Principles and Practices of Individualized OI and IUI

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


ANDROFERT

Maximize beneficial effects of treatment Minimize complica-ons and risks

Why individualize?


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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


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How stakeholders value the top 3 quality dimensions of infer-lity care


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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


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


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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


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Individualiza-on is a quality concept

Safety

Pa-ent-‐ centeredness

Effec-veness


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How to individualize?


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Individualizing S-mula-on Protocols

• Clinical characteris-cs

• Ovarian biomarkers

Iden-fy who is who

• Pa-ent-‐centered • Effec-ve • Safe

Protocol


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


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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


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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


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What biomarker do you value more?

a. Basal FSH b. AMH c. AFC d. Estradiol

AMH ~ AFC > FSH > Age


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Popula-on Cutoff Sensi-vity Specificity Accuracy

AMH

ng/m

L

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


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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


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Quality-‐based individualiza-on in COS

High responders*

Normal responders*

Low responders*

Clinical fe

atures & Biomarkers

Safety


Effec-veness

*expected


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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 Cl

omiphe

ne Citrate

Hypogonadotropic hypogonadism & hypergonadotropic hypogonadism

Anovula-on: how many cycles and how?


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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


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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


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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


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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


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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


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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%


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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


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


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


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


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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


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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


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


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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


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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


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


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)


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


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.


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Divergence in receptor-mediated signaling between LH and hCG

Choi & Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13.


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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


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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


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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


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


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


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


ANDROFERT

250 μg rhCG=6,750 IU; SC

10,000 IU uhCG; IM

5,000 IU uhCG; IM

Seru

m h

CG

leve

ls

Trinchard-Lugan et al., 2002 Itskovitz et al., 1991


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


ANDROFERT

Treatment: Profasi 500 r-hCG 250 r-hCG

Maxi

mum

hCH

per

pat

ient

0

300

600

900

BMI15 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


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


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)


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


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


Effec-veness

Safety


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?


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


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


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


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


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


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


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


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


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%)


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 P ng

P/m

g pr

otei

n

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)


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 (n

g/m

L)

Gestational age in weeks P E2

Scott et al. Fertil Steril 1991; 56:481


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


ANDROFERT

Thank you Obrigado شكرا

This presenta-on is available at hdp://www.slideshare.net/

sandroesteves

Health & Medicine

Principles and Practices of Individualized OI and IUI