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Principles and Practices of Individualized OI and IUI

Sandro Esteves, profile picture
Sandro Esteves

1. The document discusses principles of individualizing infertility treatment plans based on patient characteristics and biomarkers to maximize effectiveness and safety. 2. Individualizing ovarian stimulation protocols and luteal support involves identifying patient risk factors for poor response or ovarian hyperstimulation syndrome based on age, BMI, medical history, antral follicle count, and anti-Müllerian hormone levels. 3. Biomarkers like AMH and AFC help identify patients who may require more or less aggressive stimulation to balance treatment success and complication risk.

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        Principles  and  Prac-ces  of   Individualiza-on  in  OI/IUI   Sandro  C.  Esteves,  MD.,  PhD.   Medical  Director,  ANDROFERT   Andrology  &  Human  Reproduc=on  Clinic    Campinas,  BRAZIL  
Learning  Objec-ves   1.  Why  individualize       2.  How  to  individualize  OS     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?     Consulting & diagnosis Decide treatment strategy & ovarian stimulation Planned intercourse or IUI Treatment outcome Control Control Control 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   Dancet  et  al.  Hum  Reprod  2011;  Mainz  Int  J  Qual  Health  Care  2013     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
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  
  Incidence1:   3-­‐6%  moderate  OHSS   ~2%  severe  OHSS Safety   1Aboulghar. Fertil Steril. 2012;97:523-6; 2Confidential Enquiry into Maternal and Child Health, 2007; 3ICMART 1.5  million  cycles/year3   ~500  deaths  (last  10  years)   :  3/100,000  cycles2   OHSS  most  serious  complica-on  of  OI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT
           OI/CC:  13.5%  of  mild  forms1              IUI:  2-­‐8%  cycle  cancella-on2       Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356   OHSS  in  OI  and  IUI  Safety   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT
OHSS  must  be   PREVENTED    rather  than   treated    
Lack  of  psychological  support  and  poor  quality   of  service  ~60%  treatment  discon-nua-on     22  studies     21,453  pa=ents   8  countries   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT
Individualiza-on  is  a  quality  concept   Safety   Pa-ent-­‐   centeredness   Effec-veness   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
How  to  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
Individualizing  S-mula-on  Protocols   • Clinical   characteris-cs   • Ovarian  biomarkers   Iden-fy     who  is  who     • Pa-ent-­‐centered   • Effec-ve   • Safe   Protocol   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
  Young  and  aged  pa-ents   BMI     Polycys-c  ovaries     PCOS   Previous  OHSS   History  of  poor  response   Easily   Recognized     Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Humaidan et al., Fertil Steril. 2010; 94:389-400.   Iden-fying  who  is  who  before  OS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT
    The  Roderdam  Consensus     Polycys-c  ovary:       Ultrasound  showing  ≥12  follicles  (2-­‐9  mm)  AND/OR   ovarian  volume  >10  cm3     Polycys-c  ovary  syndrome:  2  out  of  3      1.  Oligo-­‐  and/or  anovula=on      2.  Clinical  and/or  biochemical  hyperandrogenism    3.  Polycys=c  Ovary   OHSS  Risk:  PCOS  >  isolated  PCOS  characteris-cs     Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Hum Reprod. 2004;19:41-7; Humaidan et al., Fertil Steril. 2010; 94:389-400 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT
Not  easily   recognized     Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Humaidan et al., Fertil Steril. 2010; 94:389-400.   BIOMARKERS  of   Ovarian  Response   Sensi-ve  and  aged  ovaries   Iden-fying  who  is  who  before  OS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
What biomarker do you value more? a. Basal FSH b. AMH c. AFC d. Estradiol
AMH  ~  AFC  >  FSH  >  Age   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 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, 19 2015 ANDROFERT
1Nardo  et  al.  Fer$l  Steril  2009;  2Checa  et  al.  Fer$l  Steril  2010     AMH   (ng/mL)   AFC   False   Result   Risk     OHSS1,2   >3.5   >16   ~15%   pmol/L   X1000/140   Level   2a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
Quality-­‐based  individualiza-on  in  COS   High   responders*   Normal     responders*   Low   responders*   Clinical  features  &  Biomarkers   Safety   Pa-ent-­‐   centeredness   Effec-veness   *expected   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
50  mg/d   100  mg/d   150  mg/d   Ovula-on  Ovula-on   2  –  3  cycles  with  the  same  dose   Ovula-on   No     Ovula-on        No   Ovula-on   No     Ovula-on   No  pregnancy  Subop-mal  Endometrium   (thickness  <7mm)   Injectable   Gonadotropins   Clomiphene  Citrate   Hypogonadotropic   hypogonadism  &   hypergonadotropic   hypogonadism   Anovula-on:  how  many  cycles  and  how?   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
CC  –  ASRM  Prac-ce  Guidelines  2013   •  No  indica-on:   – Low  ovarian  reserve     – severe  male  factor  infer-lity   – Tubal  pathology   •  Anovulatory  women  who  ovulate  with  CC:   – PR  >50%  in  6  cycles;  lower  in  obese  (~16%)   •  Therapy  beyond  6  cycles  not  recommended     ASRM  Prac=ce  CommiPee.  Fer$l  Steril  2013;100:343–8   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
How to individualize use of injectable gonadotropins and what to expect?
ASRM  Prac-ce  Guidelines  2008   •  Pre-­‐Tx  evalua-on:   – Thyroid  func-on  and  hyperprolac-nemia     – HSG,  TVUS   – Semen  analysis   •  Low  dose-­‐gonadotropin  (37.5-­‐75  IU/day)   •  Monitoring:  TVUS,  E2  levels     •  Ovula-on  trigger:  hCG,  GnRHa   •  Luteal  phase  support  recommended   ASRM  Prac=ce  CommiPee.  Fer$l  Steril  2008;90:S7-­‐12   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
Where  to  do  it?     •  ISO  9001  cer-fied  Andrology  lab   •  External  QC     Semen  parameters:    Sperm  count  &  mo=lity    Morphology  &  vitality    Leukocyte  count    Post-­‐washing  mo=le  sperm  count    Sperm  DNA  fragmenta=on   Expanded  Semen  Analysis   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT
Where  to  do  it?     Semen  parameters:    Morphology  >4%  (strict  criteria)    Leukocytes  <  1  million/mL  (Endtz  test)    Post-­‐processing  total  sperm  count  >5  million   Ø   2-­‐layer  discon=nuous  coloidal  gradient  (Isolate)   Ø   Swim-­‐up  method    Sperm  DNA  fragmenta-on  (SCD)  <20%   Semen  criteria  for  OI/IUI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
Strict  morphology   ≤4%   >4%   Montanaro-­‐Gauci  et  al.  (2001)   2.6%   15.6%   Ombelet  et  al.  (1997)   12.1%   16.5%   Karabinus  and  Gelety  (1997)   6.5%   9.0%   Lindheim  et  al.  (1996)   1.0%   19.5%   Toner  et  al.  (1995)   7.0%   11.3%   Matorras  et  al.  (1995)   10.9%   13.0%   PR  per  cycle   8.7%   (64/731)   12.8%   (208/1628)   P  <0.001   Predic-ve  value  of  normal  sperm   morphology  (WHO  2010)  for  IUI   Adapted  from:  J  Van  Waart,  TF  Kruger,  CJ  Lombard  et  al.  Predic=ve  value  of  normal  sperm  morphology  in   intrauterine  insemina=on  (IUI):  a  structured  literature  review.  Hum.  Reprod.  Update  (2001)  7:495-­‐500   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT
19% 1.5% Normal Elevated Live Birth Rates with Intrauterine Insemination OR = 0.07 [95% CI: 0.01-0.48] Feijo & Esteves Fertil Steril 2014;101:58-63 ART Outcome in Men with High Sperm DNA Damage Predic-ve  value  of  normal  sperm  DNA   fragmenta-on  for  IUI   Normal  values  <20%   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT Bungum et al. Hum Reprod 2007; 22: 74–9
CC/TMX/AI  +  injectable  gonadotropin   CC  D2-­‐D7  +  50-­‐75  IU  gonadotropin  D8  on   Injectable  gonadotropin  alone   D2/D3  variable  star-ng  doses   HMG,  uFSH   rec-­‐hFSH   Protocols  with  gonadotropins     in  OI/IUI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
Our  method  in  OI/IUI:  low  dose  step-­‐up   gonadotropin  alone  s-mula-on •  Star-ng  dose:  37.5  -­‐  50  IU  (rec-­‐hFSH  pen  injec-on)*   •  Step-­‐up  (by  12.5  to  37.5  IU)  if  no  follicles  >10mm  auer  7  days   •  Step-­‐up  every  7  days  un-l  dominant  follicle  appear   •  Rec-­‐hCG  (250  mcg):  ≥18mm  and  endometrium  ≥7mm     •  LPS:  progesterone  gel  90  mg  once/day   2   3   4   5   7  6   8   9   10   11   12   13  1   Ultrasound   Menses   Start  day   14   15   *Menormin  added  in  PCO  pa=ents;     Medroxiprogesteron  10  mg/d  to  induce  menses   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
•  N  =  968  cycles   •  >70%  ovulatory  cycles;  >85%  monofollicular  growth   •  Threshold  to  produce  a  dominant  follicle:     Ø  37.5  to  75  IU  (~75%)   •  Average  s-mula-on  dura-on:  15  days   •  CPR  auer  6  cycles:  ~60%  (WHO  type  II)   •  IUI  auer  3  cycles:  28.7%  (cervix,  idiopathic,  male)     •  No  moderate/severe  OHSS   •  ~10-­‐15%  cancella-on  (mul-follicular  development)   Low  dose  step-­‐up  gonadotropin  alone   s-mula-on  in  anovulatory  WHO  II  pa-ents ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
Prac-cal  aspects  in  low-­‐ dose  gonadotropin   treatment     Be  pa-ent!     It  may  take  10  days  or  more  for  a  dominant  follicle  to   appear  during  the  first  treatment  cycle   TVUS  scan  before  star-ng:   progestin (medroxyprogesterone acetate, 5-10 mg/d) to induce a withdrawal bleed if endometrium thickness >8 mm ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 No.   Studies   No.   Par-cipants   Odds-­‐ra-o   Pregnancy   7   556     OR:  1.76     (95%  CI:  1.16  to  2.66)   Miscarriage   4   120   OR:  1.2   (95%  CI:  0.67  to  1.9)   Mul-ple   Pregnancy   4   120   OR:  0.73     (95%  CI:  0.32  to  1.67)     OHSS   2   200   OR:  4.44     (95%  CI:  0.48  to  41.25)     Level 1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
Conven-onal  vs  low  dose  step-­‐up   s-mula-on  in  IUI     Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 2  RCT;  n=  297   ≥75  IU/day   50-­‐75  IU/ day   OR   OHSS   13%   2.7%     5.52     (95%  CI:  1.85-­‐16.52)   Pregnancy   31.1%   28.2%   1.15    (95%  CI:  0.69-­‐1.92)   Level   1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
Level 1a   3  RCT;  “equal  dose  group”   Higher  PR  with  rec-­‐hFSH     (16.4%  vs  12.3%)   RR: 1.39 (95% CI: 1.00-1.96) Meta-­‐analysis  6  RCT  (N=713  pts;  1,581  cycles)   Recombinant  X  urinary  gonadotropins  in  IUI     Similar  PR:  14.5%  vs  14.9%  but  rec-­‐FSH  dose  50%  lower     (RR:  0.970;  95%  CI:  0.68-­‐1.37)     Can=neau  et  al.  Cochrane  Database  Syst  Rev.  2007;  18(2):CD005356   37.5   62.5   50   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
LH  supplementa-on  in  WHO  group  I   (LH levels <1.2 UI/L) Higher  follicular  and  endometrial  development     pts.  receiving  LH  (67%  vs  20%;  p=0.02)   Shoham et al., 2008 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
Clomiphene-­‐resistant     Fewer  intermediate-­‐sized  follicles  and  OHSS  in  LH-­‐supl.   vs  FSH  group;  similar  ovula-on  rate  (Plateau,  2006)   Previous  Excessive  Response   Higher  monofollicular  development  in  LH  group  (32%   vs  13%;  p=0.04)  Hughes  et  al.,  2005   IUI     Higher  monofollicular  development  in  LH  group  w/o   intermediate-­‐size  (42%  vs  11%;  p=0.03);  Lower  cycle   cancella-on  due  to  OHSS  risk  (-­‐7%  difference)    Segnella  et  al.,  2011   LH  supplementa-on  in  WHO  group  II   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
1.  PCOS  w/previous  excessive  response  to  FSH   75  IU  rec-­‐LH  from  D1  (min.  7  days)   2.  Hypo-­‐hypo    75  IU  rec-­‐LH  from  D1   3.  Poor  responders;  advanced  age  (>35  yr.)   Rec-­‐FSH  +  rec-­‐LH  (2:1  ra=o)  from  Sd1  (225  IU/day)   2   3   4   5   7  6   8   9   10   11   12   13  1   Ultrasound   Menses   14   15   Our  method  of  LH  supplementa-on  in  OI/IUI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
Gonadotropins  containing  LH  ac-vity   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, 40 2015 ANDROFERT
HMG:  lower  expression  of  LH  receptor   and  other  genes  involved  in  steroids   biosynthesis  in  GC   Down-­‐regula5on  due  to  constant  ligand   exposure  of  receptors  to  hCG       Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Func-onal  and  molecular  differences  in   prepara-ons  with  LH  ac-vity   HMG  vs  FSH+recLH  in  WHO I Similar  follicular  development  but  higher  PR  auer  3  cycles  in   rec-­‐LH  group  (56%  vs  23%;  p=0.01)    Carone  et  al.,  2012   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
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 Leao & Esteves. Clinics 2014; 69(4): 279–293. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
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, 43 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. Fertil Steril 2009; Menon KM et al. Biol Reprod 2004;; Ruvolo et al. Fertil Steril 2007 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
Injectable  gonadotropins:     when,  how  and  what  to  expect?   Injectable  gonadotropins  when…   §  3  CC  ovulatory  cycles  but  no  pregnancy   §  Subop-mal  endometrium  thickness  or  no  response  w/CC   §  WHO  I  (hypo-­‐hypo)  anovula-on   Low-­‐dose  step-­‐up  is  the  best  protocol   Higher  PR  than  CC  without  increased  risks   Higher  potency  and  efficacy  w/recombinants   LH  supplementa-on  mandatory  in  WHO  I  and    beneficial  in  selected  WHO  II  pa-ents       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
How to individualize ovulation trigger in OI and IUI cycles?
14h 14h 20h 48h  0   20  h   Natural  LH   surge   hCG   Adapted  from  Chan  et  al.  Hum  Reprod.  2003;18:2294-­‐7   Day  6   Both  hCG  and  GnRHa  used  to  trigger  ovula-on   as  surrogates  for  the  mid-­‐cycle  LH  surge   GnRHa   36-48 h Day  8   Rescues CL, maintaining luteal function until placental steroidogenesis is well established ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
When:     Ø   mean  diameter  dominant  follicle  2D  TVUS          23-­‐28  mm  (988  IUI  with  CC  &  tetrozole)2        ≥16  mm  (620  IUI  with  gonadotropins)3        ~19  mm  (615  IUI  with  gonadotropins)4     hCG for triggering ovulation 1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; 2Palatnik et al, Fertil Steril 2012;97:1089–94; 3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60; 4Shalom- Paz E et al. Gynecol Endocrinol. 2014;30:107-10; 5Andersen et al. Hum Reprod 1995;10:3202–5 Ovula-on  occurs  38.3  ±  0.54  h  later5   Ø   -med  intercourse  and  IUI           ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT
Why  do  some  pa-ents  fail  to  ovulate   auer  hCG  injec-on?     1.  Errors  hCG  administra-on   2.  Type  of  hCG     3.  LH  receptor  deficiency   4.  Blood/intrafollicular  level   barely  achieved     5.  Not  enough  -me  for   intrafollicular  hCG  ac-on   Most  stable   gonadotropin*   *temporary changes in refrigeration chain do not affect bioactivity ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
Urinary   Recombinant   Timelines   1948   2001   Ac-ve  protein   30%   >99%   Other  proteins   70%   None   Bioac-vity   800  IU/mg   27,000  IU/mg   Half-­‐life   30  h   29.6  h   Presenta-on   lyophilized  vials     (5,000-­‐10,000  IU)     pre-­‐filled  syringe   and  pen  device       (250  mcg  ≅  6,750  IU)   Route   IM   SC   ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8 hCG for triggering ovulation ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT
250 μg rhCG=6,750 IU; SC 10,000 IU uhCG; IM 5,000 IU uhCG; IM SerumhCGlevels Trinchard-Lugan et al., 2002 Itskovitz et al., 1991 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
Propor-on  of  total   immunoreac-vity  (%)   Pregnyl®   Choragon®   Profasi®   Ovitrelle®   Intact  bioac-ve  hCG   50   30   96   >99   Hyperglycosylated  hCG   0.6   4   0.5   <0.1   Free  β  subunit   6.2   8   2.4   <0.1   β-­‐core  fragment1   43   58   1.2   -­‐-­‐   Epidermal  growth   factor2   181-­‐204   154   4-­‐10   -­‐-­‐   Gervais et al. Glycobiology 2003;13:179-89; Yarram et al. Fertil Steril 2004;82:232-3 1degradation product of hCG; 2EGF is a contaminant (ng/5000IU) Func-onally  intact  hCG  and  contamina-on   in  urinary  formula-ons   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT
Treatment: Profasi 500 r-hCG 250 r-hCG MaximumhCHperpatient 0 300 600 900 BMI 15 25 35 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. Injec-ng  hCG:  size  and  BMI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT
Markle et al. Fertil Steril 2002; 78:71-2 4.4%   10.8%   15.2%   Timing   Recons=tu=on   or  Injec=on   technique   Total   %  Errors  (N=65)   Human  errors  auer  urinary  hCG   administra-on   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT
Clinical  efficacy:  u-­‐hCG  vs  rec-­‐hCG   RCT   N   Odds-­‐ra-o   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)     Side  Effects   3   374   OR:  0.39  (95%  CI:  0.25  to  0.61)   Level 1a   Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719. Similar,  but  fewer  side-­‐effects  with  rec-­‐hCG   Recommended  Dose  OI/IUI:  5,000  IU  (u-­‐hCG)   and  250  mcg  (rec-­‐hCG)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 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  recons=tute   Not  maPer   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
ü Beder  safety  profile   ü Beder  tolerated   ü Easy  to  teach  pa-ents   ü Pa-ent-­‐friendly     •  Easy  to  handle   •  More  convenient  (self-­‐injec=on)     Rec-­‐hCG  pen  injector  method  of  choice   for  hCG  administra-on  at  Androfert       Pa-ent-­‐   centeredness   Effec-veness   Safety   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
hCG stimulates granulosa-lutein cells to produce vascular endothelial growth factor (VEGF)1,2 VEGF binds to VEGFR-2 on the endothelial cell membranes leading to increased vascular permeability, causing OHSS1,2 Risk factors for OHSS2,3: Multifollicular development Estradiol ≥ 5,000 ng/L 1Soares, et al., Hum Reprod Update 2008, 14:321; 2Fiedler & Ezcurra Reprod Biol Endocrinol 2012,10:32;3Papanikolaou et al. Fertil Steril 2006, 85:112–120 Alternatives: Cancellation or IVF w/GnRH agonist When  to  avoid  hCG  administra-on  in   OI/IUI?       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT
hCG  x  GnRH  agonist  as     surrogates  for  mid-­‐cycle  LH  surge  in  IUI   Meta-­‐analysis  (3  RCT;  N=180)   Pregnancy  rate:    OR  1.27  (0.68-­‐2.40)   Cantineau et al. Cochrane Database Syst Rev. 2010(4):CD006942 14h   14h   20h   48h  0   20h   4h   GnRHa   Natural   LH  surge   Luteal   phase   defect   Our preference: §  0.2 mg triptorelin SC §  Same criteria hCG administration ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015 ANDROFERT
hCG  and  GnRHa  surrogate  for  mid-­‐cycle  LH    surge   Rec-­‐hCG  equivalent  efficacy  and  beder  safety    and  tolerability  profile  than  u-­‐hCG     Type  of  hCG,  human  errors  and  BMI  should    be  considered  in  pa-ents  who  fail  to  ovulate   Ovula-on  trigger  in  OI/IUI       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015 ANDROFERT
How to individualize luteal phase support in OI and IUI cycles?
Progesterone  cri-cal  for  endometrial   recep-vity   q  Prepares endometrium for implantation q  Maintains pregnancy q  May help prevent miscarriage ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 62 2015 ANDROFERT
Corpus  luteum  func-on  dependent  on   pulsa-le  LH  release  from  pituitary   Mid-­‐cycle  LH  levels   Natural  cycle   6.0  IU/l   hCG  trigger   0.2  IU/l   GnRHa  trigger   1.5  IU/l   Tavaniotou & Devroey, 2003; Humaidan et al. 2005 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 63 2015 ANDROFERT
Ovulation hCG Day 8 Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991; Weissman et al., 1986 ; Bonduelle et al., 1988 Day 6.5 Trigger hCG LH activity deficiency period GnRHa 28-32 hours Early  luteal  phase  auer  hCG  and   GnRHa  triggering   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 64 2015 ANDROFERT
LPS  mandatory  in  IVF  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, 65 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 Evidence  on  LPS  in  s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 66 2015 ANDROFERT
Our  method  in  OI/IUI:  vaginal   progesterone  gel • Single  daily  administra-on  (90  mg  P)   hCG  cycles:    Begin  2  days  post-­‐hCG  administra=on  (OI)  or      day  of  insemina=on  (IUI)   GnRHa  cycles:    Same  vaginal  P  regimen  +  hCG  bolus  (~1000      IU)  day  insemina=on   • If  pregnancy  occurs,  con-nue  P  for  10  weeks   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 67 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, 68 2015 ANDROFERT
0 5 10 15 20 25 30 35 40 IM P Vaginal P ng/mL Endometrial Levels 0 0.5 1 1.5 2 2.5 3 3.5 IM P Vaginal PngP/mgprotein Serum Levels P<0.0001   P<0.0001   Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3 P in oil (50mg) vs. Crinone 8% (90 mg) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 69 2015 ANDROFERT
Luteal-­‐placental  shiu  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, 70 2015 ANDROFERT
Principles  and  Prac-ces  of   Individualiza-on  in  OI/IUI   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  OI/IUI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 71 2015 ANDROFERT
Thank  you        ‫ا‬‫شكر‬ Obrigado   This  presenta-on  is  available  at   hdp://www.slideshare.net/ sandroesteves  

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Principles and Practices of Individualized OI and IUI

  • 1.         Principles  and  Prac-ces  of   Individualiza-on  in  OI/IUI   Sandro  C.  Esteves,  MD.,  PhD.   Medical  Director,  ANDROFERT   Andrology  &  Human  Reproduc=on  Clinic    Campinas,  BRAZIL  
  • 2. Learning  Objec-ves   1.  Why  individualize       2.  How  to  individualize  OS     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?     Consulting & diagnosis Decide treatment strategy & ovarian stimulation Planned intercourse or IUI Treatment outcome Control Control Control 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   Dancet  et  al.  Hum  Reprod  2011;  Mainz  Int  J  Qual  Health  Care  2013     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
  • 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.   Incidence1:   3-­‐6%  moderate  OHSS   ~2%  severe  OHSS Safety   1Aboulghar. Fertil Steril. 2012;97:523-6; 2Confidential Enquiry into Maternal and Child Health, 2007; 3ICMART 1.5  million  cycles/year3   ~500  deaths  (last  10  years)   :  3/100,000  cycles2   OHSS  most  serious  complica-on  of  OI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT
  • 8.            OI/CC:  13.5%  of  mild  forms1              IUI:  2-­‐8%  cycle  cancella-on2       Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356   OHSS  in  OI  and  IUI  Safety   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT
  • 9. OHSS  must  be   PREVENTED    rather  than   treated    
  • 10. Lack  of  psychological  support  and  poor  quality   of  service  ~60%  treatment  discon-nua-on     22  studies     21,453  pa=ents   8  countries   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT
  • 11. Individualiza-on  is  a  quality  concept   Safety   Pa-ent-­‐   centeredness   Effec-veness   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
  • 12. How  to  individualize?     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
  • 13. Individualizing  S-mula-on  Protocols   • Clinical   characteris-cs   • Ovarian  biomarkers   Iden-fy     who  is  who     • Pa-ent-­‐centered   • Effec-ve   • Safe   Protocol   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
  • 14.   Young  and  aged  pa-ents   BMI     Polycys-c  ovaries     PCOS   Previous  OHSS   History  of  poor  response   Easily   Recognized     Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Humaidan et al., Fertil Steril. 2010; 94:389-400.   Iden-fying  who  is  who  before  OS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT
  • 15.     The  Roderdam  Consensus     Polycys-c  ovary:       Ultrasound  showing  ≥12  follicles  (2-­‐9  mm)  AND/OR   ovarian  volume  >10  cm3     Polycys-c  ovary  syndrome:  2  out  of  3      1.  Oligo-­‐  and/or  anovula=on      2.  Clinical  and/or  biochemical  hyperandrogenism    3.  Polycys=c  Ovary   OHSS  Risk:  PCOS  >  isolated  PCOS  characteris-cs     Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Hum Reprod. 2004;19:41-7; Humaidan et al., Fertil Steril. 2010; 94:389-400 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT
  • 16. Not  easily   recognized     Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Humaidan et al., Fertil Steril. 2010; 94:389-400.   BIOMARKERS  of   Ovarian  Response   Sensi-ve  and  aged  ovaries   Iden-fying  who  is  who  before  OS   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
  • 17. What biomarker do you value more? a. Basal FSH b. AMH c. AFC d. Estradiol
  • 18. AMH  ~  AFC  >  FSH  >  Age   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT
  • 19. 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, 19 2015 ANDROFERT
  • 20. 1Nardo  et  al.  Fer$l  Steril  2009;  2Checa  et  al.  Fer$l  Steril  2010     AMH   (ng/mL)   AFC   False   Result   Risk     OHSS1,2   >3.5   >16   ~15%   pmol/L   X1000/140   Level   2a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
  • 21. Quality-­‐based  individualiza-on  in  COS   High   responders*   Normal     responders*   Low   responders*   Clinical  features  &  Biomarkers   Safety   Pa-ent-­‐   centeredness   Effec-veness   *expected   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
  • 22. 50  mg/d   100  mg/d   150  mg/d   Ovula-on  Ovula-on   2  –  3  cycles  with  the  same  dose   Ovula-on   No     Ovula-on        No   Ovula-on   No     Ovula-on   No  pregnancy  Subop-mal  Endometrium   (thickness  <7mm)   Injectable   Gonadotropins   Clomiphene  Citrate   Hypogonadotropic   hypogonadism  &   hypergonadotropic   hypogonadism   Anovula-on:  how  many  cycles  and  how?   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
  • 23. CC  –  ASRM  Prac-ce  Guidelines  2013   •  No  indica-on:   – Low  ovarian  reserve     – severe  male  factor  infer-lity   – Tubal  pathology   •  Anovulatory  women  who  ovulate  with  CC:   – PR  >50%  in  6  cycles;  lower  in  obese  (~16%)   •  Therapy  beyond  6  cycles  not  recommended     ASRM  Prac=ce  CommiPee.  Fer$l  Steril  2013;100:343–8   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
  • 24. How to individualize use of injectable gonadotropins and what to expect?
  • 25. ASRM  Prac-ce  Guidelines  2008   •  Pre-­‐Tx  evalua-on:   – Thyroid  func-on  and  hyperprolac-nemia     – HSG,  TVUS   – Semen  analysis   •  Low  dose-­‐gonadotropin  (37.5-­‐75  IU/day)   •  Monitoring:  TVUS,  E2  levels     •  Ovula-on  trigger:  hCG,  GnRHa   •  Luteal  phase  support  recommended   ASRM  Prac=ce  CommiPee.  Fer$l  Steril  2008;90:S7-­‐12   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
  • 26. Where  to  do  it?     •  ISO  9001  cer-fied  Andrology  lab   •  External  QC     Semen  parameters:    Sperm  count  &  mo=lity    Morphology  &  vitality    Leukocyte  count    Post-­‐washing  mo=le  sperm  count    Sperm  DNA  fragmenta=on   Expanded  Semen  Analysis   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT
  • 27. Where  to  do  it?     Semen  parameters:    Morphology  >4%  (strict  criteria)    Leukocytes  <  1  million/mL  (Endtz  test)    Post-­‐processing  total  sperm  count  >5  million   Ø   2-­‐layer  discon=nuous  coloidal  gradient  (Isolate)   Ø   Swim-­‐up  method    Sperm  DNA  fragmenta-on  (SCD)  <20%   Semen  criteria  for  OI/IUI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
  • 28. Strict  morphology   ≤4%   >4%   Montanaro-­‐Gauci  et  al.  (2001)   2.6%   15.6%   Ombelet  et  al.  (1997)   12.1%   16.5%   Karabinus  and  Gelety  (1997)   6.5%   9.0%   Lindheim  et  al.  (1996)   1.0%   19.5%   Toner  et  al.  (1995)   7.0%   11.3%   Matorras  et  al.  (1995)   10.9%   13.0%   PR  per  cycle   8.7%   (64/731)   12.8%   (208/1628)   P  <0.001   Predic-ve  value  of  normal  sperm   morphology  (WHO  2010)  for  IUI   Adapted  from:  J  Van  Waart,  TF  Kruger,  CJ  Lombard  et  al.  Predic=ve  value  of  normal  sperm  morphology  in   intrauterine  insemina=on  (IUI):  a  structured  literature  review.  Hum.  Reprod.  Update  (2001)  7:495-­‐500   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT
  • 29. 19% 1.5% Normal Elevated Live Birth Rates with Intrauterine Insemination OR = 0.07 [95% CI: 0.01-0.48] Feijo & Esteves Fertil Steril 2014;101:58-63 ART Outcome in Men with High Sperm DNA Damage Predic-ve  value  of  normal  sperm  DNA   fragmenta-on  for  IUI   Normal  values  <20%   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT Bungum et al. Hum Reprod 2007; 22: 74–9
  • 30. CC/TMX/AI  +  injectable  gonadotropin   CC  D2-­‐D7  +  50-­‐75  IU  gonadotropin  D8  on   Injectable  gonadotropin  alone   D2/D3  variable  star-ng  doses   HMG,  uFSH   rec-­‐hFSH   Protocols  with  gonadotropins     in  OI/IUI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
  • 31. Our  method  in  OI/IUI:  low  dose  step-­‐up   gonadotropin  alone  s-mula-on •  Star-ng  dose:  37.5  -­‐  50  IU  (rec-­‐hFSH  pen  injec-on)*   •  Step-­‐up  (by  12.5  to  37.5  IU)  if  no  follicles  >10mm  auer  7  days   •  Step-­‐up  every  7  days  un-l  dominant  follicle  appear   •  Rec-­‐hCG  (250  mcg):  ≥18mm  and  endometrium  ≥7mm     •  LPS:  progesterone  gel  90  mg  once/day   2   3   4   5   7  6   8   9   10   11   12   13  1   Ultrasound   Menses   Start  day   14   15   *Menormin  added  in  PCO  pa=ents;     Medroxiprogesteron  10  mg/d  to  induce  menses   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
  • 32. •  N  =  968  cycles   •  >70%  ovulatory  cycles;  >85%  monofollicular  growth   •  Threshold  to  produce  a  dominant  follicle:     Ø  37.5  to  75  IU  (~75%)   •  Average  s-mula-on  dura-on:  15  days   •  CPR  auer  6  cycles:  ~60%  (WHO  type  II)   •  IUI  auer  3  cycles:  28.7%  (cervix,  idiopathic,  male)     •  No  moderate/severe  OHSS   •  ~10-­‐15%  cancella-on  (mul-follicular  development)   Low  dose  step-­‐up  gonadotropin  alone   s-mula-on  in  anovulatory  WHO  II  pa-ents ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
  • 33. Prac-cal  aspects  in  low-­‐ dose  gonadotropin   treatment     Be  pa-ent!     It  may  take  10  days  or  more  for  a  dominant  follicle  to   appear  during  the  first  treatment  cycle   TVUS  scan  before  star-ng:   progestin (medroxyprogesterone acetate, 5-10 mg/d) to induce a withdrawal bleed if endometrium thickness >8 mm ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
  • 34. Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 No.   Studies   No.   Par-cipants   Odds-­‐ra-o   Pregnancy   7   556     OR:  1.76     (95%  CI:  1.16  to  2.66)   Miscarriage   4   120   OR:  1.2   (95%  CI:  0.67  to  1.9)   Mul-ple   Pregnancy   4   120   OR:  0.73     (95%  CI:  0.32  to  1.67)     OHSS   2   200   OR:  4.44     (95%  CI:  0.48  to  41.25)     Level 1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
  • 35. Conven-onal  vs  low  dose  step-­‐up   s-mula-on  in  IUI     Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 2  RCT;  n=  297   ≥75  IU/day   50-­‐75  IU/ day   OR   OHSS   13%   2.7%     5.52     (95%  CI:  1.85-­‐16.52)   Pregnancy   31.1%   28.2%   1.15    (95%  CI:  0.69-­‐1.92)   Level   1a   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
  • 36. Level 1a   3  RCT;  “equal  dose  group”   Higher  PR  with  rec-­‐hFSH     (16.4%  vs  12.3%)   RR: 1.39 (95% CI: 1.00-1.96) Meta-­‐analysis  6  RCT  (N=713  pts;  1,581  cycles)   Recombinant  X  urinary  gonadotropins  in  IUI     Similar  PR:  14.5%  vs  14.9%  but  rec-­‐FSH  dose  50%  lower     (RR:  0.970;  95%  CI:  0.68-­‐1.37)     Can=neau  et  al.  Cochrane  Database  Syst  Rev.  2007;  18(2):CD005356   37.5   62.5   50   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT
  • 37. LH  supplementa-on  in  WHO  group  I   (LH levels <1.2 UI/L) Higher  follicular  and  endometrial  development     pts.  receiving  LH  (67%  vs  20%;  p=0.02)   Shoham et al., 2008 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
  • 38. Clomiphene-­‐resistant     Fewer  intermediate-­‐sized  follicles  and  OHSS  in  LH-­‐supl.   vs  FSH  group;  similar  ovula-on  rate  (Plateau,  2006)   Previous  Excessive  Response   Higher  monofollicular  development  in  LH  group  (32%   vs  13%;  p=0.04)  Hughes  et  al.,  2005   IUI     Higher  monofollicular  development  in  LH  group  w/o   intermediate-­‐size  (42%  vs  11%;  p=0.03);  Lower  cycle   cancella-on  due  to  OHSS  risk  (-­‐7%  difference)    Segnella  et  al.,  2011   LH  supplementa-on  in  WHO  group  II   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
  • 39. 1.  PCOS  w/previous  excessive  response  to  FSH   75  IU  rec-­‐LH  from  D1  (min.  7  days)   2.  Hypo-­‐hypo    75  IU  rec-­‐LH  from  D1   3.  Poor  responders;  advanced  age  (>35  yr.)   Rec-­‐FSH  +  rec-­‐LH  (2:1  ra=o)  from  Sd1  (225  IU/day)   2   3   4   5   7  6   8   9   10   11   12   13  1   Ultrasound   Menses   14   15   Our  method  of  LH  supplementa-on  in  OI/IUI ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
  • 40. Gonadotropins  containing  LH  ac-vity   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, 40 2015 ANDROFERT
  • 41. HMG:  lower  expression  of  LH  receptor   and  other  genes  involved  in  steroids   biosynthesis  in  GC   Down-­‐regula5on  due  to  constant  ligand   exposure  of  receptors  to  hCG       Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol Reprod 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Func-onal  and  molecular  differences  in   prepara-ons  with  LH  ac-vity   HMG  vs  FSH+recLH  in  WHO I Similar  follicular  development  but  higher  PR  auer  3  cycles  in   rec-­‐LH  group  (56%  vs  23%;  p=0.01)    Carone  et  al.,  2012   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
  • 42. 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 Leao & Esteves. Clinics 2014; 69(4): 279–293. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
  • 43. 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, 43 2015 ANDROFERT
  • 44. 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. Fertil Steril 2009; Menon KM et al. Biol Reprod 2004;; Ruvolo et al. Fertil Steril 2007 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
  • 45. Injectable  gonadotropins:     when,  how  and  what  to  expect?   Injectable  gonadotropins  when…   §  3  CC  ovulatory  cycles  but  no  pregnancy   §  Subop-mal  endometrium  thickness  or  no  response  w/CC   §  WHO  I  (hypo-­‐hypo)  anovula-on   Low-­‐dose  step-­‐up  is  the  best  protocol   Higher  PR  than  CC  without  increased  risks   Higher  potency  and  efficacy  w/recombinants   LH  supplementa-on  mandatory  in  WHO  I  and    beneficial  in  selected  WHO  II  pa-ents       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
  • 46. How to individualize ovulation trigger in OI and IUI cycles?
  • 47. 14h 14h 20h 48h  0   20  h   Natural  LH   surge   hCG   Adapted  from  Chan  et  al.  Hum  Reprod.  2003;18:2294-­‐7   Day  6   Both  hCG  and  GnRHa  used  to  trigger  ovula-on   as  surrogates  for  the  mid-­‐cycle  LH  surge   GnRHa   36-48 h Day  8   Rescues CL, maintaining luteal function until placental steroidogenesis is well established ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
  • 48. When:     Ø   mean  diameter  dominant  follicle  2D  TVUS          23-­‐28  mm  (988  IUI  with  CC  &  tetrozole)2        ≥16  mm  (620  IUI  with  gonadotropins)3        ~19  mm  (615  IUI  with  gonadotropins)4     hCG for triggering ovulation 1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; 2Palatnik et al, Fertil Steril 2012;97:1089–94; 3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60; 4Shalom- Paz E et al. Gynecol Endocrinol. 2014;30:107-10; 5Andersen et al. Hum Reprod 1995;10:3202–5 Ovula-on  occurs  38.3  ±  0.54  h  later5   Ø   -med  intercourse  and  IUI           ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT
  • 49. Why  do  some  pa-ents  fail  to  ovulate   auer  hCG  injec-on?     1.  Errors  hCG  administra-on   2.  Type  of  hCG     3.  LH  receptor  deficiency   4.  Blood/intrafollicular  level   barely  achieved     5.  Not  enough  -me  for   intrafollicular  hCG  ac-on   Most  stable   gonadotropin*   *temporary changes in refrigeration chain do not affect bioactivity ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
  • 50. Urinary   Recombinant   Timelines   1948   2001   Ac-ve  protein   30%   >99%   Other  proteins   70%   None   Bioac-vity   800  IU/mg   27,000  IU/mg   Half-­‐life   30  h   29.6  h   Presenta-on   lyophilized  vials     (5,000-­‐10,000  IU)     pre-­‐filled  syringe   and  pen  device       (250  mcg  ≅  6,750  IU)   Route   IM   SC   ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8 hCG for triggering ovulation ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT
  • 51. 250 μg rhCG=6,750 IU; SC 10,000 IU uhCG; IM 5,000 IU uhCG; IM SerumhCGlevels Trinchard-Lugan et al., 2002 Itskovitz et al., 1991 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
  • 52. Propor-on  of  total   immunoreac-vity  (%)   Pregnyl®   Choragon®   Profasi®   Ovitrelle®   Intact  bioac-ve  hCG   50   30   96   >99   Hyperglycosylated  hCG   0.6   4   0.5   <0.1   Free  β  subunit   6.2   8   2.4   <0.1   β-­‐core  fragment1   43   58   1.2   -­‐-­‐   Epidermal  growth   factor2   181-­‐204   154   4-­‐10   -­‐-­‐   Gervais et al. Glycobiology 2003;13:179-89; Yarram et al. Fertil Steril 2004;82:232-3 1degradation product of hCG; 2EGF is a contaminant (ng/5000IU) Func-onally  intact  hCG  and  contamina-on   in  urinary  formula-ons   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT
  • 53. Treatment: Profasi 500 r-hCG 250 r-hCG MaximumhCHperpatient 0 300 600 900 BMI 15 25 35 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. Injec-ng  hCG:  size  and  BMI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015 ANDROFERT
  • 54. Markle et al. Fertil Steril 2002; 78:71-2 4.4%   10.8%   15.2%   Timing   Recons=tu=on   or  Injec=on   technique   Total   %  Errors  (N=65)   Human  errors  auer  urinary  hCG   administra-on   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015 ANDROFERT
  • 55. Clinical  efficacy:  u-­‐hCG  vs  rec-­‐hCG   RCT   N   Odds-­‐ra-o   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)     Side  Effects   3   374   OR:  0.39  (95%  CI:  0.25  to  0.61)   Level 1a   Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719. Similar,  but  fewer  side-­‐effects  with  rec-­‐hCG   Recommended  Dose  OI/IUI:  5,000  IU  (u-­‐hCG)   and  250  mcg  (rec-­‐hCG)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015 ANDROFERT
  • 56. 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  recons=tute   Not  maPer   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015 ANDROFERT
  • 57. ü Beder  safety  profile   ü Beder  tolerated   ü Easy  to  teach  pa-ents   ü Pa-ent-­‐friendly     •  Easy  to  handle   •  More  convenient  (self-­‐injec=on)     Rec-­‐hCG  pen  injector  method  of  choice   for  hCG  administra-on  at  Androfert       Pa-ent-­‐   centeredness   Effec-veness   Safety   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015 ANDROFERT
  • 58. hCG stimulates granulosa-lutein cells to produce vascular endothelial growth factor (VEGF)1,2 VEGF binds to VEGFR-2 on the endothelial cell membranes leading to increased vascular permeability, causing OHSS1,2 Risk factors for OHSS2,3: Multifollicular development Estradiol ≥ 5,000 ng/L 1Soares, et al., Hum Reprod Update 2008, 14:321; 2Fiedler & Ezcurra Reprod Biol Endocrinol 2012,10:32;3Papanikolaou et al. Fertil Steril 2006, 85:112–120 Alternatives: Cancellation or IVF w/GnRH agonist When  to  avoid  hCG  administra-on  in   OI/IUI?       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015 ANDROFERT
  • 59. hCG  x  GnRH  agonist  as     surrogates  for  mid-­‐cycle  LH  surge  in  IUI   Meta-­‐analysis  (3  RCT;  N=180)   Pregnancy  rate:    OR  1.27  (0.68-­‐2.40)   Cantineau et al. Cochrane Database Syst Rev. 2010(4):CD006942 14h   14h   20h   48h  0   20h   4h   GnRHa   Natural   LH  surge   Luteal   phase   defect   Our preference: §  0.2 mg triptorelin SC §  Same criteria hCG administration ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015 ANDROFERT
  • 60. hCG  and  GnRHa  surrogate  for  mid-­‐cycle  LH    surge   Rec-­‐hCG  equivalent  efficacy  and  beder  safety    and  tolerability  profile  than  u-­‐hCG     Type  of  hCG,  human  errors  and  BMI  should    be  considered  in  pa-ents  who  fail  to  ovulate   Ovula-on  trigger  in  OI/IUI       ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015 ANDROFERT
  • 61. How to individualize luteal phase support in OI and IUI cycles?
  • 62. Progesterone  cri-cal  for  endometrial   recep-vity   q  Prepares endometrium for implantation q  Maintains pregnancy q  May help prevent miscarriage ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 62 2015 ANDROFERT
  • 63. Corpus  luteum  func-on  dependent  on   pulsa-le  LH  release  from  pituitary   Mid-­‐cycle  LH  levels   Natural  cycle   6.0  IU/l   hCG  trigger   0.2  IU/l   GnRHa  trigger   1.5  IU/l   Tavaniotou & Devroey, 2003; Humaidan et al. 2005 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 63 2015 ANDROFERT
  • 64. Ovulation hCG Day 8 Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991; Weissman et al., 1986 ; Bonduelle et al., 1988 Day 6.5 Trigger hCG LH activity deficiency period GnRHa 28-32 hours Early  luteal  phase  auer  hCG  and   GnRHa  triggering   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 64 2015 ANDROFERT
  • 65. LPS  mandatory  in  IVF  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, 65 2015 ANDROFERT
  • 66. 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 Evidence  on  LPS  in  s-mulated  cycles   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 66 2015 ANDROFERT
  • 67. Our  method  in  OI/IUI:  vaginal   progesterone  gel • Single  daily  administra-on  (90  mg  P)   hCG  cycles:    Begin  2  days  post-­‐hCG  administra=on  (OI)  or      day  of  insemina=on  (IUI)   GnRHa  cycles:    Same  vaginal  P  regimen  +  hCG  bolus  (~1000      IU)  day  insemina=on   • If  pregnancy  occurs,  con-nue  P  for  10  weeks   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 67 2015 ANDROFERT
  • 68. 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, 68 2015 ANDROFERT
  • 69. 0 5 10 15 20 25 30 35 40 IM P Vaginal P ng/mL Endometrial Levels 0 0.5 1 1.5 2 2.5 3 3.5 IM P Vaginal PngP/mgprotein Serum Levels P<0.0001   P<0.0001   Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3 P in oil (50mg) vs. Crinone 8% (90 mg) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 69 2015 ANDROFERT
  • 70. Luteal-­‐placental  shiu  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, 70 2015 ANDROFERT
  • 71. Principles  and  Prac-ces  of   Individualiza-on  in  OI/IUI   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  OI/IUI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 71 2015 ANDROFERT
  • 72. Thank  you        ‫ا‬‫شكر‬ Obrigado   This  presenta-on  is  available  at   hdp://www.slideshare.net/ sandroesteves