Controlled ovarianControlled ovarian

hyperstimulationhyperstimulation

Dr. Vincenzo VolpicelliDr. Vincenzo Volpicelli

Fertility Center Fertility Center CarditoCardito

Seconda Università degli Studi di Napoli Seconda Università degli Studi di Napoli

Dipartimento di Scienze della VitaDipartimento di Scienze della Vita

SUNfertSUNfert

Seconda Università degli Studi di Napoli Seconda Università degli Studi di Napoli

Traditional COHTraditional COH

HMG or r-FSH 300 IU on 2° day cycle

HCG 10.000 IU on leading follicle >17 mm and at least two follicles >15 mm

Pick-up after 33-36 h

P4 50 mg i.m. for luteal supplementation

Traditional Traditional COHCOH

• FSH remain elevatedFSH remain elevated

• recruitment and growth of ovarian follicles recruitment and growth of ovarian follicles continues throughout treatmentcontinues throughout treatment

* Filicori M: * Filicori M: Characterization of the physiological pattern of episodic Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle gonadotropin secretion throughout the human menstrual cycle . . J Clin J Clin Endocrinol Metab Endocrinol Metab . 1986;62:1136–1144. 1986;62:1136–1144

This FSH serum pattern profoundly diverges This FSH serum pattern profoundly diverges from the spontaneous menstrual cyclefrom the spontaneous menstrual cycle

Traditional COHTraditional COH

• heterogeneous size cohortsheterogeneous size cohorts of follicles of follicles are often found at hCG dayare often found at hCG day

• the optimal outcome of COH would be the optimal outcome of COH would be the selective attainment of numerous the selective attainment of numerous large mature homogeneous follicles.large mature homogeneous follicles.

* * Arnot AM , Vandekerckhove P , DeBono MA , Rutherford AJ . Arnot AM , Vandekerckhove P , DeBono MA , Rutherford AJ . Follicular volume Follicular volume and number during in-vitro fertilization (association with oocyte developmental and number during in-vitro fertilization (association with oocyte developmental capacity and pregnancy rate) capacity and pregnancy rate) . . Hum Reprod Hum Reprod . 1995;10:256–261 . 1995;10:256–261

Traditional Traditional protocolprotocol

LH-RH-a Long LH-RH-a Long protocolprotocol

n° ampulesn° ampules 5.75.7 2525

Mature oocytesMature oocytes 88 1616

Fertilization rateFertilization rate 83%83% 78%78%

PR/ETPR/ET 28%28% 31%31%

Cost-savingCost-saving + + ++ + + — —— —

MFMF — —— — + + ++ + +

StressStress — —— — + + ++ + +

Gn-RH-a protocolsGn-RH-a protocols

long protocollong protocol short (“flare-up”) protocol short (“flare-up”) protocol ultrashort protocolultrashort protocolmicrodose flare protocolmicrodose flare protocol

Long protocol:Long protocol:

1. Avoid pre-menses FSH surge2. Follicles timing3. Avoid premature LH surge4. Higher follicular recruitment

(synchronization)5. Improvement immune attitude6. Expensive cost

High respondersHigh respondersPCOSPCOS

short protocolsshort protocols

1. follicles timing 2. avoid premature LH surge3. lower follicular recruitment4. make procedures easier

Poor respondersPoor responders

Serum levelsSerum levels Short protocolShort protocol Long protocolLong protocol

E2 idem Idem

D4 ++++++ ++depression ++++++ ++ Pregnancy rate/cicle 9.2%9.2% 16. 5%16. 5%

PR/transfer 9..9%9..9% 23. 5%23. 5%

patients

«poor responders» «High responders»

PCOS

> 40 years hyrsutism

HMG ampules + + - -+ + - - + + + ++ + + +

Cancelled cycles + + - -+ + - - + + + ++ + + +

Short/long protocol (Volpicelli V. 2003)

PR/transfer in Gn-RH-aPR/transfer in Gn-RH-a

FIV nel periodo 92-96 (da FIV-NAT ’97) sec. FIV nel periodo 92-96 (da FIV-NAT ’97) sec. Barrière et al. 1999Barrière et al. 1999

Flare-up Flare-up protocolprotocol 19.2%19.2%

Long protocol Long protocol 25.7%25.7%

MediaMedia 24.8%24.8%

without without analoguesanalogues 23.2%23.2%

Gn-RH-a Long protocol 1Gn-RH-a Long protocol 1

• Gn-Rh-a depot 3.75 mg in one dose on 21Gn-Rh-a depot 3.75 mg in one dose on 21stst day only of day only of previous cycle or previous cycle or

• Gn-Rh-a low-dose daily on the 21Gn-Rh-a low-dose daily on the 21stst day of previous cicle to day of previous cicle to HCG day:HCG day:

• Buserelin (Suprefact fl 5.5 ml) 0.3 ml fl s.c. Buserelin (Suprefact fl 5.5 ml) 0.3 ml fl s.c. • Buserelin nasally 1 buff x 3/d (300 Buserelin nasally 1 buff x 3/d (300 μμg)g)• Leuproreline (Enantone die fl s.c.) 0.2 ml/dayLeuproreline (Enantone die fl s.c.) 0.2 ml/day• Triptoreline (Decapeptyl die fl s.c.) 0.2 mlTriptoreline (Decapeptyl die fl s.c.) 0.2 ml

oror• on any day when:on any day when:

» LH <0.5 LH <0.5 » EE22 <30 <30» No ovarian cyst >10 mmNo ovarian cyst >10 mm

Gn-RH-a long protocol 2Gn-RH-a long protocol 2

•r-FSH/HMG 300-650 IU/day on 2r-FSH/HMG 300-650 IU/day on 2ndnd cycle day to HCG day cycle day to HCG day

•HCG 10.000 IU on the least two follicles >18 mmHCG 10.000 IU on the least two follicles >18 mm

•Pick-up after 33-36 hoursPick-up after 33-36 hours

•P4 supplementationP4 supplementation

•HCG 5.000 IU six days after E-THCG 5.000 IU six days after E-T

Fertility Center CarditoFertility Center Cardito

Gn-RH-a long protocolGn-RH-a long protocol

Gn-RH-a long protocolGn-RH-a long protocol

Short (flare-up) protocolShort (flare-up) protocol

• Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day onlyday only

• r-FSH 225-600 IU/d on 3th day (step-down regimen)

• HCG 10.000 IU (18 mm + 15-16)• Pick-up after 33-36 h• HCGHCG (+ P4)

Gn-RH-a flare low dose protocol

• on 1on 1stst cycle day at HCG day: cycle day at HCG day:» Triptoreline (decapeptyl die) 0.2 ml (0.1 mg) s.c. dailyTriptoreline (decapeptyl die) 0.2 ml (0.1 mg) s.c. daily» Leuproreline acetate (enantone die) 0.2 ml (1 mg) s.c. dailyLeuproreline acetate (enantone die) 0.2 ml (1 mg) s.c. daily» Buserelin (Suprefact flac 5.5 ml) 0.3 ml s.c.Buserelin (Suprefact flac 5.5 ml) 0.3 ml s.c.» Buserelin nasally 3 buff/day (300 Buserelin nasally 3 buff/day (300 μμg)g)

oror• on any day when:on any day when:

» LH <0.5 LH <0.5 » EE22 <30 <30» No ovarian cyst >10 mmNo ovarian cyst >10 mm

• r-FSH/HMG 300-650 UI/d on 3r-FSH/HMG 300-650 UI/d on 3rdrd cycle day cycle day

After administration s.c. enantone die reachs a serum peak of 32.3 mg/ml in 0.6 hAfter administration s.c. enantone die reachs a serum peak of 32.3 mg/ml in 0.6 h

•EE-P for 1-2 cyclesEE-P for 1-2 cycles

Gn-RH-a ultrashort Gn-RH-a ultrashort protocolprotocol

• on 2on 2nd nd cycle day for three days:cycle day for three days:» Triptoreline 0.2 ml s.cTriptoreline 0.2 ml s.c» Leuproreline 0.2 ml s.c.Leuproreline 0.2 ml s.c.» Buserelin 0.5 ml s.c.Buserelin 0.5 ml s.c.» Buserelin nasally 3 buff/day Buserelin nasally 3 buff/day

oror• on any day when:on any day when:

» LH <0.5 LH <0.5 » EE22 <30 <30» No ovarian cyst >10 mmNo ovarian cyst >10 mm

• r-FSH/HMG on the 2r-FSH/HMG on the 2ndnd cycle day cycle day

UltrashortUltrashort LongLongHMG ampoules + + ++ + +cancelled cycles ~ ~ ~~ ~ ~ ~ ~ ~~ ~ ~n. oocytes ~ ~ ~~ ~ ~ ~ ~ ~~ ~ ~fertilization rate ~ ~ ~~ ~ ~ ~ ~ ~~ ~ ~embryo cleavage rate ~ ~ ~~ ~ ~ ~ ~ ~~ ~ ~supernumerary embryos

+ + ++ + +

Samuel F. Marcus: “ “Comparative trial between an ultra-short and long protocol of luteinizing hormone-releasing hormone agonist for ovarian stimulation in in-vitro fertilization”. Human Reproduction, 1993; Vol. 8, No. 2, pp. 238-243

HCG low-dose long protocol HCG low-dose long protocol • Granulosa cells in ovarian follicles of largerin ovarian follicles of larger size (>10–

12 mm) normally express the LH/hCG receptor and become sensitive to LH activity stimulation (1).

• For a long time it was thought that this physiologic phenomenon was finalized to make mature follicles susceptible to the midcycle LH surge and thus ovulate.

• Nevertheless, GCs LH/hCG receptors may also be highly relevant to permit continued dominant follicle growth in the spontaneous mid-late follicular phase, at a time when the physiologic serum FSH decline may curtail adequate GC support and growth.

• At this time LH appears capable of exerting virtually all LH appears capable of exerting virtually all the physiologic actions of FSHthe physiologic actions of FSH on GCs (2).

1. Zeleznik AJ , Hillier SG . The role of gonadotropins in the selection of the preovulatory follicle . Clin Obstet Gynecol . 1984;27:927–940 . 2. Campbell BK , Dobson H , Baird DT , Scaramuzzi RJ . Examination of the relative role of FSH and LH in the mechanism of ovulatory follicle selection in sheep . J Reprod Fertil . 1999;117:355–367

HCG low-dose in a-long protocol HCG low-dose in a-long protocol

Based on this information we postulated that LH activity could substitute FSH administration in the late stages of COH to allow larger follicles growth and maturation (1).

1. Filicori M , Cognigni GE , Taraborrelli S , Parmegiani L , Bernardi S , Ciampaglia W .: “Intracytoplasmic sperm injection pregnancy after low-dose human chorionic gonadotropin alone to support ovarian folliculogenesis “.. Fertil Steril . 2002;78:414–416

HCG low-dose long protocol HCG low-dose long protocol • The longer half-life and greater affinity for the

LH/hCG receptor of hCG account for a potency ratio estimate of hCG-to-LH of around 1:6 (1,2).

• hCG alone (200hCG alone (200 IU/d), corresponding to IU/d), corresponding to roughly 1,200 IU/d of LHroughly 1,200 IU/d of LH

• The hCG is also drastically less expensive than recombinant FSH or hMG .

1. Stokman PG , de Leeuw R , van den Wijngaard HA , Kloosterboer HJ , Vemer HM , Sanders AL . Human chorionic gonadotropin in commercial human menopausal gonadotropin preparations . Fertil Steril . 1993;60:175–178

2. Sullivan MW , Stewart-Akers A , Krasnow JS , Berga SL , Zeleznik AJ . Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH) (a role for LH in the final

stages of follicular maturation) . J Clin Endocrinol Metab . 1999;84:228–232

HCG low-dose in long protocol HCG low-dose in long protocol • Gn-RH-a long protocol

• r-FSH/hMG (1:1/2) 225-300 IU on 2° day at least six follicles >12 mm and E2 >300 pg/ml

• hCG 250 IU/day alonehCG 250 IU/day alone until the end of COH

1. Filicori M: Fertil Steril 2005: 84, 2:394-401

•reduced r-FSH/hMG consumptionreduced r-FSH/hMG consumption•outcome comparable to traditional COH regimens; outcome comparable to traditional COH regimens; •reduced number of small preovulatory follicles;reduced number of small preovulatory follicles;•did not cause premature luteinization; did not cause premature luteinization; •more estrogenic intrafollicular environment more estrogenic intrafollicular environment (1)(1)

or

variable amounts of r-FSH and low-dose (10-50) IU hCGvariable amounts of r-FSH and low-dose (10-50) IU hCG

gonadotropin and steroid at HCG daygonadotropin and steroid at HCG day

Group A Group B P value

(no hCG) (hCG)

• LH (IU/L) 0.6±0.1 0.7±0.3 NS

• FSH (IU/L) 11.3±1.211.3±1.2 4.3±0.64.3±0.6 <.001

• hCG (IU/L) 0.4±0.2 8.1±0.5 <.001

• E2 (pg/mL) 2.358±2342.358±234 3.235±3173.235±317 <.05

• P (ng/mL) 1.1±0.1 1.1±0.1 NS

• T (ng/mL) 0.9±0.1 1.1±0.1 <.05

Filicori M: Fertil Steril 2005: 84, 2:394-401

Clinical outcomeClinical outcomeno-HCGno-HCG HCGHCG

COH daysCOH days 11.6±0.211.6±0.2 11.9±0.111.9±0.1 NSNS

r-FSH/hMG daysr-FSH/hMG days 11.6±0.211.6±0.2 8.6±0.18.6±0.1 <.001<.001

Daily hCG duration (days)Daily hCG duration (days) — — 3.3±0.13.3±0.1 ——

r-FSH/hMG dose (IU)r-FSH/hMG dose (IU) 2,779±1602,779±160 1,960±991,960±99 <.001<.001

Immature oocytes (n)Immature oocytes (n) 1.4±0.21.4±0.2 1.6±0.31.6±0.3 NS NS

Mature oocytes (n)Mature oocytes (n) 8.0±0.78.0±0.7 8.2±0.68.2±0.6 NSNS

Fertilization rate (%)Fertilization rate (%) 48±4% (0–100)48±4% (0–100) 74±3% (36–100)74±3% (36–100) <.001<.001

Good quality embryos (%)Good quality embryos (%) 86±6%86±6% 84±5%84±5% NSNS

Embryos transferred (n)Embryos transferred (n) 2.3±0.22.3±0.2 2.5±0.12.5±0.1 NSNS

Implantation rates (%)Implantation rates (%) 11%11% 12%12% NSNS

Pregnancy rates (%)Pregnancy rates (%) 21%21% 25%25% NSNS

Filicori M: Fertil Steril 2005: 84, 2:394-401

FSH/HMG long protocol FSH/HMG long protocol

• Gn-RH-a depot on 21° day of previous cycle only• or Gn-RH-a low dose on 21° day up HCG day

• r-FSH 225-450 UI, step-down regimen, on 2nd at 8th cycle day

•HMGHMG on 9th until HCG day (if LH < 1 mUI/ml)until HCG day (if LH < 1 mUI/ml)

•r-FSH continuedr-FSH continued until HCG day (if LH ≥5 mUI/ml)until HCG day (if LH ≥5 mUI/ml)

oror

Ye H: Fertil Steril 2006;86,3S:S420-S421Ye H: Fertil Steril 2006;86,3S:S420-S421

8

r-FSH/HMG Long protocol

11 22 33 44 55 66 77 88 991100

1111

1122 . . . .. . . .

LH >5 LH >5 mIU/mlmIU/ml

LH <1 LH <1 mIU/mlmIU/ml

r-FSHr-FSH HMGHMG Gn-RH-a low dose

21

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21

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r-FSH/HMG Long protocol r-FSH/HMG Long protocol

Normal LHNormal LH Low LHLow LH

r-FSH r-FSH r- & HMG r- & HMG r-FSH r-FSH r- & HMG r- & HMG

Oocytes MII 1414 1212 1313 1010

Oocyt fert 10.510.5 8.88.8 9.99.9 7.27.2

Embryos 2.42.4 1.51.5 1.91.9 1.31.3

Implant % 35.8%35.8% 31.4%31.4% 40.7%40.7% 32.3%32.3%

Pregn rate 55.2%55.2% 43.8%43.8% 61.7%61.7% 54.1%54.1%

miscarriage 00 7.1%7.1% 18.9%18.9% 3.0%3.0%

Antagonists (1990s)Antagonists (1990s)

**Orgalutran, Cetrotide 0.25 mg flOrgalutran, Cetrotide 0.25 mg fl s.c s.c

•They bind immediately to the receptor

•this leads to immediate pituitary down-regulation

•and do not activate classic postreceptor events;

•Receptor target

•no “flare-up”

Gn-RH Antagonists

Lubecca Method, delayed somministration

0.25 mg s.c. on 6° COH day or leading follicle >14 mm until HCG day

California methodearly administration (very high-responders)

On 1° COH day until leading follicle ≥18 mm and at least two follicles ≥ 15 mmOvulation triggering with Gn-RH-a long-acting

on 1° days Gn stimulation on 1° days Gn stimulation

on 5°-6° dayson 5°-6° days

on leading follicle on leading follicle ≥14 mm≥14 mm

• HMG or r-FSH + HMG or r-FSH + LH addedLH added

Antagonists protocolAntagonists protocol

Fixed and early start of the antagonist is probably more Fixed and early start of the antagonist is probably more effective than an individualized and late start. effective than an individualized and late start.

Gn-RH AntagonistGn-RH Antagonist

advantages:• Prevention surge LHPrevention surge LH• larger cohort of larger cohort of

follicles follicles • Avoidance of adverse Avoidance of adverse

effects of agonistseffects of agonists• More friendly More friendly

stimulation protocolstimulation protocol OHSSOHSS

disavantages • LDP peak E2 on HCG

day mature follicles oocytes embryos PR

LH addedLH added

• The early follicular phase is characterized by the presence of LH receptors on theca cells and the presence of FSH receptors on granulosa cells, with a prevalence of FSH activity.

• The middle-late follicular phase is characterized by the presence of LH receptors on both theca and granulosa cells, with a prevalence of LH activity and declining FSH levels.

• This leads to a selection of the dominant follicle and monofollicular ovulation.

. Filicori M. Use of luteinizing hormone in the treatment of infertility: time for reassessment? . Filicori M. Use of luteinizing hormone in the treatment of infertility: time for reassessment? Fertil Steril 20003;79:253–5. Fertil Steril 20003;79:253–5.

LH addedLH added• Granulosa cells in ovarian follicles of larger size (>10–Granulosa cells in ovarian follicles of larger size (>10–

12 mm) normally express the LH/hCG receptor and 12 mm) normally express the LH/hCG receptor and become sensitive to LH activity stimulation become sensitive to LH activity stimulation **

• Campbell et al. showed that pulsatile LH Campbell et al. showed that pulsatile LH administration in sheep maintained elevated ovulatory administration in sheep maintained elevated ovulatory rates despite FSH withdrawal rates despite FSH withdrawal ****

• LH/hCG receptors may also be highly relevant to LH/hCG receptors may also be highly relevant to permit continued dominant follicle growth in the permit continued dominant follicle growth in the spontaneous mid-late follicular phase, at a time when spontaneous mid-late follicular phase, at a time when the physiologic serum FSH decline the physiologic serum FSH decline * ** *

* Zeleznik AJ , Hillier SG .: * Zeleznik AJ , Hillier SG .: Clin Obstet Gynecol Clin Obstet Gynecol . 1984;27:927–940 . 1984;27:927–940 * * Campbell BK , Dobson H , Baird DT , Scaramuzzi RJ .: J Reprod Fertil . * * Campbell BK , Dobson H , Baird DT , Scaramuzzi RJ .: J Reprod Fertil . 1999;117:355–367 1999;117:355–367

− LH <1 UI/ml at the start of Gn LH <1 UI/ml at the start of Gn stimulationstimulation

− Gn-RH-a flare protocol (LH Gn-RH-a flare protocol (LH suppression)suppression)

− Gn-RH antagonist during stimulationGn-RH antagonist during stimulation− >35 years>35 years− Poor respondersPoor responders− High responders (LH prevalence activity High responders (LH prevalence activity

decrease n. small follicles and OHSS decrease n. small follicles and OHSS risk)risk)

LH ADDED target

LH added targetLH added target

0

20

40

60

80

100

120

0 5 10 15 20

T-LH-r

G-FSH-r

G-LH-r

LH added targetLH added target• the early follicular phase is characterized by the

presence of LH receptors on theca cells and FSH receptors on granulosa cells, with a prevalence of FSH activity.

• The middle-late follicular phase is characterized by the presence of LH receptors on both teca and granulosa cells, with a prevalence of LH activity and declining FSH levels*

* Filicori 2003

LH added targetLH added target

Cycle’s

phaseFSH rec LH rec

Prevalence activity of

early follicolar

+ + + (G) + (T) FSH

late follicolar

+ + (G)+ + + (T&G)

LH

luteal - - + + + (CL) LH

LH added targetLH added target

* Filicori 2003

• FSH: earlier cycle follicular phase:» follicles recruitment

» Follicles growth

• LH: late cycle follicular phase:» mature oocytes» Ovulation

• LH: Luteal cycle phase: »corpus luteum, LDP

Rationale for LH added (Sullivan 1999)

• The rationale for this hypothesis is that the FSH-stimulated induction of LH receptors on granulosa cells could enable the maturing follicle to respond to LH and thereby continue to mature in the presence of continuously declining FSH concentrations

Rationale for LH added (Sullivan 1999)• It is generally accepted that E2 production by the maturing follicle

occurs by way of the two-cell, two-gonadotropin model. • In this model, theca cells produce androstenedione and theca cells produce androstenedione and

testosterone under LH stimulationtestosterone under LH stimulation, and FSH induces granulosa FSH induces granulosa cell aromatasecell aromatase, thus enabling the thecally derived androgens to be metabolized to E2.

• Assuming the validity of this model in humans, our results indicate that thecal androgen production is exquisitely sensitive to LH, as a plasma LH concentration of 1.5 IU/L was sufficient to maintain E2 production as well as plasma androstenedione concentrations.

• Our observation of E2 production despite very low serum LH concentrations is in agreement with other published data showing that women treated with GnRH agonists to suppress gonadotropin secretion maintain E2 production in the presence of very low levels of serum LH (<0.5 IU/L).

Our current study also indicates that although LH concentrations of approximately 1.5 IU/L are able to sustain thecal androgen production, these levels of LH are unable to maintain granulosa cell aromatase activity when FSH concentrations decline. (vedi (vedi iperandrogenismo in PCOS)iperandrogenismo in PCOS)

LH Added protocolLH Added protocol 1515

r-LH 375 IU twice a day (7.30 and 19.30 h) for the last 2 days of COH r-LH 375 IU twice a day (7.30 and 19.30 h) for the last 2 days of COH

ororLeading follicle ≥14 mmLeading follicle ≥14 mm

*Sullivan MW et al: “Ovarian Responses in Women to Recombinant Follicle-Stimulating Hormone and *Sullivan MW et al: “Ovarian Responses in Women to Recombinant Follicle-Stimulating Hormone and Luteinizing Hormone (LH): A Role for LH in the Final Stages of Follicular Maturation”Luteinizing Hormone (LH): A Role for LH in the Final Stages of Follicular Maturation” J J Clin Endocrinol Metab Clin Endocrinol Metab . 1999;84:228–232 .. 1999;84:228–232 .

leuprolide acetate 1 mg daily, sc, from menstrual day 21 for 14 days (+ 7 days) leuprolide acetate 1 mg daily, sc, from menstrual day 21 for 14 days (+ 7 days)

LH <2.5 IU/L and E2 <20 pg/mL

r-FSH starting at 150 IU sc daily at 07.30 h. for 4 days

excluded from further treatment if E2 >20 pg/ml and/or LH >2,5 IU after 21 days leuprolide

On 5° day •If serum E2 levels were less than 100 pg/mL, the r-FSH dose was increased to 225 IU •If serum E2 levels were greather than 100pg/mL, the r-FSH was If serum E2 levels were greather than 100pg/mL, the r-FSH was maintained at 150 maintained at 150 IU/day IU/day

LH added vs. HMG LH added vs. HMG in over 38 in over 38 **

** Gomez-Palomares J. L. ; Acevedo-Martin B. ; Andres L. ; Ricciarelli E. ; Hernandez E. R.; Reproductive biomedicine online   ISSN 1472-6483; 2008

r-FSH + HMG 75 UI (group I) and r-FSH + r-LH 75 UI (group II)

HMG group HMG group LH groupLH group

n. follicles on 6 day 6.72 2.22 5.87 1.29

COH days 10.5 1.7 12 1.8

M II oocytes 75.3% 93.1%

Pregnancy rate 26% 47%47%

Luteal supplementation in Luteal supplementation in agonists/antagonists protocolsagonists/antagonists protocols

• Pituitary depletion

• Pituitary desensitization

• Negative estrogen feed-back

• Compulsory supplementation E/P

HCG supplementation absolutely necessary !!!HCG supplementation absolutely necessary !!!

PP4 4 secretionsecretion

Follicular Follicular phasephase

Luteal phase Luteal phase **

OvaryOvary 48%48% 95%95%

Adrenal glandAdrenal gland 48%48% 4%4%

from from pregnenolonepregnenolone 4%4% 1%1%

*P*P44 serum level: serum level: 4 ng/ml is low level; 40 ng/ml is high4 ng/ml is low level; 40 ng/ml is high

luteal Pluteal P4 4 supplementationsupplementation

☻Few studies in the last 20 yearsFew studies in the last 20 years☻Currently, no reliable method for specific diagnosis Currently, no reliable method for specific diagnosis of Pof P44 deficiency in luteal phase deficiency in luteal phase☻Regimens often determined by clinical experienceRegimens often determined by clinical experience

The rationale for PThe rationale for P44 supplementation: supplementation:

1.1. Aspiration of the granulosa cellsAspiration of the granulosa cells2.2. Presence of high levels of EPresence of high levels of E22

3.3. Analogues Analogues poor luteal function poor luteal function (due to (due to

residual suppression of pituitary LH secretion)residual suppression of pituitary LH secretion)ASRM Practice Committee: “Exogenous progesterone supplementation” Fertil Steril ASRM Practice Committee: “Exogenous progesterone supplementation” Fertil Steril

2008;89,4:789-792.2008;89,4:789-792.

luteal Pluteal P44 supplementation supplementation

PP44 50 mg/d i.m. Or 50 mg/d i.m. Or200-600 mg/day vaginally200-600 mg/day vaginally

Starting: Starting: 3 days after IUI3 days after IUI

ororat E-T dayat E-T day

Prontogest fl im 100 mg Prontogest fl im 100 mg

luteal Pluteal P44 supplementation supplementation

Higher pregnancy rate Higher pregnancy rate **

Lack of evidenceLack of evidence in literature in literature * ** *Increased of hypospadias Increased of hypospadias (progestins derived from (progestins derived from

androgens and that bind to androgen receptors) androgens and that bind to androgen receptors) * * ** * ** * Yovich JL et al: “Early luteal serum progestyerone concentration are higher in pregnancy cycles”. Fertil Steril Yovich JL et al: “Early luteal serum progestyerone concentration are higher in pregnancy cycles”. Fertil Steril 1985;44:185-189. 1985;44:185-189.

**** Ziad R. Hubayter: “luteal supplementation in in vitro fertilization: Ziad R. Hubayter: “luteal supplementation in in vitro fertilization: more question than answersmore question than answers”. Fertil ”. Fertil

Steril 2008; 89,4:749758.Steril 2008; 89,4:749758.

******ASRM Practice Committee: “Exogenous progesterone supplementation” Fertil Steril 2008;89,4:789-792.ASRM Practice Committee: “Exogenous progesterone supplementation” Fertil Steril 2008;89,4:789-792.Carmichael SL et al: “Maternal progestin intake and risk of hypospadias”. Arch Pediatr Adolesc Med 2005;159:957Carmichael SL et al: “Maternal progestin intake and risk of hypospadias”. Arch Pediatr Adolesc Med 2005;159:957

PP44

**Posaci C, Smitz J, Camus M, Osmanagaoglu K, Devroey P: “Progesterone for the luteal Posaci C, Smitz J, Camus M, Osmanagaoglu K, Devroey P: “Progesterone for the luteal support of ART: clinical options”. Human Reprod 2000; 15,S1:129-148.support of ART: clinical options”. Human Reprod 2000; 15,S1:129-148.

Orally:Orally: • bioavailabilty diminished by the liver first passbioavailabilty diminished by the liver first pass• the serum level typically returns to baseline level by the serum level typically returns to baseline level by 6 hours6 hours•dizziness and somnolencedizziness and somnolence•fatigue, headache, urinary frequencyfatigue, headache, urinary frequency

vaginal route:vaginal route: •the level remains elevated for up the level remains elevated for up 48 hours48 hours•Crinone gel 8% once a day and contains 90 mg of PCrinone gel 8% once a day and contains 90 mg of P44

•Progeffik gel 200 mg 1-3/dayProgeffik gel 200 mg 1-3/day•Uterine tissue higher level PUterine tissue higher level P44 despite a lower serum P despite a lower serum P44

•Vaginal irritationVaginal irritation

Intramuscular: Intramuscular: •P4 in oil result in higher plasma concentration P4 in oil result in higher plasma concentration •and and longer durationlonger duration ** •Severe allergic reaction Severe allergic reaction •Adult respiratory distress syndromeAdult respiratory distress syndrome•Eosinophilic pneumonitisEosinophilic pneumonitis

luteal supplementation in luteal supplementation in agonist/antagonist protocolsagonist/antagonist protocols

Pituitary desensitization for 2-3 w after Pituitary desensitization for 2-3 w after last administrationlast administration

* * Belaisch-Allart J et al: “ JL et al: “The effect of HCG supplementation after combined Belaisch-Allart J et al: “ JL et al: “The effect of HCG supplementation after combined Gn-RH agonist/HMG treatment in an IVF programme”. Human Reprod 1990;5:163-166.Gn-RH agonist/HMG treatment in an IVF programme”. Human Reprod 1990;5:163-166.

Worldwide standard practiceWorldwide standard practice **

luteal suppl agonist/antagonist protocolsluteal suppl agonist/antagonist protocols

PP44

**Martinez F: “ Human Corionic Gonadotropin and intravaginal natural progesterone are Martinez F: “ Human Corionic Gonadotropin and intravaginal natural progesterone are equally effective for luteal phase support in IVF”. Gynecol Endocrinol 2000; 14:316-320.equally effective for luteal phase support in IVF”. Gynecol Endocrinol 2000; 14:316-320.

HCGHCG : : •more effectivemore effective•Increased production of EIncreased production of E22 and P and P44

•Better endocrine profileBetter endocrine profile•No differences in pregnancy outcomeNo differences in pregnancy outcome•OHSS risk (EOHSS risk (E22 peak at HCG day) peak at HCG day)

or/andor/and

Luteal ELuteal E2 2 supplementationsupplementation

• E2 orally 2-6 mg/d (Progynova cpr 2 mg) *• Start on:

» E-T day E-T day or or » 7 days after E-T7 days after E-T

• Increases implantation rate• Increases pregnancy rate

In IVF cycles, the levels of EIn IVF cycles, the levels of E2 2 and Pand P44 drop in the mid-late luteal phase drop in the mid-late luteal phase

Lower ELower E22 at 11 days after pick-up is associated with lower pregnancy rate at 11 days after pick-up is associated with lower pregnancy rate

* Lukaszuk K: Fertil Steril 2005;83:1372-1376* Lukaszuk K: Fertil Steril 2005;83:1372-1376

poor responders protocolspoor responders protocols

Poor responders Poor responders definitiondefinition

• The original definition of low response to ovarian response by Garcia et Acosta was based on low peak E2 concentrations alone

• They stimulated patients with hMG (150 IU IM daily) and defined low responders as patients with a peak E2 concentration of <300 pg/mL

Poor respondersPoor responders • diminished ovarian reserve• A lower expression of FSH receptor in the granulosa

cells • Advanced maternal age• E2 < 500 pg/mL on day of hCG • <4 de Graaf follicles on HCG day• lower fertilization rates • lower cleavage rates • lower resulting embryos• Lower implantation rate• lower pregnancy rates

10–25% of the ART population*10–25% of the ART population*

* * Keay Keay et alet al., 1997., 1997 ; Karande and Gleicher, 1999; Karande and Gleicher, 1999 ; Fasouliotis ; Fasouliotis et alet al., 2000., 2000 ; Tarlatzis ; Tarlatzis et alet al., 2003., 2003

““occult ovarian failure”

occult ovarian failure”

Low RespondersLow Responders

Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr” Fertil Steril 2005;84,3: 555-569

outcome suboptimal: outcome suboptimal:

•poor ovarian response poor ovarian response •poor oocyte/embryo quality poor oocyte/embryo quality

in spite of stimulation regimens usedin spite of stimulation regimens used

increase Gn dose increase Gn dose

• first and simplest approach

• limited benefit to 450 IU per day

• 300 IU r-FSH + hMG 150 IU

• beyond this amount little or no improvement

Murat Arslan: Fertil Steril 2005; 84,3:555-569

the stop Gn-RH-a protocolthe stop Gn-RH-a protocol

• Gn-RH-a low dose on 21° day until the beginning of menstruation.

• Stop analogues

• gonadotropins from day 2 of the cycle until HCG day

Target of this protocol:Target of this protocol:Stop to pre-menstrual FSH Stop to pre-menstrual FSH and, subsequently, and, subsequently, stop to size discrepancy in the developing folliclesstop to size discrepancy in the developing follicles

CC + HMG + AntagonistCC + HMG + Antagonist

• CC 150 mg/d on 1°-5° days • HMG (r-FSH) large dosage (450-600 IU/d) on

2-3° cycle day

Antagonist delayed administration: Antagonist delayed administration: •on 6°-8° stimulation dayson 6°-8° stimulation days•or leader follicle ≥ 14 mm if very few folliclesor leader follicle ≥ 14 mm if very few follicles

• HCG 10.000 UI on day dominant follicle ≥18 mm

•Luteal supplementation: HCG 2.000 IU/d (+ PLuteal supplementation: HCG 2.000 IU/d (+ P44) )

E-P Antagonist delayed protocolE-P Antagonist delayed protocol Farmakon Dosage Time length

E-P pillE-P pillprevious

cycle14-21 days

FSH/HMG 300 + 150 2° cycle d up HCG d

CC 150 mg/d 1° cycle d 5-7 days

Antagon 0.25 mg/d 7-8° d up HCG d

HCG 10.000 IU >18 mm

Age >40Age >40 Long protocolCC + HMG + Antagonist

n° ampules 50 83

follicles >14 3.7 5.8

E2 on day 5 36 74

E2 on day 9 169 945 (400-1480)

E2 on HCG day 744 833 (410-2160)

Cancellation rate 34% 4.8%

total oocytes 3.3 5.5

Mature oocytes 2.6 4.29

n° embryo 1.4 1.6

PR 15.3% 22.2%

Implant rate 7.6% 13.5%Weghofer, 2004Weghofer, 2004

Luteal estradiol protocolLuteal estradiol protocol

• Oral micronized E2 2 mg twice a day» On luteal day 21» At 3 days of COH

• r-FSH 375-450 IU/d down regimen on 2° day

microdose flare Gn-RH-a on 3° COH daymicrodose flare Gn-RH-a on 3° COH day

orordelayed Gn-RH antagonist delayed Gn-RH antagonist

Dragisic KG Fertil Steril 2005;84:1023-1026

HCG low-dose (10-50 IU/d) on 8° dayHCG low-dose (10-50 IU/d) on 8° day

lowering FSH levels with estrogen, the ovary will respond when high doses of FSH are lowering FSH levels with estrogen, the ovary will respond when high doses of FSH are added in COH protocoladded in COH protocol

Luteal estradiol protocol Luteal estradiol protocol **

outcomeoutcome All cyclesLuteal

EstradiolStandard protocol

Clinical Pr 38,3% 40,9% 31,3%

Miscarriage rate 43,5% 38,9% 60,0%

Delivery rate

20.0% 25.0%25.0% 12.5%

* Frattarelli J, et al: “A luteal estradiol protocol for expected poor-responders improves * Frattarelli J, et al: “A luteal estradiol protocol for expected poor-responders improves embryo number and quality” Fertil Steril 2008;89,5:1118-22embryo number and quality” Fertil Steril 2008;89,5:1118-22

AACEP ProtocolAACEP Protocol• E-P pills for 1 to 3 weeksE-P pills for 1 to 3 weeks

• Gn-RH-a low-dose in a standard long protocol overlapping the last 5 to 7 Gn-RH-a low-dose in a standard long protocol overlapping the last 5 to 7 days of E-P pills until onset of menses days of E-P pills until onset of menses

• Gn-Rh antagonist low-dose (0.125 mg/day) on cycle day 2Gn-Rh antagonist low-dose (0.125 mg/day) on cycle day 2

• Estradiol valerateEstradiol valerate** 2 mg/d on 1° to 10° cycle day 2 mg/d on 1° to 10° cycle day• Estrogen suppositoriesEstrogen suppositories**** were used to maintain the endometrium until at were used to maintain the endometrium until at

last one follicle measured 15 mmlast one follicle measured 15 mm

• r-FSH in initial doses of 600 or 750 IU/day, decreasing to 225 IU/day of r-r-FSH in initial doses of 600 or 750 IU/day, decreasing to 225 IU/day of r-FSH. FSH.

Fisch JD, Keskintepe L and Sher G: “Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming in low responders with prior in vitro fertilization failure”. Fertil Steril 2008;89,2:342-347

* Progynova cpr 2 mg * Progynova cpr 2 mg ** ** Vagifem cpr vaginali 0.025 mgVagifem cpr vaginali 0.025 mg

AACEP ProtocolAACEP Protocol

EE--P P

pp

II

ll

ll

ss

**aa

gg

oo

nn

ii

ss

tt

1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 17 …

E T

PP44PP

44PP44

AA AA AA AA AA AA AA AA AA AA AA PP44PP

44PP44

EE EE EE EE EE EE EE EE EE EE

HHCCGG

r-FSH 150 IUr-FSH 150 IU A antagonistA antagonist

Unstimulated IVF

• the growth of the dominant follicle is tracked with ultrasounds and blood tests

• the egg is retrieved when the dominant follicle is deemed large enough

Unstimulated IVF • less risk than traditional IVF• the risk of OHSS is eliminated• less costly• fewer office visits• less physical and emotional stress

According to data reported to the Society of Assisted Reproductive Technology (SART) in 2006 and 2007

Unstimulated IVF According to data reported to the Society of Assisted Reproductive Technology (SART) in 2006 and 2007

Clinical parametersyounger than 35 years

patients aged 35 to 42 years

Clinical pregnancy rates per cycle

19.2% 11.4%

Egg retrieval 26.8% 22.3%

Embryo transfer 35.9% 24.3%

live birth rate 15.2% 8.9%

implantation rates were statistically higher for unstimulated IVF compared with stimulated IVF

1. Gordon JD, Dimattina M, Reh A, et al. Utilization and success rates of unstimulated in vitro fertilization in the United States: an analysis of the Society for Assisted Reproductive Technology database. Fertil Steril. 2013 Apr 13. doi: 10.1016/j.fertnstert.2013.03.037. [Epub ahead of print.]2. Bendikson K. Natural cycle IVF: today and tomorrow. April 14, 2010. Available at: http://uscfertility.org/blog/post/213-natural-cycle-ivf-today-and-tomorrow. Accessed July 31, 2013.

High RespondersHigh Responders

High responders perform favorably High responders perform favorably with gentler stimulation that minimizes with gentler stimulation that minimizes the occurrence of OHSSthe occurrence of OHSS

The number of oocytes retrieved is The number of oocytes retrieved is predictive of clinical pregnancy only predictive of clinical pregnancy only in patients over 40 years of age in patients over 40 years of age

M. Luna-Rojas, B. Sandler, M. Duke, A.B. Copperman, L. Grunfeld, J. Barritt M. Luna-Rojas, B. Sandler, M. Duke, A.B. Copperman, L. Grunfeld, J. Barritt Fertility and SterilityFertility and Sterility September 2004 (Vol. 82, Page S206) September 2004 (Vol. 82, Page S206)

OHSS Classification (Volpicelli V. CIC Roma 1998)OHSS Classification (Volpicelli V. CIC Roma 1998) SLIGHTYSLIGHTY MODERATEMODERATE SEVERESEVERE

I° I° II° II° III° III° IV° IV° V° V° VI° VI°

ovary (cm)ovary (cm) < 5< 5 5-85-8 8-118-11 12-2012-20 > 20> 20 >20>20

Abdomen distensionAbdomen distension ++ ++ ++ ++++ ++++++ ++++++++

Abdomen painsAbdomen pains ++ ++ ++++ ++++++ ++++++++

Peritoneal flogosisPeritoneal flogosis ++ ++ ++ ++++ ++++++

VomitingVomiting ++ ++ ++ ++++ ++++ ++++++

NauseaNausea ++ ++ ++ ++ ++ ++++

DiarrhoeaDiarrhoea ++ ++ ++++

HydrothoraceHydrothorace Ascites Ascites [1][1] ++ Electrolytic Imbalance Electrolytic Imbalance ++ ++++

HypovolemiaHypovolemia ++++ ++++++

Venous central pressure Venous central pressure

Hypovolemic shockHypovolemic shock ++ ++++

AcidosisAcidosis ++ ++++

Kidney perfusionKidney perfusion

OliguriaOliguria ++ HyperazotemiaHyperazotemia ++++ ++++++

[1] Key symptom to hypersevere syndrome Key symptom to hypersevere syndrome

High responders protocolHigh responders protocol

• CC 100 mg/d 3°-7° days• r-FSH 150 UI s.c. on cycle day 9 at HCG day• antagonist 0.25 mg/d delayed regimen• Aspirin 100 mg/d on 1° at 45° cycle day

• HCG 10.000 UI on leading follicle ≥18 mm

Low dose aspirin protocolLow dose aspirin protocol

Start in previous cycle of COHStart in previous cycle of COH

100 mg/day until pick-up day100 mg/day until pick-up day

r-FSH 450 IU/d

HCG 20 IU/d

Microdose flare on 2° day of COH or

Delayed antagonistFrattarelli JL et al: “Low-dose aspirin use does not improve in vitro Frattarelli JL et al: “Low-dose aspirin use does not improve in vitro fertilization outcomes in poor responders”. Fertil Steril 2008;89,5:1113-17 fertilization outcomes in poor responders”. Fertil Steril 2008;89,5:1113-17

High responders protocol 2High responders protocol 2

• Gn 225 UI/d on 2° cycle daysGn 225 UI/d on 2° cycle days

• step-down regimenstep-down regimen

• antagonist 0.25 mg/d on 2° antagonist 0.25 mg/d on 2° day up HCG dayday up HCG day

DoxycyclineDoxycycline** 80 mg/Kg/day 80 mg/Kg/day (inhibits vascular (inhibits vascular leakage)leakage)

* Folkman HJ: fertil Steril 2007;88,S1:O14* Folkman HJ: fertil Steril 2007;88,S1:O14

*Bassado cpr 100 mg*Bassado cpr 100 mg

FSH – Antagonist – Agonist + HCG

• received triptorelin 0.2 mg in addition to the hCG. The GnRH-a dose was administered at the same time as the hCG; this was devised to achieve the induction of an endogenous LH surge that would coincide with the LH-like

• 34–36 hours before oocyte retrieval.

AA high responders IIIAA high responders III

• FSH 225 IU/d on the 2° cycle day (step-down regimen)

• antagonist 0.25 mg/d on the 2° cycle at HCG day• Agonist (0.50 mg) as HCG trigger to achieve an

endogenous LH surge

• when E2 ≥ 3.700 pg/ml (range 3.000-7.500)

• 0% OHSS0% OHSS

Agonist vs. HCG as triggerAgonist vs. HCG as trigger

Gn-RH-a:Gn-RH-a: HCG 10.000 UIHCG 10.000 UI

mature oocytespremature oocytesimplantation rateclinical pregnancyongoing pregnancyOHSS

OHSS/CoastingOHSS/Coasting

• Until drop of estrogen level Until drop of estrogen level <3.000 pg/ml<3.000 pg/ml

• Coasting >3 days no affects on Coasting >3 days no affects on PrPr

Egbase PE , Al Sharhan M , Berlingieri P , Grudzinskas JG . Egbase PE , Al Sharhan M , Berlingieri P , Grudzinskas JG . Serum oestradiol and Serum oestradiol and progesterone concentrations during prolonged coasting in 15 women at risk of progesterone concentrations during prolonged coasting in 15 women at risk of ovarian hyperstimulation syndrome following ovarian stimulation for assisted ovarian hyperstimulation syndrome following ovarian stimulation for assisted reproduction treatment reproduction treatment . . Hum Reprod Hum Reprod . 2000;15:2082–2086 . 2000;15:2082–2086

OHSS/CoastingOHSS/Coasting

inverse relationship inverse relationship duration of coasting/number duration of coasting/number of mature oocytes retrievedof mature oocytes retrievedPregnancy ratePregnancy rate

* * Ulug U , Ben Shlomo I , Bahceci M . Predictors of success during the coasting period in high-Ulug U , Ben Shlomo I , Bahceci M . Predictors of success during the coasting period in high-responder patients undergoing controlled ovarian stimulation for assisted conception . Fertil responder patients undergoing controlled ovarian stimulation for assisted conception . Fertil Steril . 2004;82:338–342 Steril . 2004;82:338–342

M. Aygun, F. Vanlioglu, G. Karlikaya, H. Karagozoglu, B. Kumbak, S. Kahraman: “M. Aygun, F. Vanlioglu, G. Karlikaya, H. Karagozoglu, B. Kumbak, S. Kahraman: “Coasting Coasting may effect endometrial thickness and outcome”. Fertil Steril 2004; may effect endometrial thickness and outcome”. Fertil Steril 2004; 82, S 2, S21182, S 2, S211

CoastingCoasting

• Gn-RH-a long protocollong protocol• HMG or r-FSH 225 IU step-down regimen • On 2On 2ndnd cycle day at HCG or coasting day cycle day at HCG or coasting day

Owj , E . Tehrani Negad , E . Amirchaghmaghi , Z . Ezabadi , A . Baghestani: Owj , E . Tehrani Negad , E . Amirchaghmaghi , Z . Ezabadi , A . Baghestani: “The Evaluation of Withholding Gonadotropins (Coasting) Effects on the “The Evaluation of Withholding Gonadotropins (Coasting) Effects on the Outcome of In-Vitro Fertilization Cycles”.  Fertil Steril 2005;84,S254Outcome of In-Vitro Fertilization Cycles”.  Fertil Steril 2005;84,S254

Coasting Coasting

HCG 10.000 IU when E2 <3.000 pg/ml)HCG 10.000 IU when E2 <3.000 pg/ml)

““Ganirelix salvage” Ganirelix salvage”

• Gn-RH-a long protocol on late luteal phase Gn-RH-a long protocol on late luteal phase previousprevious

• r-FSH 225 IU/d starting dose (down regimen)r-FSH 225 IU/d starting dose (down regimen)

Antagonist Antagonist 0.25 mg daily dose 0.25 mg daily dose at Eat E22 > 4.000 > 4.000

and orand or>10 follicles in each ovary>10 follicles in each ovary

daily measurement of serum daily measurement of serum EE22

HCG 10.000 IU at E2 HCG 10.000 IU at E2 ≤3.000 pg/ml≤3.000 pg/ml

M . Wittenberger , R . Gustofson , A . Armstrong , J . Segars: “A Cost Comparison of “Ganirelix M . Wittenberger , R . Gustofson , A . Armstrong , J . Segars: “A Cost Comparison of “Ganirelix Salvage” Protocol Versus “Coasting” Strategy for Patients at Risk for Ovarian Hyperstimulation Salvage” Protocol Versus “Coasting” Strategy for Patients at Risk for Ovarian Hyperstimulation Syndrome (OHSS)” .  Fertility and Sterility 2005, 84 ,S318Syndrome (OHSS)” .  Fertility and Sterility 2005, 84 ,S318

““Ganirelix salvage”Ganirelix salvage”

•reduce Ereduce E22 levels (4.219 levels (4.219 2.613/24 h)2.613/24 h)•and avoid cycle cancellationand avoid cycle cancellation

•24 oocytes mean/cycle 24 oocytes mean/cycle •79.2% MII79.2% MII

Gustofson RL,, Segars JH and Larsen FW: “Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome”. Human Reproduction 2006 21(11):2830-2837

3535

PCOS ProtocolPCOS Protocol

• Pre-treatment with metformin ≥6 months• 2.000 mg/day• Improvment in menstrual cyclicity• Long-protocol agonist• Higher pregnancy outcome

Essah et al Fertil Steril 2006;86,1:230-232 Essah et al Fertil Steril 2006;86,1:230-232

IVF cycle cost (ASRM’s average)

total IVF cycle total IVF cycle $ 12,500 $ 12,500

with “coasting” werewith “coasting” were $ 400/day $ 400/day

the cost per day of the cost per day of “ganirelix salvage”“ganirelix salvage” $ 553 $ 553

cycle cancellation prior to cycle cancellation prior to retrievalretrieval

$ 6379 $ 6379

plus the costs associated with plus the costs associated with either “coasting” or “ganirelix either “coasting” or “ganirelix salvagesalvage

M.D. Wittenberger, R.L. Gustofson, A. Armstrong, J.H. SegarsM.D. Wittenberger, R.L. Gustofson, A. Armstrong, J.H. Segars : “ : “A Cost Comparison of A Cost Comparison of “Ganirelix Salvage” Protocol Versus “Coasting” Strategy for Patients at Risk for Ovarian “Ganirelix Salvage” Protocol Versus “Coasting” Strategy for Patients at Risk for Ovarian Hyperstimulation Syndrome (OHSS)”. Fertil Steril 2995; 84Hyperstimulation Syndrome (OHSS)”. Fertil Steril 2995; 84,S1:S318

OHSS OHSS SUPPLEMENTATIONSUPPLEMENTATION• Micronized progesterone vaginally* 90-Micronized progesterone vaginally* 90-

100 mg/d100 mg/d

• EE2 2 orally** 4 mg/dorally** 4 mg/d

• No HCG ! ! !No HCG ! ! !

* * crinone 8% vaginal gel; prometrium cps 100 mgcrinone 8% vaginal gel; prometrium cps 100 mg ** ** progynova cpr 2 mg; sprediol spray 1.5 mg; progynova cpr 2 mg; sprediol spray 1.5 mg;

sandrena gelsandrena gel

Natural cycle modificationNatural cycle modification• when dominant follicle ≥ 14 mm (8°-9°

days)• r-FSH 75 UI/d up HCG day • ± antagonist 0.25 mg/d up HCG day• HCG 5.000 UI (leading follicle ≥18 mm

and at least two follicles ≥15 mm)

• Women aged 40 yearsWomen aged 40 years• FSH elevatedFSH elevated• Poor respondersPoor responders• Cost-saving alternativeCost-saving alternative

•50 mg/d of im P4 in oil after oocyte retrieval

Luteal supplementationLuteal supplementation

• The luteal phase was supported with 50 mg/d of IM P in oil initiated immediately (?) after oocyte retrieval.

Prontogest, AMSA fl i.m. 100 mgProntogest, AMSA fl i.m. 100 mg

SUMMARYSUMMARY

• Controversies on gonadotropins Controversies on gonadotropins

• Controversies on analoguesControversies on analogues

• Controversies on E-P pillsControversies on E-P pills

• Controversies on LH addedControversies on LH addedArslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr”vitro fertilization : two decades of experience after the birth of Elizabeth Carr” Fertil Steril 2005;84,3: 555-569Fertil Steril 2005;84,3: 555-569

HMG or r-FSH?HMG or r-FSH?

• higher clinical pregnancy higher clinical pregnancy rate with hMGrate with hMG

• but no significant but no significant differences in ongoing differences in ongoing pregnancy rates or live pregnancy rates or live births births

Van Wely M , Westergaard L , Bossuyt P , Van Der Veen M . Effectiveness of human menopausal gonadotropin versus recombinant follicle-stimulating hormone for controlled ovarian hyperstimulation in assisted reproductive cycles (a meta-analysis) . Fertil Steril . 2003;80:1086–1093 .

intermediate respondersintermediate responders

excellent outcome:excellent outcome:

• with either a Gn-RH-a (long protocol) with either a Gn-RH-a (long protocol)

• or a GnRH antagonistor a GnRH antagonist• but tailoring of gonadotropin dose but tailoring of gonadotropin dose

must be performed to achieve must be performed to achieve optimized results.optimized results.

Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr”for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr” Fertil Steril 2005;84,3: 555-569Fertil Steril 2005;84,3: 555-569

LH ADDEDLH ADDED

Suheil J. Muasher, Rony T. Abdallah, Ziad R. Hubayter: “Optimal stimulation protocols for in Suheil J. Muasher, Rony T. Abdallah, Ziad R. Hubayter: “Optimal stimulation protocols for in vitro fertilization” Fertil Steril 2006; 86,2:267-273vitro fertilization” Fertil Steril 2006; 86,2:267-273

Adding LH should be considered in Adding LH should be considered in severe situations of LH severe situations of LH suppression:suppression:

1.1. use of potent GnRH-agonists use of potent GnRH-agonists

2.2. Gn-RH-antagonistsGn-RH-antagonists

3.3. Over 35 yearsOver 35 years

Conclusion(s)Conclusion(s)

• Ovarian stimulation is a critical step in in vitro Ovarian stimulation is a critical step in in vitro fertilization therapy. fertilization therapy.

• A variety of controlled ovarian hyperstimulation A variety of controlled ovarian hyperstimulation regimens are available and efficacious, regimens are available and efficacious,

• but but individualization of management is essentialindividualization of management is essential and depends on assessment of the ovarian and depends on assessment of the ovarian reserve. reserve.

• Identification of the etiologies of poor ovarian Identification of the etiologies of poor ovarian response constitutes a formidable challenge response constitutes a formidable challenge facing reproductive endocrinologists.facing reproductive endocrinologists.

Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr”of Elizabeth Carr” Fertil Steril 2005;84,3: 555-569Fertil Steril 2005;84,3: 555-569