnicas de Obtencão de Espermatozóides na Azoospermia - Como fazer?
Sandro Esteves
 
Varicocele e Infertilidade
Sandro Esteves
 
Como Revisar um Artigo Científico
Sandro Esteves
 
Poder Amostral e Estatística
Sandro Esteves
 
Novel concepts in male factor infertility: clinical and laboratory perspectives
Sandro Esteves
 
Public lecture - Stem Cell and Male Infertility
Sandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Steps Before Spe...
Sandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Chances of Harve...
Sandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Azoospermia Diff...
Sandro Esteves
 
Clinical Utility of Sperm DNA Fragmentation Testing in Male Infertility Treat...
Sandro Esteves
 

Recently uploaded (20)

PDF
B C German Homoeopathy Medicineby Dr Brij Mohan Prasad
bcgermanhomoeo
 
PPTX
Neoplasia III.pptxjhghgjhfj fjfhgfgdfdfsrbvhv
LeachimEmais
 
PPTX
preoerative assessment in anesthesia and critical care medicine
mdbhatta1271
 
PDF
Lecture 8- Cornea and Sclera .pdf 5tg year
momen mohammed
 
PPTX
CARDIOVASCULAR AND RENAL DRUGS.pptx for health study
sultankorme4
 
PDF
OSCE SERIES - Set 7 ( Questions & Answers ).pdf
Jim Jacob Roy
 
PPTX
Neonate anatomy and physiology presentation
KavyaSamuthiravelu1
 
PDF
OSCE Series ( Questions & Answers ) - Set 6.pdf
Jim Jacob Roy
 
PPTX
Vaccines and immunization including cold chain , Open vial policy.pptx
Dr. Anu Marhatta
 
PPTX
Post Op complications in general surgery
ssusera41aec
 
PDF
AGE(Acute Gastroenteritis)pdf. Specific.
NasibullahSadiqi
 
PPTX
NRP and care of Newborn.pptx- APPT presentation about neonatal resuscitation ...
GururajaRamaiah1
 
PPTX
Electrolyte Disturbance in Paediatric - Nitthi.pptx
28cbdv8bc7
 
DOCX
PEADIATRICS NOTES.docx lecture notes for medical students
lenixjeff
 
PPTX
Approach to chest pain, SOB, palpitation and prolonged fever
ZhenChienOoi
 
PPTX
HYPERSENSITIVITY REACTIONS - Pathophysiology Notes for Second Year Pharm D St...
Ameena Kadar K A
 
PDF
The_EHRA_Book_of_Interventional Electrophysiology.pdf
FransiscaMetta
 
PPT
Dermatology for member of royalcollege.ppt
Nida Us Sahr
 
PPTX
y4d nutrition and diet in pregnancy and postpartum
raunakbasantwani11
 
PPTX
Effects of lipid metabolism 22 asfelagi.pptx
merga3881
 
B C German Homoeopathy Medicineby Dr Brij Mohan Prasad
bcgermanhomoeo
 
Neoplasia III.pptxjhghgjhfj fjfhgfgdfdfsrbvhv
LeachimEmais
 
preoerative assessment in anesthesia and critical care medicine
mdbhatta1271
 
Lecture 8- Cornea and Sclera .pdf 5tg year
momen mohammed
 
CARDIOVASCULAR AND RENAL DRUGS.pptx for health study
sultankorme4
 
OSCE SERIES - Set 7 ( Questions & Answers ).pdf
Jim Jacob Roy
 
Neonate anatomy and physiology presentation
KavyaSamuthiravelu1
 
OSCE Series ( Questions & Answers ) - Set 6.pdf
Jim Jacob Roy
 
Vaccines and immunization including cold chain , Open vial policy.pptx
Dr. Anu Marhatta
 
Post Op complications in general surgery
ssusera41aec
 
AGE(Acute Gastroenteritis)pdf. Specific.
NasibullahSadiqi
 
NRP and care of Newborn.pptx- APPT presentation about neonatal resuscitation ...
GururajaRamaiah1
 
Electrolyte Disturbance in Paediatric - Nitthi.pptx
28cbdv8bc7
 
PEADIATRICS NOTES.docx lecture notes for medical students
lenixjeff
 
Approach to chest pain, SOB, palpitation and prolonged fever
ZhenChienOoi
 
HYPERSENSITIVITY REACTIONS - Pathophysiology Notes for Second Year Pharm D St...
Ameena Kadar K A
 
The_EHRA_Book_of_Interventional Electrophysiology.pdf
FransiscaMetta
 
Dermatology for member of royalcollege.ppt
Nida Us Sahr
 
y4d nutrition and diet in pregnancy and postpartum
raunakbasantwani11
 
Effects of lipid metabolism 22 asfelagi.pptx
merga3881
 

Principles and Practices of Individualization in ART

  • 1.         Principles  and  Prac-ces  of   Individualiza-on  in  ART   Sandro  C.  Esteves,  MD.,  PhD.   Medical  Director,  ANDROFERT   Andrology  &  Human  Reproduc=on  Clinic    Campinas,  BRAZIL  
  • 2. Learning  Objec-ves   1.  Individualiza-on:  a  quality  concept   2.  How  to  individualize  COS  to  different   pa-ent  subgroups   3.  How  to  individualize  triggering     4.  How  to  individualize  luteal  support   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
  • 3. Why  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT
  • 4. Maximize  beneficial   effects  of  treatment   Minimize  complica-ons  and  risks   Why  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015 ANDROFERT
  • 5. Top  3  clinical  dimensions  for  quality   improvement  in  infer-lity  care   •  Effec-veness:      Technical  aspects  to  deliver  the  best  possible  outcome    (e.g.  pregnancy,  live  birth,  cumula=ve  LBR)   •  Safety:    Complica=ons  (OHSS),  adverse  effects,  risks  (pa=ent  &    offspring),  errors/mistakes   •  Pa-ent-­‐centeredness:      Informa=on  and  pa=ent  involvement,  competence  and    aPen=on  of  clinic  and  staff,  accessibility,  coordina=on    and  integra=on,  emo=onal  support   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT Dancet  et  al.  Hum  Reprod  2011;  Mainz  Int  J  Qual  Health  Care  2013    
  • 6. How  stakeholders  value  the  top  3  quality   dimensions  of  infer-lity  care   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT 0% 50% 100% Doctors  &   embryologists   Nurses   Pa-ents   Safety   Effec-veness   Pa-ent-­‐ centeredness   Dancet  et  al.     Hum  Reprod  2013  
  • 7. Lack  of  psychological  support  and  poor  quality   of  service  ~60%  treatment  discon-nua-on     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT 22  studies     21,453  pa=ents   8  countries  
  • 8. Individualiza-on  is  a  quality  concept   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT Safety   Pa-ent-­‐   centeredness   Effec-veness  
  • 9. How  to  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
  • 10. Individualizing  S-mula-on  Protocols   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT • Clinical   characteris-cs   • Ovarian  biomarkers   Iden-fy     who  is  who     • Pa-ent-­‐centered   • Effec-ve   • Safe   Protocol  
  • 11. What biomarker do you value more? a. Basal FSH b. AMH c. AFC d. Age
  • 12. AMH  ~  AFC  >  FSH  >  Age   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
  • 13. Popula-on   Cutoff   Sensi-vity   Specificity   Accuracy   AMH  ng/mL     High-­‐ responder1   2.1   85%   79%   0.82   Poor   responder2   0.82   76%   86%   0.88   *Beckman-­‐Couter  genera-on  II  assay;  1>20  oocytes  retrieved;  2≤4  oocytes  retrieved   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16       AMH  &  AFC  should  be  internally  validated   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
  • 14. Quality-­‐based  individualiza-on  in  COS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT High   responders*   Normal     responders*   Low   responders*   Biomarkers   Safety   Pa-ent-­‐   centeredness   Effec-veness   *expected  
  • 15. High  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT •  Main  goal:  Safety   •  Clinical  quality  indicator:  OHSS   •  Protocol  of  choice*:      Antagonist  (flexible;  cetrorelix)    Tailored  recFSH  (112.5-­‐150  IU/d;  follitropin                        alfa;  pen  injector)       *Androfert,  Brazil  
  • 16. GnRH  antagonists  in  high  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT 9  RCT;  966  PCO  women   Rela-ve  Risk   Dura-on  of  ovarian  s-mula-on   -­‐0.74  (95%  CI  -­‐1.12;  -­‐0.36)   Gonadotropin  dose   -­‐0.28  (95%  CI  -­‐0.43;  -­‐0.13)   Oocytes  retrieved   0.01  (95%  CI  -­‐0.24-­‐0.26)   Risk  of  OHSS   Mild   Moderate  and  Severe   20%  vs  32%     1.23  (95%  CI  0.67-­‐2.26)   0.59  (95%  CI  0.45-­‐0.76)   Clinical  PR   1.01  (95%  CI  0.88;  1.15)   Miscarriage  rate   0.79  (95%  CI  0.49;  1.28)   Pundir J et al. RBM Online 2012; 24:6-22
  • 17. iCOS  (n=118):  rec-­‐hFSH  112.5-­‐150  IU  +  GnRH  antagonist  (flexible)   cCOS  (n=131):  rec-­‐FSH  150-­‐225  IU  +  GnRH  agonist  (nafarelin)     39.3   18.5   14.0   57.0   14.3   14.7   4.8   56.0   0   10   20   30   40   50   60   Observed   Excessive   Response  (%)   Oocytes  retrieved   (N)   OHSS  (%)   Pregnancy  (%)   cCOS   iCOS  *p<0.05   *   *   Individualized  vs  conven-onal  COS  in   high  responders   Excessive  response  >20  oocytes  retrieved;  Mild/severe  OHSS  reported;   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT *  
  • 18. Poor  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT •  Main  goal:  pa-ent-­‐centeredness     •  Clinical  quality  indicators:   – Compliance  (drop-­‐out  rate)   – Pa-ent  burden  (cancela-on  rate)   •  Protocol  of  choice*:      Antagonist  (flexible;  cetrorelix)    recFSH  +  recLH  (follitropin  alfa  +  lutropin  alfa          2:1  ra=o:  300  IU  recFSH  +  150  IU  recLH);          from  s=mula=on  D1       *Androfert,  Brazil  
  • 19. 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, 19 2015 ANDROFERT
  • 20. Lehert et al 2012 Increase  of  ≈1   oocyte  per  1,000   UI  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, 20 2015 ANDROFERT
  • 21. Individualized  vs.  Conven-onal  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)   Cancella=on  (%)   Pregnancy/cycle   (%)   cCOS  (Long  GnRHa  +  300-­‐450  IU  recFSH  alone)   iCOS  (GnRH  antagonist  +  rFSH  (225-­‐300  IU)  +rLH  (75-­‐150  IU))   Expected  poor  response:  AMH<0.82  ng/dL;  Observed  poor  response  <5  oocytes  retrieved;   Leão  RBF,  Nakano  FY,  Esteves  SC.  Fer5l  Steril  2013;  100  (Suppl.):  S16     *p<0.05   * * * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
  • 22. Normal  responders   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT •  Main  goal:  effec-veness   •  Clinical  quality  indicators:  number  oocytes   •  Protocol  of  choice*:      <35yr:  Antagonist  +  recFSH      cetrorelix  (flexible);  187.5-­‐262.5  IU/d  follitropin     alfa  pen  injector      >35yr:  Antagonist  +  recFSH/recLH      cetrorelix  (flexible);  follitropin  alfa  +  lutropin  alfa   2:1  ra=o;  225-­‐300  IU/d;  from  s=mula=on  D1       *Androfert,  Brazil  
  • 23. Nega-ve   predictor   Posi-ve   predictor   van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589 Female  Age   (OR=0.95;  CI:  0.94-­‐0.96)     Number  of  oocytes  retrieved   (OR=1.04;  CI:  1.02-­‐1.07)     Level 1a   Predictors  of  pregnancy  in  IVF   14  studies     >30,000  pa=ents   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
  • 24. What is the optimum number of retrieved oocytes to increase pregnancy rates ? a.  4 to 8 b.  9-12 c.  13-17 d.  The higher the better
  • 25. 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 Livebirthrate(%) Oocyte number Observed live birth rate Predicted live birth rate Sunkara  et  al.  Hum  Reprod  2011   450,135 IVF cycles Best  chance  of  live  birth  is  associated   with  ~15  oocytes   number of oocytes that best optimized LBR was 15 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
  • 26. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT ...irrespec-ve  of  age  group  
  • 27. The  higher  the  cohort  size,  the  higher  the   chance  of  having  euploid  embryos   Ata  et  al.  RBM  Online  (2012)  24,  614–620       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
  • 28. Do you take into account the severity of male factor infertility when planning COS? a.  Yes b.  No c.  Never though about it
  • 29. 41.4 47 43.3 20 100 64 61 34.2 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) Live Birth (%) Non-obstructive (N=365) Obstructive (N=146) P<0.01   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
  • 30.  3,412  cycles   Oocyte  number  and  LBR  at  Androfert   (ICSI  cycles  involving  severe  male  factor)     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT 0%   10%   20%   30%   40%   50%   60%   1   2   3   4   5   6   7   8   9   10   11   12   13   14   15   20   25   Number  of  oocytes   Clinical  pregnancy   Live  birth  
  • 31. Each  addi-onal  warming  cycle  increases   the  chance  of  achieving  a  live  birth 40.4% 48.0% ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0% Female Age ≤38 332/822 63/239 17/49 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
  • 32. Oocyte yield by gonadotropin      ↑  1.5  oocytes  (GnRH  antagonist  cycles)   Devroey  et  al.,  2012      ↑  3.1  oocytes  (GnRH  antagonist)     Bosch  et  al.,  2008      ↑  1.8  oocytes  (GnRH  agonist  cycles)   MERIT  Study,  2006        ↑  2.8  oocytes  (GnRH  agonist  cycles)   Hompes  et  al.,  2008        ↑  2.1  oocytes  (16  RCT;  different  protocols)   Lehert  et  al.,  2010   Higher  with   rec-­‐FSH  vs.     hMG,     HP-­‐hMG,  and   uFSH   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
  • 33. LH  supplementa-on  improves  clinical   pregnancy  in  women  >35  yr   Hill    et  al.  Fer5l  Steril    2012   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
  • 34. LH  ac-vity  by  rec-­‐LH  vs  hMG   Adapted  from:  Leao  &  Esteves.  Clinics  2014;  69(4):  279–293.   Product   LH  ac-vity   (IU/vial)   LH   content*   Purity   hMG   75   hCG   ~5%   HP-­‐hMG   75   hCG   ~70%   Lutroprin  alfa  (rec-­‐hLH)   75   LH   >99%   2:1  Follitropin  alfa  +   Lutroprin  alfa     (rec-­‐hFSH  +  rec-­‐hLH)   75   LH   >99%   *hCG  concentrated  or  added  during  purifica-on  process  (8IU  hCG  ~  75IU  LH)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
  • 35. LH  and  hCG  elicit  different  gene   expression     LH   hCG   LHR  and  FSHR  expression                                                               (Trafficking  of  re=noic  acid  :  RXRB,  TTR,  ALDH8A1)   Meiosis  and  follicular  matura-on                                                                             (TRA  :  RXRB,  TTR,  ALDH8A1;  IL11;  AKT3)   Follicular  development  (IL11;  AKT3)   Cellular  growth  (RXRB,  TTR,  ALDH8A1;  IL11;AKT3)   Ovarian  stereodogenesis    (TRA  :  RXRB,  TTR,  ALDH8A1)   Embryo  development  &  survival  (AKT3)   Aromatase   inhibi-on   (PPARS)   Apoptosis   enhancement     (DNAsi)   LH   hCG   Grondal  ML  et  al.  FerFl  Steril  2009;  Menon  KM  et  al.  Biol  Reprod  2004;  Ruvolo  et  al.  Fer=l  Steril  2007     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
  • 36. COS  with  LH  ac-vity  delivered  by  rec-­‐ LH  vs  hMG  in  IVF   Authors,  yr.   Design   N   Main  findings   Buhler  &   Fisher,  2011   Matched  case-­‐ control   4719   Higher  CPR  in  fixed  2:1  rec-­‐ FSH  +  rec-­‐LH  (31%)  vs  hMG   (26%)  and  vs  combo  (rec-­‐FSH   +  hMG,  25%);  p=0.02   Fábregues  et   al,  2013   Cross-­‐over   study   66   Higher  N  oocytes  in  fixed  2:1   rec-­‐FSH  +  rec-­‐LH  (9.8)  vs  HP-­‐ hMG  (7.3);  p<0.01.  Higher  N   frozen  embryos  in  recLH   Dahan  et  al,   2014   Observa=onal     201   Higher  N  oocytes  in  rec-­‐LH   (12)  vs  hMG  (10);  p=0.008.   Higher  CPR  rec-­‐LH  (36%  vs   20%;  p=0.02)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
  • 37. Individualizing  trigger  and  LPS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT High   responders   Normal     responders   Low   responders   Safety   Pa-ent-­‐   centeredness   Effec-veness  
  • 38. 14h 14h 20h 48h  0   20  h   Natural  LH   surge   hCG   Adapted  from  Chan  et  al.  Hum  Reprod.  2003;18:2294-­‐7   Day  6   hCG  and  GnRHa  elicit  final  follicular  matura-on   as  surrogates  for  the  mid-­‐cycle  LH  surge   GnRHa   36-48 h ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT Day  8  
  • 39. GnRH-­‐agonist  vs  hCG    trigger   Fresh  autologous  cycles   Moderate/   severe  OHSS   OR  0.10     0.01-­‐0.82   Live  birth   OR  0.44   0.29-­‐0.68   Youssef et al. Cochrane Database Syst Rev. 2011 High  responders   Fresh  ET   Freeze  all   GnRH-­‐a  trigger   One  size  trigger  does  not  fit  all   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
  • 40. Freeze-­‐all  embryo  policy:  is  it  for  all?     •  Non-­‐inferior  in  effec-veness  in  high-­‐ quality  vitrifica-on  programs,  but…   •  Safety     – Increase  ART  unit  workload   – Perinatal  outcome     •  Higher  rate  of  large  for  gesta-onal  age  (Wennerholm HR 2013)   •  Pa-ent-­‐centeredness   – Psychological  &  cost  burden     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
  • 41.     Modified  LPS  for  fresh  ET  in   GnRH-­‐a  trigger   No.  follicles  day  OPU   1,500  IU  hCG  at  OPU  &  1,000   OPU+5  &  standard  LPS  ≤  14   1,500  IU  hCG  at  OPU  +   standard  LPS  15-­‐25   1,000  IU  hCG  at  OPU  +   standard  LPS  or  Freeze  all  26-­‐30   Freeze  all  >30   Humaidan  et  al.  Hum  Reprod.  2013;28(9):2511-­‐21   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT 14h   14h   20h   48h  0   20  h   4h   GnRHa   Natural   LH  surge   Luteal  phase   defect  
  • 42. Individualizing  trigger   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT Normal  &  poor   responders   rec-­‐hCG   u-­‐hCG   hCG  trigger  
  • 43. RCT   N   Effect   Oocytes   retrieved   9   1409   MD:  -­‐0.04     95%  CI:  -­‐0.69  to  0.61   Live  birth   6   1,019   OR:  1.04   95%  CI:  0.79  to  1.37   Miscarriage   7   1,106   OR:  0.69   95%  CI:  0.41  to  1.18   Severe  OHSS   3   549   OR:  1.49     95%  CI:  0.54  to  4.1   Youssef  et  al.  Cochrane  Database  Syst  Rev.  2011;  13(4):CD003719   Databases  searched  up  to  January  2010   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015 ANDROFERT
  • 44. Farrag et al. JARG 2008; 25:461-6 8.4 7.3 7.1 4.7 0 2 4 6 8 10 No. Retrieved oocytes No. MII with mature cytoplasm rec-hCG (250 mcg; n=42) u-hCG (10,000 IU; n=47) *p<0.01 * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
  • 45. Effec-veness     RCT  comparing  trigger  with  rec-­‐hCG  (250  mcg)  vs   u-­‐hCG  (10,000  IU)  on  delivery  rates  in  eSET   antagonist  cycles   26.7% 44.1% Delivery rate (%) u-hCG rec-hCG N=119   aged<32   OR:  2.16  (95%  CI:  1.01-­‐4.67;  p=0.04)   Papanikolaou  EG  et  al.  Fer5l  Steril  2010;  94:2902-­‐4   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
  • 46. RCT   N   Odds-­‐ra-o   Local  site  reac-ons*   rec-­‐hCG  vs.  u-­‐hCG   3   374   0.39    95%  CI:  0.25  to  0.61   Driscoll  et  al.  2000:  27%  vs  42%   ERHCG  group  2000:  23%  vs  45%   Abdelmassih  et  al.  2005:  23%  vs  45%   Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719 * Pain and/or inflammation   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2015 ANDROFERT
  • 47. hCG  preferences  in  treatment-­‐ experienced  pa-ents  at  Androfert       Total (n=76) 60% 29% 3% 8% prefer new pen prefer pre-filled syringe prefer lyophilized powder to reconstitute Not matter ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
  • 48. Why  immature  oocytes?     1.  Follicles  <13mm   2.  LH  receptor  deficiency   3.  Blood/intrafollicular  level   barely  achieved     4.  Not  enough  -me  for   intrafollicular  hCG  ac-on   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT Trigger  is  the  most  important  injec-on   of  the  cycle  
  • 49. Weight (kgs) 55 64 90 Blood volume (lts) (7% of weight) 3.8 4.4 14 Fat (kgs) (essential 13.5% of weight) 7.4 8.6 27 hCG Blood Threshold hCG Intrafollicular Threshold Blood represents about 7% of the body mass or about 4.5 kg (volume ~ 4.4 liters) in a 64 kg (141 lb) person." Cameron, J.. Physics of the Body. 2nd Edition. Madison, WI:, 1999: 182. Injecting hCG: Size and BMI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
  • 50. What is the optimum interval between trigger and oocyte retrieval? a.  34 to 35h b.  35 to 36h c.  36-38h d.  >38h e.  Doesn’t matter much
  • 51.   63 73 76 79 82 Oocyte  maturity  %   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
  • 52. Individualizing  LPS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT Normal  &  poor   responders   Fresh  ET   FET  
  • 53. In  FET  cycles,  all  of  the  current  methods  of   endometrial  prepara-on  appear  to  be  equally   effec-ve  in  terms  of  ongoing  pregnancy  rate*   •  Meta-­‐analysis  of  20  compara=ve  studies     •  ~13,000  cycles   •  Natural  and  ar=ficial  cycles  with  and  w/o   GnRH  agonist   •  Safety  &  pa-ent-­‐centeredness  not  addressed       Groenewoud  ER  et  al.  Hum  Reprod  Update.  2013;19:458-­‐70   *in  eumenorrhoic  pa-ents   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT
  • 54. Luteal  phase  abnormal  in  s-mulated   cycles   •  Corpus  luteum  func-on   dependent  on  pulsa-le  LH   release  from  pituitary   •  Supraphysiologic  steroid  levels   (by  mul-follicular  development)   inhibits  LH  secre-on   •  Low  LH  levels  causes  luteolysis,   implanta-on  failure  and   shortened  luteal  phase   Jones 1996; Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Fauser & Devroey 2003; Trinchard-Lugan et al 2002; Sherbahn 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT
  • 55. LPS  mandatory  in  s-mulated  cycles •  hCG  vs.  Placebo  or  No  treatment:   Higher  ongoing  PR  (OR=1.75; 95% CI: 1.09-2.81) •  Progesterone  vs.  Placebo  or  No  treatment:   Higher  clinical  PR  (OR=1.83; 95% CI: 1.29-2.61) Higher  ongoing  PR  (OR=1.87; 95% CI: 1.19-2.94) Higher  live  birth  rates  (OR=2.95; 95% CI: 1.02-8.56) Level   1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015 ANDROFERT
  • 56. Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011 High-­‐quality  evidence  on  LPS  in   s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
  • 57. P routes & types Evidence Effect Conclusion Vaginal as effective as IM/oral 13 RCT; 2 MA; >2,000 cycles Similar CPR, LBR & miscarriage True Vaginal safer and more patient- friendly than IM/oral 3 RCT; 1 MA; >2,000 cycles Lower side effects; Increased patient satisfaction True Among vaginal P, patients prefer gel 7 RCT; 1 MA; >2,400 cycles Easier to use; better adherence; lower discharge True Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010; van der Linden et al Cochrane 2011 High-­‐quality  evidence  on  LPS  in   s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
  • 58. 1  hour   3  hours   2  hours   4  hours   Time   Bioadhesion of vaginal P is essential because it takes ~4h to reach steady state in the uterus (first-pass effect) Bulletti C et al. Hum Reprod 1997 aqueous   lipid   -ssue   micronized  progesterone  in  an  ‘oil-­‐in-­‐water’   emulsion  (Crinone®  8%)     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT
  • 59. Similar  outcome  in  low  vs.  high  dosage   Crinone  8%  (90  mg/d)  vs.  200-­‐800  mg/d  (capsules;  tablets;   pressaries) No.  studies   No.     OR;  95%  CI   Live  birth   2   1485   1.01;  0.81-­‐1.26   Clinical  PR   12   4973   1.04;  0.92-­‐1.17   Miscarriage  rate   8   2350   1.27;  0.85-­‐1.89   Mul-ple  PR   4   905   0.95;  0.57-­‐1.58   Van der Linden et al Cochrane 2011 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015 ANDROFERT
  • 60. Vaginal  P  started  at  the  -me  of  OPU  reduces   uterine  contrac-ons  at  the  -me  of  ET 4.6 2.8 4.5 4.2 UC on day of hCG UC on day of ET Crinone started on the day of OPU (n=43) Crinone started on the evening of ET (n=41) P<0.001 Fanchin et al. Fertil Steril 1999 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015 ANDROFERT
  • 61. Luteal-­‐placental  shiw  on  P  produc-on   occurs  around  7-­‐12th  gesta-onal  week 0 100 200 300 400 500 600 700 800 900 0 10 20 30 40 50 60 70 80 4 5 6 7 8 9 10 E2(pg/mL) P(ng/mL) Gestational age in weeks P E2 Scott et al. Fertil Steril 1991; 56:481 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 61 2015 ANDROFERT
  • 62. Principles  and  Prac-ces  of  Individualized   ART  at  Androfert   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 62 2015 ANDROFERT High   responders   Normal     responders   Low   responders   Clinical  features  +  AMH   Antagonist  protocol;  tailored  COS  rec-­‐FSH   (112.5-­‐150  IU)  +  tailored  trigger  (GnRHa  or   rec-­‐hCG);  tailored  LPS  (modified  LPS  or   vaginal  P  gel  OPU)   Antagonist  protocol;  tailored  COS  w/rec-­‐ FSH  (<35yr)  or  rec-­‐FSH+rec-­‐LH  2:1  ra-o   (>35  yr);  rec-­‐hCG  trigger;  LPS  vaginal  P  gel   Antagonist    protocol;  recFSH  +  recLH  2:1   ra-o  +  rec-­‐hCG  trigger;  LPS  vaginal  P  gel    
  • 63. Principles  and  Prac-ces  of   Individualiza-on  in  ART   Conclusions •  Individualiza-on  is  a  quality  concept   •  Safety,  effec-veness  and  pa-ent-­‐centeredness   are  important  principles  in  a  quality-­‐based   individualized  infer-lity  care     •  Novel  biomarkers  combined  with  new  devices   &  drug  regimens  can  be  used  to  deliver  a  high   quality  evidence-­‐based  individualized  ART   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 63 2015 ANDROFERT
  • 64. Thank  you        ‫ا‬‫شكر‬ Obrigado   This  presenta-on  is  available  at   hxp://www.slideshare.net/ sandroesteves