Sandro Esteves, profile picture
Uploaded bySandro Esteves
5,259 views

Top Five Problems You Have with Ovulation Induction and How to Solve Them

The document discusses the top five problems with ovulation induction and how to solve them. It addresses whether protocols need to be individualized, how long clomiphene citrate should be used, the advantages of recombinant versus urinary gonadotropins, the advantages of recombinant versus urinary hCG, and whether LH supplementation is needed. It provides evidence-based recommendations including that protocols should be tailored based on biomarkers and individual factors, clomiphene citrate is usually first-line for up to 3 cycles, and recombinant gonadotropins yield higher pregnancy rates than clomiphene without increased risks.

Embed presentation

The Top Five Problems You Have With Ovulation Induction and How to Solve Them Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Khobar & Gassim, KSA – June, 2013
Esteves, 2 The Top Five Problems You Have With Ovulation Induction and How to Solve Them Esteves SC – June 2013 Review this Lecture at: http://www.androfert.com.br/review
Esteves, 3 Level Type of evidence 1a Obtained from meta-analysis of randomised trials 1b Obtained from at least one randomised trial 2a Obtained from one well-designed controlled study without randomisation 2b Obtained from at least one other type of well- designed quasi-experimental study 3 Obtained from well-designed non-experimental studies (comparative and correlation studies, case series) 4 Obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009) Level of Evidence  Information applied to OI and IUI population  Evidence-based Medicine Grade A recommendation • Good and consistent scientific evidence
Esteves, 4 Is there a need to individualize the protocol per patient? Clomiphene citrate for how many cycles and how? Is there any advantage of recombinant versus urinary gonadotropins? Is there any advantage of recombinant versus urinary hCG for triggering LH surge? Is there a need of LH supplementation in OI cycles? What is in it for me?
Esteves, 5 Is There a Need to Individualize the Protocol per Patient?
Esteves, 6 Singleton live birth at term Maximize Treatment Beneficial Effects 1Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; 2Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; 2Tur et al, Fertil Steril. 2005; 83: 116-121; 3Aboulghar. Fertil Steril. 2012;97:523-6. Multiple Pregnancy2 10-40% Minimize Complications and Risks in OI and IUI Cycle Cancellation1 2-8% Risk of OHSS OHSS3 Severe 2% Moderate 3-6%
 Demographics and anthropometrics (Age, BMI, Race)  Genetic profile  Cause of Infertility  Years of Infertility  Health status  Nutritional status Esteves, 7
1Reproductive Hormones Report - GCC Countries (Feb 2011) 2Bologna criteria: Ferraretti et al. Hum Reprod 2011.Esteves, 8 • Prevalence of Patients with Poor Response to Ovarian Stimulation2 0 5 10 15 20 25 30 35 40 < 30 years 30-35 years 36-39 years 40-42 years >42 years  Cancellation Rate  < 4 oocytes Up to 68% Prevalence of Infertile Patients (WHO II) with PCO in Clinical Practice1 Up to 45% Infertility Patients aged 35 or above1
Esteves, 9 La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097; Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700 Reflect No. Pre-antral and Small Antral Follicles (≤4-8mm); gonadotropin-independent Low inter and intra-cycle variation assessment at any cycle day in a single measurement AMHAFC TVUS at early follicular phase (D2-D4) 2-10 mm (mean diameter); 2D-plane Reflect No. AF at a given time that can be stimulated by gonadotropins Low inter-cycle variation
Esteves, 10 Evidence Level 1a Biomarkers
1Lee et al. Hum Reprod 2008; 2Checa et al. Fertil Steril. 2010; 3Broer et al. Hum Reprod Update 2011; 3Nelson et al. Hum Reprod. 2009; *Bologna criteria: Ferraretti et al. Hum Reprod 2011Esteves, 11 Response to Ovarian Stimulation Anti- Mullerian Hormone (ng/mL) Antral Follicle Count False Positive Rate Risk of OHSS1,2 ≥ 3.4 > 16 ~15% Risk of Poor Response*3 < 1.1 < 5 pmol/L X1000/140 Level 2a
Esteves, 12 Clomiphene Citrate for How Many Cycles and How?
Pituitary GnRH FSH/LH estrogen Hypothalamus Ovary ClomipheneCitrate Esteves, 13 Structurally similar to estrogen binds to estrogen receptors (ER)1 CC binds to ER for extended periods of time depleting ER concentrations1 Ovulatory women: CC increases GnRH pulse frequency2 PCOS: CC increases GnRH pulse amplitude3 frequency is already high HowitWorks? 1Clark & Markaverich. Pharmacol Ther 1982;15:467; 2Kerin JF et al. J Clin Endocrinol Metab 1985;61:265; 3Kettel et al. Fertil Steril 1993;59:532; 4Ibrahim et al. Arch Gynecol Obstet. 2012;286:1581; 5Annapurna et al. Int J Fertil Womens Med 1997;42:215. Negative Effect on Endometrium4 and Cervical Mucus5
ClomipheneCitrate Esteves, 14 How to Use? 2 3 4 5 76 8 9 10 11 12 131 Dose: 50 mg/d for 5 days Menses Start day Ultrasound CC Adapted form the ASRM Practice Committee. Fertil Steril 2003;5:1302–8 Ultrasound
Points to ConsiderClomipheneCitrate Esteves, 15 PCOS: >75% of anovulatory infertility ~25% CC-resistant (mainly obese & hyperandrogenic) ~15% who ovulate have thin endometrium/poor mucus Ultrasound monitoring: 1. Dose can be adjusted, if necessary, in subsequent cycles. 2. Allows endometrial evaluation. In IUI, endometrial appearance/thickness more important than follicle size for hCG administration 3. Assessment for risk of OHSS.
50 mg/d 100 mg/d 150 mg/d OvulationOvulation 2 – 3 cycles with the same dose Ovulation No Ovulation No Ovulation No Ovulation How Many cycles? No pregnancySuboptimal Endometrium (Endometrial thickness <7mm) Injectable Gonadotropins ClomipheneCitrate Esteves, 16 Hypogonadotropic Hypogonadism Adapted from the ASRM Practice Committee. Fertil Steril 2003;5:1302–8
Esteves, 17 Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 Higher PR with gonadotropins (28%) compared with CC (18%) without increased risks Gonadotropins inOI/IUI No. Studies No. Participants Odds-ratio 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) Multiple Pregnancy 4 120 OR: 0.73 (95% CI: 0.32 to 1.67) OHSS 2 200 OR: 4.44 (0.48 to 41.25) Level 1a
Esteves, 18 Low Dose Step-up StimulationGonadotropins inOI/IUI Starting dose: 37.5-50 IU (rec-hFSH); Adjust (by 37.5 IU) if no follicles >10mm after 7-10 stimulation days; Adjust every 7 days until dominant follicle appear; hCG ≥18mm and endometrium ≥7mm 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses Start day 14 15 • >70% ovulatory cycles; >85% monofollicular development • Threshold to produce a dominant follicle: 37.5 to 75 IU (~75%) • Average stimulation duration: 15 days • CPR after 6 cycles: ~60% • No OHSS; ~10-15% cancellation (multifollicular development) Results In PCOS
Points to Consider Esteves, 19 Gonadotropins inOI/IUI 2. Be patient! It may take 10 days or more for a dominant follicle to appear during the first treatment cycle with low-dose gonadotropin. 1. TVUS scan before starting: if endometrium thickness >8 mm, a short course of a progestin (medroxyprogesterone acetate, 5-10 mg/d) is given to induce a withdrawal bleed.
Esteves, 20 Low Dose Step-up Stimulation Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 Conventional vs low-dose step-up in IUI; 2 RCT (n= 297) 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) Similar PR and Lower Risk of OHSS by Using Low dose step-up in IUI Level 1a Gonadotropins inOI/IUI
Esteves, 21 In general, 3 to 6 cycles Level 2a But recent evidence shows that Additional Testing should be offered after 3 unsuccessful cycles Diagnostic Laparoscopy (LPS) Sperm Chromatin Integrity Testing Bonneau et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61; Bungum et al. Hum Reprod 2007; 22: 174–9; Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29.
Sperm Chromatin Dispersion Test: Sperm with absent “halos” have DNA strand breaks Semen/Spermatozoa Quantitative (Normal <20%) Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29. 19% 1.5% Normal Elevated Live Birth Rates with Intrauterine Insemination OR = 0.07 [95% CI: 0.01-0.48] Bungum et al. Hum Reprod 2007; 22: 74–9
Benefits of LPS: Gold standard for diagnosing tubal pathology, adhesions and endometriosis Allow treatment of identified lesions  spontaneous conception In poor prognosis, bypass OI/IUI IVF Diagnostic Laparoscopy(LPS) Esteves, 23 Findings After 3 OI/IUI Failures in Unexplained Infertility1,2 Pelvic disease 50 – 90% Adhesions 10 – 48.4% Endometriosis I/II II/IV 36 – 73% 22 – 50% 4.1 – 26.3% Tubal Disease 1-27% After LPS: PR = 68%1 14% - No treatment 17% - OI/IIU 37% - IVF/ICSI 1Bonneau C et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61; 2Jacobson. Cochrane Database of Systematic Reviews 2010;20;(1):CD001398.
Response to OI depends on patient profile. Biomarkers, AMH and AFC, correctly identify “Who is Who” before OI. CC is usually the first line choice for OI/IIU. Switch to injectable gonadotropins: 3 ovulatory cycles but no pregnancy Suboptimal endometrium thickness (< 7mm) No response with CC 150 mg/d Esteves, 24
Esteves, 25 Injectable Gonadotropins yields Higher PR than CC without Increased Risks. Mild Stimulation with Low-dose Step-up Protocol is Advantageous. Consider Sperm Chromatin Testing and Diagnostic LPS after 3 Failed OI/IUI Cycles.
Is There Any Advantage of Recombinant versus Urinary Gonadotropins for OI?
Recombinant hFSH is more potent than HP-Urinary FSH Meta-analysis Rec-hFSH vs HP-uFSH in IUI 6 RCT; (N=713 pts; 1,581 cycles) Similar PR: 14.5% vs 14.9% with rec-FSH dose 50% lower (RR: 0.970; 95% CI: 0.68-1.37) Esteves, 27 Level 1a Matorras et al. Fertil Steril. 2011;95(6):1937-42 3 RCT; “equal dose group” Higher PR with rec-hFSH (16.4% vs 12.3%) RR: 1.394 (95% CI: 1.00-1.96)
Esteves, 28 Up to 70% impurities
Bassett et al. Reprod Biomed Online 2005;10:169–177. Purity (protein content) Mean specific activity (IU/mg protein) LH activity (IU/vial) Injected protein per 75 IU (mcg) hMG < 5% ~100 75 ~750 hMG-HP < 70% 2,000–2,500 75 ~33 rec-hFSH* > 99% 13,645 0 6.1 Esteves, 29 Gonadotropins inOI/IUI *Follitropin alfa
Esteves, 30 68% 25% Folitropin alfa prefilled ready-to- use pen Needle-free reconstitution, conventional syringe Patient Preferences Easy of use 58% Dosing mechanism 43% Less chance of error 26% Reasons Weiss N. RBMonline 2007;15:31-7 Level 2a • Allowed injections at home • Improved pts. satisfaction (QOL)
*Steelman-Pohley Rat Bioassay, 1953; Bassett et al. Reprod Biomed Online 2005;10:169– 177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. Conventional Bioassay* High variability Rat ovary weight gain Urinary gonadotropins Follitropin beta Esteves, 31 Gonadotropins inOI/IUI Gonadotropin injected sc 1x 3days Sacrifice day 4 and collect Ovaries Ovaries are weighed and data processed
Bassett et al. Reprod Biomed Online 2005;10:169–177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. FbM: Novel analitycal method Protein content in solution by mass Minimal batch-to- batch variability (1.6%) Follitropin alfa Esteves, 32 Gonadotropins inOI/IUI Size Exclusion High Performance Liquid Chromatography (SE- HPLC) 37.5 Mild Stimulation with Precise Dose Adjustments 112.5 75.0
Is There Any Advantage of Recombinant versus Urinary hCG for Triggering Ovulation?
Esteves, 34 hCG Presentation Via Urinary lyophilized vials (5,000-10,000 IU) IM Recombinant choriogonadotropin alfa pre-filled syringes (250 mcg ≅ 6,750 IU) SC 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. Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8 hCGtotrigger ovulationinOI/IUI Recommended Dose: 5,000 IU (250 mcg for rec-hCG) Systematic review (2009) unable to define best hCG dose When: 19–30 mm (~25 mm)1 2D TVUS Dominant Follicle Size Mean Diameter 23-28 mm (988 IUIs with CC & Letrozole)2 ≥16 mm (620 IUIs with gonadotropins)3
Recombinant vs Urinary hCG for Triggering Ovulation RCT N Effect 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 OR: odds ratio; MD: mean difference Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.Esteves, 35 ClinicalEfficacy
Is There Any Advantage of Using Recombinant versus Urinary Products in OI/IUI? Recombinant products are more potent. Similar pregnancy rates using 50% less rec- hFSH. Higher PR using the same dose. Rec-hCG is better tolerated. Fewer side effects.
Is There Any Advantage of Using Recombinant versus Urinary Products in OI/IUI? Other advantages of recombinants vs urinaries: Allow SC self-injection Higher purity and specific activity Patient-friendly Less time-consuming; less hospital/clinic visits Allow mild stimulation by small dose adjustments Higher dose precision; FbM
Is There a Need for LH Supplementation in OI Cycles?
Esteves, 39 • Mild Stimulation (low dose rec-hFSH + GnRH ant.): • 5 oocytes retrieved; • IR = 31% • Conventional Stimulation : • 10 oocytes retrieved; • IR = 29% Verberg et al. Hum Reprod Update 2009; 15: 5–12. Promotion of Steroidogenesis (TCs) early Follicular Phase • Adequate estrogen production • Uterine/endometrial changes Stimulation of final Follicular Maturation (GCs) late FP Esteves, 39 Alviggi et al. Reprod Biomed Online 2006;12:221.
Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.Esteves, 40 • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation Normal • Suppression of GC proliferation • Follicular atresia (non-dominant follicles) • Premature luteinization • Oocyte development compromised High • Insufficient androgen (and estrogen) synthesis • Follicular maturation impaired • Inadequate endometrial proliferation Low
LH levels <1.2 UI/L (WHO group I) Higher follicular development pts. receiving LH (67% vs 20%; p=0.02): Shoham et al., 2008 Similar follicular development HMG vs FSH + rLH; Higher cumulative PR after 3 cycles in FSH + rec-hLH (56% vs 23%; p=0.01): Carone et al., 2012 Level 1b Esteves, 41 WHO group II Clomiphene-resistant: fewer intermediate-sized follicles and OHSS in LH-supl. vs FSH group; similar ovulation rate; Plateau, 2006 Previous over-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 cancellation due to OHSS (-7% difference); Segnella et al., 2011 LHSupplementation inOI/IUI
Esteves, 42 • ~80% normogonadotropic women undergoing Ovarian Stimulation1-3 Normal • 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)4 • Poor responders5 • Slow/Hypo-responders6 • Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)7 Low 1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod 2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175;5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al. RBMOnline 2009; 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637; LHSupplementation inOI/IUI
Reduced ovarian paracrine activity Hurwitz & Santoro 2004 LH receptor poly- morphisms Alviggi et al., 2006 Androgen secretory capacity reduced • Piltonen et al., 2003 Decreased numbers of functional LH receptors • Vihko et al. 1996 Reduced LH bioactivity while imnuno- reactivity unchanged • Mitchell et al. 1995; Marama et al 1984 Action of LH at the follicular level increases androgen production for its later aromatization to estrogens; May restore the follicular milieu in selected pts. to recover oocyte quality. LHSupplementation inOI/IUI
Mochtar et al, 2007 3 RCT (N=310) r-hFSH+rLH vs. r-hFSH alone* OPR OR 1.85 (95% CI: 1.10; 3.11) Bosdou et al, 2012 7 RCT (N= 603) r-hFSH+rLH vs. r-hFSH alone* CPR LBR (only 1 RCT) RD: +6%, (95% CI: -0.3; +13.0) RD: +19% (95% CI: +1.0; +36.0%) Hill et al, 2012 7 RCT (N=902) r-hFSH+rLH vs. r-hFSH alone CPR OR 1.37 (95% CI: 1.03; 1.83) *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.Esteves, 44
Esteves, 45 1. PCOS w/previous excessive response with low dose step-up stimulation Add 75 IU LH activity starting from D1 (min. 7 days) LHSupplementation inOI/IUI 2. Hypo-hypo/Poor responders 1:1 or 2:1 FSH/LH ratio from stimulation D1 Add 75 IU LH activity starting on D6 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses 14 15
*derives primarily from hCG, which is concentrated during purification or added to achieve the desired LH-like biological activity. Beta unit Carboxyl terminal segment Longer in hCG; higher receptor affinity Absent in LH and present in hCG (Longer Half-life) Purity (LH content) hCG content (IU/vial) LH activity (IU/vial) Specific activity (LH/mg protein) Rec-hLH >99% 0 75 22,000 IU hMG-HP 3% ~70 75* ≥ 60 IU Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.Esteves, 46
In Pts. Treated with HMG, expression of LH/hCG receptor and other genes involved in steroids biosynthesis in GCs are lowered May reflect LH receptors down-regulation: Constant ligand exposure during follicular phase due to longer half life and higher binding affinity of hCG compared with rec-hLH May explain the observed lower progesterone levels: Caused by lower LH-induced cholesterol uptake, a decrease in the novo cholesterol synthesis and a decrease in steroid synthesis. 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.Esteves, 47 Level 2a
Esteves, 48 Individualized approaches maximize treatment beneficial effects and minimize complications and risks. Biomarkers, AMH and AFC, are useful to predict ovarian response and to define an individualized stimulation. Mild stimulation with low-dose step-up gonadotropin protocol is advantageous. Is there a need to individualize the protocol per patient? The Top Five Problems With OI and How to Solve Them
Esteves, 49 The Top Five Problems With OI and How to Solve Them CC for 3-6 cycles as the first line choice for OI/IIU. Injectable gonadotropin when: 3 CC ovulatory cycles but no pregnancy Suboptimal endometrium thickness (< 7mm) after CC-OI No response with CC 150 mg/d WHO I (hypo-hypo) anovulation Injectable gonadotropins yields higher PR than CC without increased risks. Consider sperm chromatin testing and diagnostic laparoscopy after 3 failed OI/IUI cycles with gonadotropins. Clomiphene citrate for how many cycles and how?
Esteves, 50 The Top Five Problems With OI and How to Solve Them Recombinants are safer, purer and more potent than urinary gonadotropins. Similar pregnancy rates using 50% less rec-hFSH. Higher PR using the same dose. Recombinant, as pen injector devices, allows SC self- administration and individualized stimulation using small dose adjustments with great precision. Recombinant hCG, as pre-filled syringes, allows SC self-administration and is better tolerated than u-hCG. Is there any advantage of recombinant versus urinary products for OI and LH surge trigger ?
Esteves, 51 The Top Five Problems With OI and How to Solve Them Is there a need of LH supplementation in OI cycles? Crucial for adequate follicular development and endometrial proliferation in WHO I (~75 IU). Promotes monofollicular growth and decreases cancellation in WHO II (CC-resistent and hyper-responders). Increase androgen production for aromatization to estrogen. May restore follicular millieu in less responsive ovaries (>35y-o, diminished ovarian reserve, slow responders). LH activity is hCG-dependent in urinaries and pure LH-dependent in recombinants. Choice of formulations may influence oocyte and corpus luteum competence.
Top Five Problems You Have with Ovulation Induction and How to Solve Them

More Related Content

PPTX
Iui - newer concepts
byDr Sachin Dalal
 
PPTX
Ovulation Stimulation Protocols for IUI - Dr Dhorepatil Bharati
byBharati Dhorepatil
 
PPTX
Monitoring of IVF Cycle - Dr Dhorepatil Bharati
byBharati Dhorepatil
 
PPT
Ovarian Stimulation Protocols
byHesham Gaber
 
PPTX
Ovulation Induction in I.U.I. Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bh...
byLifecare Centre
 
PPTX
Tens Secrets to Ovarian Stimulation
byjaideepmalhotra1960
 
PPTX
Unexplained Infertility - By Dr Dhorepatil Bharati
byBharati Dhorepatil
 
PPTX
AN IDEAL OVULATION INDUCTION REGIMEN
byVasundhara Hospital & Fertility Research Centre Jaipur
 
Iui - newer concepts
byDr Sachin Dalal
 
Ovulation Stimulation Protocols for IUI - Dr Dhorepatil Bharati
byBharati Dhorepatil
 
Monitoring of IVF Cycle - Dr Dhorepatil Bharati
byBharati Dhorepatil
 
Ovarian Stimulation Protocols
byHesham Gaber
 
Ovulation Induction in I.U.I. Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bh...
byLifecare Centre
 
Tens Secrets to Ovarian Stimulation
byjaideepmalhotra1960
 
Unexplained Infertility - By Dr Dhorepatil Bharati
byBharati Dhorepatil
 
AN IDEAL OVULATION INDUCTION REGIMEN
byVasundhara Hospital & Fertility Research Centre Jaipur
 

What's hot

PDF
Controlled ovarian stimulation in IVF
byAboubakr Elnashar
 
PPTX
INNOVATIONS IN ART
byNARENDRA C MALHOTRA
 
PPTX
Luteal phase support in ivf
bymagdy abdel
 
PPT
IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bha...
byLifecare Centre
 
PPT
Fet endometrial preparation
byFatih Karaosmanoglu
 
PDF
Luteal phase support in IUI and ART | Dr. Laxmi Shrikhande | ShrikhandeIVF
byDr.Laxmi Agrawal Shrikhande
 
PPTX
OVULATION INDUCTION FOR IUI BY DR SHASHWAT JANI
byDR SHASHWAT JANI
 
PPTX
Ovulation Stimulation Protocols for IUI
byBharati Dhorepatil
 
PDF
Role of LH in Controlled Ovarian Stimulation
bySandro Esteves
 
PPT
Management of poor ovarian response
byHesham Gaber
 
PPTX
MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI
byDR SHASHWAT JANI
 
PPTX
Thin Endometrium & Infertility
byLifecare Centre
 
PDF
Use of LH in IVF and IUI
bySandro Esteves
 
PPTX
Role of gonadotropins in iui
byAntima Rathore
 
PPSX
what is new in controlled ovarian stimulation?
byAboubakr Elnashar
 
PPTX
Diagnosis and Management of Poor Ovarian Reserve : Evidence & Practice
bySujoy Dasgupta
 
PPT
Embryo Transfer (ET) . Lifecare Centre Dr Sharda Jain Dr. Jyoti Agarwal Dr. ...
byLifecare Centre
 
PPTX
Anti-Mullerian Hormone (AMH) -Novel Biomarker & its Applications
byDr. Rajesh Bendre
 
PPTX
Adolescent PCOS 2023.pptx
byDrPushpaSankhwar
 
PPTX
Gonadotropins.pptx
byRaju Nair
 
Controlled ovarian stimulation in IVF
byAboubakr Elnashar
 
INNOVATIONS IN ART
byNARENDRA C MALHOTRA
 
Luteal phase support in ivf
bymagdy abdel
 
IVF – ICSI in PCOS DIFFICULTIES AND SOLUTIONS Dr. Sharda Jain Dr. Jyoti Bha...
byLifecare Centre
 
Fet endometrial preparation
byFatih Karaosmanoglu
 
Luteal phase support in IUI and ART | Dr. Laxmi Shrikhande | ShrikhandeIVF
byDr.Laxmi Agrawal Shrikhande
 
OVULATION INDUCTION FOR IUI BY DR SHASHWAT JANI
byDR SHASHWAT JANI
 
Ovulation Stimulation Protocols for IUI
byBharati Dhorepatil
 
Role of LH in Controlled Ovarian Stimulation
bySandro Esteves
 
Management of poor ovarian response
byHesham Gaber
 
MANAGEMENT OF POOR RESPONDERS IN IVF BY DR SHASHWAT JANI
byDR SHASHWAT JANI
 
Thin Endometrium & Infertility
byLifecare Centre
 
Use of LH in IVF and IUI
bySandro Esteves
 
Role of gonadotropins in iui
byAntima Rathore
 
what is new in controlled ovarian stimulation?
byAboubakr Elnashar
 
Diagnosis and Management of Poor Ovarian Reserve : Evidence & Practice
bySujoy Dasgupta
 
Embryo Transfer (ET) . Lifecare Centre Dr Sharda Jain Dr. Jyoti Agarwal Dr. ...
byLifecare Centre
 
Anti-Mullerian Hormone (AMH) -Novel Biomarker & its Applications
byDr. Rajesh Bendre
 
Adolescent PCOS 2023.pptx
byDrPushpaSankhwar
 
Gonadotropins.pptx
byRaju Nair
 

Viewers also liked

PPT
Ovulation induction
bynermine amin
 
PDF
Improving success in ovulation induction by treatment individualization
bySandro Esteves
 
PPTX
Ovarian stimulation oral agents
byAhmad Saber
 
PDF
Optimizing clinical outcome of IUI
byDr Parul Katiyar
 
PPTX
Hyperandrogenism
byShashwati Sen
 
PPTX
Panel IUI by DR SHASHWAT JANI ( Optimizing Success in Intrauterine Inseminati...
byDR SHASHWAT JANI
 
PPT
Practical tips for monitoring of an iui cycle
byLifecare Centre
 
PPTX
Hirsutism
bymandybhandal1
 
PDF
HCG timing
byAboubakr Elnashar
 
PPT
Induction Ovulation
byguest7f0a3a
 
PDF
Gonadotrpin ovarian stimulation: Aboubakr elnashar
byAboubakr Elnashar
 
PDF
Principles and Practices of Individualized OI and IUI
bySandro Esteves
 
PDF
Hirsutism
byAboubakr Elnashar
 
PDF
Recent advances in stimulation protocols
bySandro Esteves
 
PDF
Use of N-acetyl Cysteine in ovulation induction
byAboubakr Elnashar
 
PDF
Gonadotrophins in PCOS
byAboubakr Elnashar
 
PPT
Ovarian Stimulation in IUI- Overview Sr. Jyoti Bhaskar
byLifecare Centre
 
PPT
Hirsutism
bydrmcbansal
 
PDF
Caesarean Section: An interactive session
byAboubakr Elnashar
 
PDF
​Is There a Best Stimulation Protocol in OI/IUI Cycles?
bySandro Esteves
 
Ovulation induction
bynermine amin
 
Improving success in ovulation induction by treatment individualization
bySandro Esteves
 
Ovarian stimulation oral agents
byAhmad Saber
 
Optimizing clinical outcome of IUI
byDr Parul Katiyar
 
Hyperandrogenism
byShashwati Sen
 
Panel IUI by DR SHASHWAT JANI ( Optimizing Success in Intrauterine Inseminati...
byDR SHASHWAT JANI
 
Practical tips for monitoring of an iui cycle
byLifecare Centre
 
Hirsutism
bymandybhandal1
 
HCG timing
byAboubakr Elnashar
 
Induction Ovulation
byguest7f0a3a
 
Gonadotrpin ovarian stimulation: Aboubakr elnashar
byAboubakr Elnashar
 
Principles and Practices of Individualized OI and IUI
bySandro Esteves
 
Hirsutism
byAboubakr Elnashar
 
Recent advances in stimulation protocols
bySandro Esteves
 
Use of N-acetyl Cysteine in ovulation induction
byAboubakr Elnashar
 
Gonadotrophins in PCOS
byAboubakr Elnashar
 
Ovarian Stimulation in IUI- Overview Sr. Jyoti Bhaskar
byLifecare Centre
 
Hirsutism
bydrmcbansal
 
Caesarean Section: An interactive session
byAboubakr Elnashar
 
​Is There a Best Stimulation Protocol in OI/IUI Cycles?
bySandro Esteves
 

Similar to Top Five Problems You Have with Ovulation Induction and How to Solve Them

PDF
Isthereabeststimulationprotocolinoiandiuicyclesaspireiiiistanbulesteves 13092...
byRiffat Bibi
 
PPT
Ovarian Hyperstimulation in Intrauterine Insemination
byElmar Breitbach
 
PPT
Ovarian stimulation non surgical 2017
byMahmoud zakherah
 
PPT
Ovarian Stimulation in IUI- Overview. Dr. jyoti Bhaskar, Dr. Sharda Jain, Dr....
byLifecare Centre
 
PPT
Ovulation induction
bysunitafeme
 
PPTX
O.i 2021
byHesham Al-Inany
 
PPTX
Poor response in IVF : How to manage : 2018
byHesham Al-Inany
 
PPTX
Induction of ovulation
bymuhammad al hennawy
 
PPTX
Ovarian stimulation in IUI IVF and PCOs with IVF.pptx
bypharmaworld2019
 
PPTX
Optimizing Fertility: Ovulation Induction in IUI - A Comprehensive Guide
byDr.Laxmi Agrawal Shrikhande
 
PPTX
ovulation induction protocols update 2014
byHesham Al-Inany
 
PPTX
Optimizing iui results
byvandana bansal
 
PPT
Ovulation induction in IUI
byPoonam Loomba
 
PDF
Ovarian stimulation
byAhmed Elbohoty
 
PPTX
Gonadotropin Protocols for Non IVF cycle
byDr.Laxmi Agrawal Shrikhande
 
PPT
Ovulation Induction presented by Dr NIDHI GUPTA.ppt
byNidhiGupta389506
 
PDF
Estevesevolutionofovarianstimulationforart towardsanindividualizedapproach-fi...
by鋒博 蔡
 
PPTX
Stimulation Protocols for IUI | Dr. Laxmi Shrikhande
byDr.Laxmi Agrawal Shrikhande
 
PPTX
ovarian stimulation : a 2018 update
byHesham Al-Inany
 
PPT
Management of poor ovarian response
byHesham Gaber
 
Isthereabeststimulationprotocolinoiandiuicyclesaspireiiiistanbulesteves 13092...
byRiffat Bibi
 
Ovarian Hyperstimulation in Intrauterine Insemination
byElmar Breitbach
 
Ovarian stimulation non surgical 2017
byMahmoud zakherah
 
Ovarian Stimulation in IUI- Overview. Dr. jyoti Bhaskar, Dr. Sharda Jain, Dr....
byLifecare Centre
 
Ovulation induction
bysunitafeme
 
O.i 2021
byHesham Al-Inany
 
Poor response in IVF : How to manage : 2018
byHesham Al-Inany
 
Induction of ovulation
bymuhammad al hennawy
 
Ovarian stimulation in IUI IVF and PCOs with IVF.pptx
bypharmaworld2019
 
Optimizing Fertility: Ovulation Induction in IUI - A Comprehensive Guide
byDr.Laxmi Agrawal Shrikhande
 
ovulation induction protocols update 2014
byHesham Al-Inany
 
Optimizing iui results
byvandana bansal
 
Ovulation induction in IUI
byPoonam Loomba
 
Ovarian stimulation
byAhmed Elbohoty
 
Gonadotropin Protocols for Non IVF cycle
byDr.Laxmi Agrawal Shrikhande
 
Ovulation Induction presented by Dr NIDHI GUPTA.ppt
byNidhiGupta389506
 
Estevesevolutionofovarianstimulationforart towardsanindividualizedapproach-fi...
by鋒博 蔡
 
Stimulation Protocols for IUI | Dr. Laxmi Shrikhande
byDr.Laxmi Agrawal Shrikhande
 
ovarian stimulation : a 2018 update
byHesham Al-Inany
 
Management of poor ovarian response
byHesham Gaber
 

More from Sandro Esteves

PDF
MODERN REQUIREMENTS OF AN ASSISTED REPRODUCTIVE CENTER OF EXCELLENCE
bySandro Esteves
 
PDF
MATCHING OVARIAN RESERVE, OVARIAN RESPONSE AND EMBRYO IMPLANTATION – FROM THE...
bySandro Esteves
 
PPTX
Optimize oocyte yield to maximize live birth in ART
bySandro Esteves
 
PDF
Clinical Utility of Sperm DNA Fragmentation Testing: is the jury still out?
bySandro Esteves
 
PDF
On invividualization of ovarian stimulation: the arguments in favor
bySandro Esteves
 
PDF
Oocyte number, female and male age, and ART outcomes
bySandro Esteves
 
PDF
Impact of Sperm DNA Fragmentation and Dyszoospermia on Recurrent Implantation...
bySandro Esteves
 
PDF
Management of Infertile Men with Non-obstructive Azoospermia: clinical and IV...
bySandro Esteves
 
PDF
Fragmentação do DNA Espermático - Que Aplicações Clínicas?
bySandro Esteves
 
PDF
Luteal Phase Support: Key Variables to Achieve Success in ART
bySandro Esteves
 
PDF
Understanding Strategies to Maximize Cumulative Live Birth Rate
bySandro Esteves
 
PDF
Maximizing Outcomes in Assisted Reproductive Technology by Individualization
bySandro Esteves
 
PDF
Air quality: is it that important? And if so, how to measure and control it?
bySandro Esteves
 
PDF
Técnicas de Obtencão de Espermatozóides na Azoospermia - Como fazer?
bySandro Esteves
 
PDF
Varicocele e Infertilidade
bySandro Esteves
 
PDF
Como Revisar um Artigo Científico
bySandro Esteves
 
PDF
Poder Amostral e Estatística
bySandro Esteves
 
PDF
Novel concepts in male factor infertility: clinical and laboratory perspectives
bySandro Esteves
 
PDF
Public lecture - Stem Cell and Male Infertility
bySandro Esteves
 
PDF
Clinical management of men with nonobstructive azoospermia - Role of IVF Labo...
bySandro Esteves
 
MODERN REQUIREMENTS OF AN ASSISTED REPRODUCTIVE CENTER OF EXCELLENCE
bySandro Esteves
 
MATCHING OVARIAN RESERVE, OVARIAN RESPONSE AND EMBRYO IMPLANTATION – FROM THE...
bySandro Esteves
 
Optimize oocyte yield to maximize live birth in ART
bySandro Esteves
 
Clinical Utility of Sperm DNA Fragmentation Testing: is the jury still out?
bySandro Esteves
 
On invividualization of ovarian stimulation: the arguments in favor
bySandro Esteves
 
Oocyte number, female and male age, and ART outcomes
bySandro Esteves
 
Impact of Sperm DNA Fragmentation and Dyszoospermia on Recurrent Implantation...
bySandro Esteves
 
Management of Infertile Men with Non-obstructive Azoospermia: clinical and IV...
bySandro Esteves
 
Fragmentação do DNA Espermático - Que Aplicações Clínicas?
bySandro Esteves
 
Luteal Phase Support: Key Variables to Achieve Success in ART
bySandro Esteves
 
Understanding Strategies to Maximize Cumulative Live Birth Rate
bySandro Esteves
 
Maximizing Outcomes in Assisted Reproductive Technology by Individualization
bySandro Esteves
 
Air quality: is it that important? And if so, how to measure and control it?
bySandro Esteves
 
Técnicas de Obtencão de Espermatozóides na Azoospermia - Como fazer?
bySandro Esteves
 
Varicocele e Infertilidade
bySandro Esteves
 
Como Revisar um Artigo Científico
bySandro Esteves
 
Poder Amostral e Estatística
bySandro Esteves
 
Novel concepts in male factor infertility: clinical and laboratory perspectives
bySandro Esteves
 
Public lecture - Stem Cell and Male Infertility
bySandro Esteves
 
Clinical management of men with nonobstructive azoospermia - Role of IVF Labo...
bySandro Esteves
 

Recently uploaded

PPTX
DNS deviated nasal septum ent ward s.pptx
bysyedahiba121
 
PPTX
Opthalmoscopy .pptx
byamnajafri1795
 
PPTX
PRODUCTION OF ANTIBIOTICS e.g (Penicillin)
bySadaqat Ahmed
 
PPTX
FEBRUARY 2026 ONCOLOGY CARTOONS BY DR KANHU CHARAN PATRO
byKanhu Charan
 
PPTX
EQUIPMENT USED IN HEMATOLOGY LABORATORY.pptx
byKISMAT ALI
 
PDF
ARCHES OF FOOT -Prof.Dr.N.Mugunthan. KMMC Medical College & Hospitals.pdf
byKanyakumari Medical Mission Research Center, Muttom
 
PPTX
SAPIENT3.0 Medi-trivia Quiz (FINALS) | F.A.Q. 2025
byDr. Anindya
 
PPT
Rethinking Pulmonary Fibrosis: From Fine-Tuning Diagnosis to Illuminating Nov...
byPVI, PeerView Institute for Medical Education
 
PPTX
Formulation Development & Evaluation of Polyherbal Soap
bypurwaborkar@gmail.com
 
PDF
The Doctor's Balance Sheet By Dr Kanhu Charan Patro
byKanhu Charan
 
PPTX
nderstanding Male Sexual Health: Challenges and Solutions
bySujoy Dasgupta
 
PPTX
EMPHYSEMA.cardio pptx by gokulakrishnan sports
byGOKULAKRISHNAN JANARTHANAN
 
PPTX
biological effects of radiation- Nelson A
byHarvinNelson2
 
PPTX
ATA_2025_DTC_MCh_Detailed_Presentation.pptx
byAnbu Arasan
 
PPTX
Foot and ankle examination for ortho residents
bysibasishBrahma1
 
PPTX
Tonsillitis tonsillitis tonsillitis tonsillitis tonsillitis tonsillitis
byssusera62a06
 
PPTX
cardiac transplantation vp copy copy.pptx
byabay35110
 
PDF
Rethinking Pulmonary Fibrosis: From Fine-Tuning Diagnosis to Illuminating Nov...
byPVI, PeerView Institute for Medical Education
 
PPTX
CATARACT SURGERY... KAL AAJ AUR KAL... THE PAST, THE PRESENT AND THE FUTURE.
byirfanrawal
 
PPTX
BRONCHIECTASIS.cardio pptx by gokulakrishnan
byGOKULAKRISHNAN JANARTHANAN
 
DNS deviated nasal septum ent ward s.pptx
bysyedahiba121
 
Opthalmoscopy .pptx
byamnajafri1795
 
PRODUCTION OF ANTIBIOTICS e.g (Penicillin)
bySadaqat Ahmed
 
FEBRUARY 2026 ONCOLOGY CARTOONS BY DR KANHU CHARAN PATRO
byKanhu Charan
 
EQUIPMENT USED IN HEMATOLOGY LABORATORY.pptx
byKISMAT ALI
 
ARCHES OF FOOT -Prof.Dr.N.Mugunthan. KMMC Medical College & Hospitals.pdf
byKanyakumari Medical Mission Research Center, Muttom
 
SAPIENT3.0 Medi-trivia Quiz (FINALS) | F.A.Q. 2025
byDr. Anindya
 
Rethinking Pulmonary Fibrosis: From Fine-Tuning Diagnosis to Illuminating Nov...
byPVI, PeerView Institute for Medical Education
 
Formulation Development & Evaluation of Polyherbal Soap
bypurwaborkar@gmail.com
 
The Doctor's Balance Sheet By Dr Kanhu Charan Patro
byKanhu Charan
 
nderstanding Male Sexual Health: Challenges and Solutions
bySujoy Dasgupta
 
EMPHYSEMA.cardio pptx by gokulakrishnan sports
byGOKULAKRISHNAN JANARTHANAN
 
biological effects of radiation- Nelson A
byHarvinNelson2
 
ATA_2025_DTC_MCh_Detailed_Presentation.pptx
byAnbu Arasan
 
Foot and ankle examination for ortho residents
bysibasishBrahma1
 
Tonsillitis tonsillitis tonsillitis tonsillitis tonsillitis tonsillitis
byssusera62a06
 
cardiac transplantation vp copy copy.pptx
byabay35110
 
Rethinking Pulmonary Fibrosis: From Fine-Tuning Diagnosis to Illuminating Nov...
byPVI, PeerView Institute for Medical Education
 
CATARACT SURGERY... KAL AAJ AUR KAL... THE PAST, THE PRESENT AND THE FUTURE.
byirfanrawal
 
BRONCHIECTASIS.cardio pptx by gokulakrishnan
byGOKULAKRISHNAN JANARTHANAN
 

Top Five Problems You Have with Ovulation Induction and How to Solve Them

  • 1.
    The Top FiveProblems You Have With Ovulation Induction and How to Solve Them Sandro Esteves, M.D., Ph.D. Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL Khobar & Gassim, KSA – June, 2013
  • 2.
    Esteves, 2 The TopFive Problems You Have With Ovulation Induction and How to Solve Them Esteves SC – June 2013 Review this Lecture at: http://www.androfert.com.br/review
  • 3.
    Esteves, 3 Level Typeof evidence 1a Obtained from meta-analysis of randomised trials 1b Obtained from at least one randomised trial 2a Obtained from one well-designed controlled study without randomisation 2b Obtained from at least one other type of well- designed quasi-experimental study 3 Obtained from well-designed non-experimental studies (comparative and correlation studies, case series) 4 Obtained from expert committee reports or opinions or clinical experience of respected authorities Modified from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009) Level of Evidence  Information applied to OI and IUI population  Evidence-based Medicine Grade A recommendation • Good and consistent scientific evidence
  • 4.
    Esteves, 4 Is therea need to individualize the protocol per patient? Clomiphene citrate for how many cycles and how? Is there any advantage of recombinant versus urinary gonadotropins? Is there any advantage of recombinant versus urinary hCG for triggering LH surge? Is there a need of LH supplementation in OI cycles? What is in it for me?
  • 5.
    Esteves, 5 Is Therea Need to Individualize the Protocol per Patient?
  • 6.
    Esteves, 6 Singleton live birthat term Maximize Treatment Beneficial Effects 1Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; 2Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; 2Tur et al, Fertil Steril. 2005; 83: 116-121; 3Aboulghar. Fertil Steril. 2012;97:523-6. Multiple Pregnancy2 10-40% Minimize Complications and Risks in OI and IUI Cycle Cancellation1 2-8% Risk of OHSS OHSS3 Severe 2% Moderate 3-6%
  • 7.
     Demographics and anthropometrics (Age,BMI, Race)  Genetic profile  Cause of Infertility  Years of Infertility  Health status  Nutritional status Esteves, 7
  • 8.
    1Reproductive Hormones Report- GCC Countries (Feb 2011) 2Bologna criteria: Ferraretti et al. Hum Reprod 2011.Esteves, 8 • Prevalence of Patients with Poor Response to Ovarian Stimulation2 0 5 10 15 20 25 30 35 40 < 30 years 30-35 years 36-39 years 40-42 years >42 years  Cancellation Rate  < 4 oocytes Up to 68% Prevalence of Infertile Patients (WHO II) with PCO in Clinical Practice1 Up to 45% Infertility Patients aged 35 or above1
  • 9.
    Esteves, 9 La Marcaet al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097; Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700 Reflect No. Pre-antral and Small Antral Follicles (≤4-8mm); gonadotropin-independent Low inter and intra-cycle variation assessment at any cycle day in a single measurement AMHAFC TVUS at early follicular phase (D2-D4) 2-10 mm (mean diameter); 2D-plane Reflect No. AF at a given time that can be stimulated by gonadotropins Low inter-cycle variation
  • 10.
  • 11.
    1Lee et al.Hum Reprod 2008; 2Checa et al. Fertil Steril. 2010; 3Broer et al. Hum Reprod Update 2011; 3Nelson et al. Hum Reprod. 2009; *Bologna criteria: Ferraretti et al. Hum Reprod 2011Esteves, 11 Response to Ovarian Stimulation Anti- Mullerian Hormone (ng/mL) Antral Follicle Count False Positive Rate Risk of OHSS1,2 ≥ 3.4 > 16 ~15% Risk of Poor Response*3 < 1.1 < 5 pmol/L X1000/140 Level 2a
  • 12.
    Esteves, 12 Clomiphene Citratefor How Many Cycles and How?
  • 13.
    Pituitary GnRH FSH/LH estrogen Hypothalamus Ovary ClomipheneCitrate Esteves, 13 Structurally similarto estrogen binds to estrogen receptors (ER)1 CC binds to ER for extended periods of time depleting ER concentrations1 Ovulatory women: CC increases GnRH pulse frequency2 PCOS: CC increases GnRH pulse amplitude3 frequency is already high HowitWorks? 1Clark & Markaverich. Pharmacol Ther 1982;15:467; 2Kerin JF et al. J Clin Endocrinol Metab 1985;61:265; 3Kettel et al. Fertil Steril 1993;59:532; 4Ibrahim et al. Arch Gynecol Obstet. 2012;286:1581; 5Annapurna et al. Int J Fertil Womens Med 1997;42:215. Negative Effect on Endometrium4 and Cervical Mucus5
  • 14.
    ClomipheneCitrate Esteves, 14 How toUse? 2 3 4 5 76 8 9 10 11 12 131 Dose: 50 mg/d for 5 days Menses Start day Ultrasound CC Adapted form the ASRM Practice Committee. Fertil Steril 2003;5:1302–8 Ultrasound
  • 15.
    Points to ConsiderClomipheneCitrate Esteves,15 PCOS: >75% of anovulatory infertility ~25% CC-resistant (mainly obese & hyperandrogenic) ~15% who ovulate have thin endometrium/poor mucus Ultrasound monitoring: 1. Dose can be adjusted, if necessary, in subsequent cycles. 2. Allows endometrial evaluation. In IUI, endometrial appearance/thickness more important than follicle size for hCG administration 3. Assessment for risk of OHSS.
  • 16.
    50 mg/d 100mg/d 150 mg/d OvulationOvulation 2 – 3 cycles with the same dose Ovulation No Ovulation No Ovulation No Ovulation How Many cycles? No pregnancySuboptimal Endometrium (Endometrial thickness <7mm) Injectable Gonadotropins ClomipheneCitrate Esteves, 16 Hypogonadotropic Hypogonadism Adapted from the ASRM Practice Committee. Fertil Steril 2003;5:1302–8
  • 17.
    Esteves, 17 Cantineauet al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 Higher PR with gonadotropins (28%) compared with CC (18%) without increased risks Gonadotropins inOI/IUI No. Studies No. Participants Odds-ratio 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) Multiple Pregnancy 4 120 OR: 0.73 (95% CI: 0.32 to 1.67) OHSS 2 200 OR: 4.44 (0.48 to 41.25) Level 1a
  • 18.
    Esteves, 18 Low DoseStep-up StimulationGonadotropins inOI/IUI Starting dose: 37.5-50 IU (rec-hFSH); Adjust (by 37.5 IU) if no follicles >10mm after 7-10 stimulation days; Adjust every 7 days until dominant follicle appear; hCG ≥18mm and endometrium ≥7mm 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses Start day 14 15 • >70% ovulatory cycles; >85% monofollicular development • Threshold to produce a dominant follicle: 37.5 to 75 IU (~75%) • Average stimulation duration: 15 days • CPR after 6 cycles: ~60% • No OHSS; ~10-15% cancellation (multifollicular development) Results In PCOS
  • 19.
    Points to Consider Esteves,19 Gonadotropins inOI/IUI 2. Be patient! It may take 10 days or more for a dominant follicle to appear during the first treatment cycle with low-dose gonadotropin. 1. TVUS scan before starting: if endometrium thickness >8 mm, a short course of a progestin (medroxyprogesterone acetate, 5-10 mg/d) is given to induce a withdrawal bleed.
  • 20.
    Esteves, 20 Low DoseStep-up Stimulation Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356 Conventional vs low-dose step-up in IUI; 2 RCT (n= 297) 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) Similar PR and Lower Risk of OHSS by Using Low dose step-up in IUI Level 1a Gonadotropins inOI/IUI
  • 21.
    Esteves, 21 In general,3 to 6 cycles Level 2a But recent evidence shows that Additional Testing should be offered after 3 unsuccessful cycles Diagnostic Laparoscopy (LPS) Sperm Chromatin Integrity Testing Bonneau et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61; Bungum et al. Hum Reprod 2007; 22: 174–9; Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29.
  • 22.
    Sperm Chromatin DispersionTest: Sperm with absent “halos” have DNA strand breaks Semen/Spermatozoa Quantitative (Normal <20%) Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29. 19% 1.5% Normal Elevated Live Birth Rates with Intrauterine Insemination OR = 0.07 [95% CI: 0.01-0.48] Bungum et al. Hum Reprod 2007; 22: 74–9
  • 23.
    Benefits of LPS: Goldstandard for diagnosing tubal pathology, adhesions and endometriosis Allow treatment of identified lesions  spontaneous conception In poor prognosis, bypass OI/IUI IVF Diagnostic Laparoscopy(LPS) Esteves, 23 Findings After 3 OI/IUI Failures in Unexplained Infertility1,2 Pelvic disease 50 – 90% Adhesions 10 – 48.4% Endometriosis I/II II/IV 36 – 73% 22 – 50% 4.1 – 26.3% Tubal Disease 1-27% After LPS: PR = 68%1 14% - No treatment 17% - OI/IIU 37% - IVF/ICSI 1Bonneau C et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61; 2Jacobson. Cochrane Database of Systematic Reviews 2010;20;(1):CD001398.
  • 24.
    Response to OIdepends on patient profile. Biomarkers, AMH and AFC, correctly identify “Who is Who” before OI. CC is usually the first line choice for OI/IIU. Switch to injectable gonadotropins: 3 ovulatory cycles but no pregnancy Suboptimal endometrium thickness (< 7mm) No response with CC 150 mg/d Esteves, 24
  • 25.
    Esteves, 25 Injectable Gonadotropinsyields Higher PR than CC without Increased Risks. Mild Stimulation with Low-dose Step-up Protocol is Advantageous. Consider Sperm Chromatin Testing and Diagnostic LPS after 3 Failed OI/IUI Cycles.
  • 26.
    Is There AnyAdvantage of Recombinant versus Urinary Gonadotropins for OI?
  • 27.
    Recombinant hFSH ismore potent than HP-Urinary FSH Meta-analysis Rec-hFSH vs HP-uFSH in IUI 6 RCT; (N=713 pts; 1,581 cycles) Similar PR: 14.5% vs 14.9% with rec-FSH dose 50% lower (RR: 0.970; 95% CI: 0.68-1.37) Esteves, 27 Level 1a Matorras et al. Fertil Steril. 2011;95(6):1937-42 3 RCT; “equal dose group” Higher PR with rec-hFSH (16.4% vs 12.3%) RR: 1.394 (95% CI: 1.00-1.96)
  • 28.
    Esteves, 28 Up to70% impurities
  • 29.
    Bassett et al.Reprod Biomed Online 2005;10:169–177. Purity (protein content) Mean specific activity (IU/mg protein) LH activity (IU/vial) Injected protein per 75 IU (mcg) hMG < 5% ~100 75 ~750 hMG-HP < 70% 2,000–2,500 75 ~33 rec-hFSH* > 99% 13,645 0 6.1 Esteves, 29 Gonadotropins inOI/IUI *Follitropin alfa
  • 30.
    Esteves, 30 68% 25% Folitropin alfa prefilledready-to- use pen Needle-free reconstitution, conventional syringe Patient Preferences Easy of use 58% Dosing mechanism 43% Less chance of error 26% Reasons Weiss N. RBMonline 2007;15:31-7 Level 2a • Allowed injections at home • Improved pts. satisfaction (QOL)
  • 31.
    *Steelman-Pohley Rat Bioassay,1953; Bassett et al. Reprod Biomed Online 2005;10:169– 177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. Conventional Bioassay* High variability Rat ovary weight gain Urinary gonadotropins Follitropin beta Esteves, 31 Gonadotropins inOI/IUI Gonadotropin injected sc 1x 3days Sacrifice day 4 and collect Ovaries Ovaries are weighed and data processed
  • 32.
    Bassett et al.Reprod Biomed Online 2005;10:169–177; Driebergen et al. Curr Med Res Opin 2003;19:41–46. FbM: Novel analitycal method Protein content in solution by mass Minimal batch-to- batch variability (1.6%) Follitropin alfa Esteves, 32 Gonadotropins inOI/IUI Size Exclusion High Performance Liquid Chromatography (SE- HPLC) 37.5 Mild Stimulation with Precise Dose Adjustments 112.5 75.0
  • 33.
    Is There AnyAdvantage of Recombinant versus Urinary hCG for Triggering Ovulation?
  • 34.
    Esteves, 34 hCG PresentationVia Urinary lyophilized vials (5,000-10,000 IU) IM Recombinant choriogonadotropin alfa pre-filled syringes (250 mcg ≅ 6,750 IU) SC 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. Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8 hCGtotrigger ovulationinOI/IUI Recommended Dose: 5,000 IU (250 mcg for rec-hCG) Systematic review (2009) unable to define best hCG dose When: 19–30 mm (~25 mm)1 2D TVUS Dominant Follicle Size Mean Diameter 23-28 mm (988 IUIs with CC & Letrozole)2 ≥16 mm (620 IUIs with gonadotropins)3
  • 35.
    Recombinant vs Urinary hCGfor Triggering Ovulation RCT N Effect 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 OR: odds ratio; MD: mean difference Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.Esteves, 35 ClinicalEfficacy
  • 36.
    Is There AnyAdvantage of Using Recombinant versus Urinary Products in OI/IUI? Recombinant products are more potent. Similar pregnancy rates using 50% less rec- hFSH. Higher PR using the same dose. Rec-hCG is better tolerated. Fewer side effects.
  • 37.
    Is There AnyAdvantage of Using Recombinant versus Urinary Products in OI/IUI? Other advantages of recombinants vs urinaries: Allow SC self-injection Higher purity and specific activity Patient-friendly Less time-consuming; less hospital/clinic visits Allow mild stimulation by small dose adjustments Higher dose precision; FbM
  • 38.
    Is There aNeed for LH Supplementation in OI Cycles?
  • 39.
    Esteves, 39 • MildStimulation (low dose rec-hFSH + GnRH ant.): • 5 oocytes retrieved; • IR = 31% • Conventional Stimulation : • 10 oocytes retrieved; • IR = 29% Verberg et al. Hum Reprod Update 2009; 15: 5–12. Promotion of Steroidogenesis (TCs) early Follicular Phase • Adequate estrogen production • Uterine/endometrial changes Stimulation of final Follicular Maturation (GCs) late FP Esteves, 39 Alviggi et al. Reprod Biomed Online 2006;12:221.
  • 40.
    Balasch J, FábrequesF. Curr Opin Obstet Gynecol 2002, 14:265.Esteves, 40 • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation Normal • Suppression of GC proliferation • Follicular atresia (non-dominant follicles) • Premature luteinization • Oocyte development compromised High • Insufficient androgen (and estrogen) synthesis • Follicular maturation impaired • Inadequate endometrial proliferation Low
  • 41.
    LH levels <1.2UI/L (WHO group I) Higher follicular development pts. receiving LH (67% vs 20%; p=0.02): Shoham et al., 2008 Similar follicular development HMG vs FSH + rLH; Higher cumulative PR after 3 cycles in FSH + rec-hLH (56% vs 23%; p=0.01): Carone et al., 2012 Level 1b Esteves, 41 WHO group II Clomiphene-resistant: fewer intermediate-sized follicles and OHSS in LH-supl. vs FSH group; similar ovulation rate; Plateau, 2006 Previous over-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 cancellation due to OHSS (-7% difference); Segnella et al., 2011 LHSupplementation inOI/IUI
  • 42.
    Esteves, 42 • ~80%normogonadotropic women undergoing Ovarian Stimulation1-3 Normal • 15-20% of NG women have less sensitive ovaries • Older patients (≥35 years)4 • Poor responders5 • Slow/Hypo-responders6 • Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)7 Low 1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod 2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175;5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al. RBMOnline 2009; 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637; LHSupplementation inOI/IUI
  • 43.
    Reduced ovarian paracrine activity Hurwitz & Santoro 2004 LH receptor poly- morphisms Alviggiet al., 2006 Androgen secretory capacity reduced • Piltonen et al., 2003 Decreased numbers of functional LH receptors • Vihko et al. 1996 Reduced LH bioactivity while imnuno- reactivity unchanged • Mitchell et al. 1995; Marama et al 1984 Action of LH at the follicular level increases androgen production for its later aromatization to estrogens; May restore the follicular milieu in selected pts. to recover oocyte quality. LHSupplementation inOI/IUI
  • 44.
    Mochtar et al, 2007 3RCT (N=310) r-hFSH+rLH vs. r-hFSH alone* OPR OR 1.85 (95% CI: 1.10; 3.11) Bosdou et al, 2012 7 RCT (N= 603) r-hFSH+rLH vs. r-hFSH alone* CPR LBR (only 1 RCT) RD: +6%, (95% CI: -0.3; +13.0) RD: +19% (95% CI: +1.0; +36.0%) Hill et al, 2012 7 RCT (N=902) r-hFSH+rLH vs. r-hFSH alone CPR OR 1.37 (95% CI: 1.03; 1.83) *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.Esteves, 44
  • 45.
    Esteves, 45 1. PCOSw/previous excessive response with low dose step-up stimulation Add 75 IU LH activity starting from D1 (min. 7 days) LHSupplementation inOI/IUI 2. Hypo-hypo/Poor responders 1:1 or 2:1 FSH/LH ratio from stimulation D1 Add 75 IU LH activity starting on D6 2 3 4 5 76 8 9 10 11 12 131 Ultrasound Menses 14 15
  • 46.
    *derives primarily fromhCG, which is concentrated during purification or added to achieve the desired LH-like biological activity. Beta unit Carboxyl terminal segment Longer in hCG; higher receptor affinity Absent in LH and present in hCG (Longer Half-life) Purity (LH content) hCG content (IU/vial) LH activity (IU/vial) Specific activity (LH/mg protein) Rec-hLH >99% 0 75 22,000 IU hMG-HP 3% ~70 75* ≥ 60 IU Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.Esteves, 46
  • 47.
    In Pts. Treatedwith HMG, expression of LH/hCG receptor and other genes involved in steroids biosynthesis in GCs are lowered May reflect LH receptors down-regulation: Constant ligand exposure during follicular phase due to longer half life and higher binding affinity of hCG compared with rec-hLH May explain the observed lower progesterone levels: Caused by lower LH-induced cholesterol uptake, a decrease in the novo cholesterol synthesis and a decrease in steroid synthesis. 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.Esteves, 47 Level 2a
  • 48.
    Esteves, 48 Individualized approachesmaximize treatment beneficial effects and minimize complications and risks. Biomarkers, AMH and AFC, are useful to predict ovarian response and to define an individualized stimulation. Mild stimulation with low-dose step-up gonadotropin protocol is advantageous. Is there a need to individualize the protocol per patient? The Top Five Problems With OI and How to Solve Them
  • 49.
    Esteves, 49 The TopFive Problems With OI and How to Solve Them CC for 3-6 cycles as the first line choice for OI/IIU. Injectable gonadotropin when: 3 CC ovulatory cycles but no pregnancy Suboptimal endometrium thickness (< 7mm) after CC-OI No response with CC 150 mg/d WHO I (hypo-hypo) anovulation Injectable gonadotropins yields higher PR than CC without increased risks. Consider sperm chromatin testing and diagnostic laparoscopy after 3 failed OI/IUI cycles with gonadotropins. Clomiphene citrate for how many cycles and how?
  • 50.
    Esteves, 50 The TopFive Problems With OI and How to Solve Them Recombinants are safer, purer and more potent than urinary gonadotropins. Similar pregnancy rates using 50% less rec-hFSH. Higher PR using the same dose. Recombinant, as pen injector devices, allows SC self- administration and individualized stimulation using small dose adjustments with great precision. Recombinant hCG, as pre-filled syringes, allows SC self-administration and is better tolerated than u-hCG. Is there any advantage of recombinant versus urinary products for OI and LH surge trigger ?
  • 51.
    Esteves, 51 The TopFive Problems With OI and How to Solve Them Is there a need of LH supplementation in OI cycles? Crucial for adequate follicular development and endometrial proliferation in WHO I (~75 IU). Promotes monofollicular growth and decreases cancellation in WHO II (CC-resistent and hyper-responders). Increase androgen production for aromatization to estrogen. May restore follicular millieu in less responsive ovaries (>35y-o, diminished ovarian reserve, slow responders). LH activity is hCG-dependent in urinaries and pure LH-dependent in recombinants. Choice of formulations may influence oocyte and corpus luteum competence.