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Controlled ovarian hyperstimulation

Seconda Università degli Studi di Napoli. Seconda Università degli Studi di Napoli. Dipartimento di Scienze della Vita. SUNfert. Dr. Vincenzo Volpicelli. Controlled ovarian hyperstimulation. Fertility Center Cardito. Traditional COH. HMG or r-FSH 300 IU on 2° day cycle

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Controlled ovarian hyperstimulation

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  1. Seconda Università degli Studi di Napoli Seconda Università degli Studi di Napoli Dipartimento di Scienze della Vita SUNfert Dr. Vincenzo Volpicelli Controlledovarian hyperstimulation Fertility Center Cardito

  2. Traditional COH • HMG or r-FSH300 IU on 2° day cycle • HCG10.000 IU on leading follicle >17 mm and at least two follicles >15 mm • Pick-upafter 33-36 h • P450 mg i.m. for luteal supplementation

  3. Traditional COH • FSH remain elevated • recruitment and growth of ovarian follicles continues throughout treatment This FSH serum pattern profoundly diverges from the spontaneous menstrual cycle * Filicori M: Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle . J Clin Endocrinol Metab . 1986;62:1136–1144

  4. Traditional COH • heterogeneoussizecohorts of follicles are oftenfoundathCGday • the optimaloutcome of COH would be the selectiveattainment of numerous large mature homogeneousfollicles. * Arnot AM , Vandekerckhove P , DeBono MA , Rutherford AJ . Follicular volume and number during in-vitro fertilization (association with oocyte developmental capacity and pregnancy rate) . Hum Reprod . 1995;10:256–261

  5. Gn-RH-a protocols long protocol short (“flare-up”) protocol ultrashort protocol microdose flare protocol

  6. Long protocol: • Avoid pre-menses FSH surge • Follicles timing • Avoid premature LH surge • Higher follicular recruitment (synchronization) • Improvement immune attitude • Expensive cost High responders PCOS

  7. short protocols • follicles timing • avoid premature LH surge • lower follicular recruitment • make procedures easier Poor responders

  8. Short/long protocol (Volpicelli V. 2003)

  9. PR/transfer in Gn-RH-a FIV nel periodo 92-96 (da FIV-NAT ’97) sec. Barrière et al. 1999

  10. Gn-RH-a Long protocol 1 • Gn-Rh-adepot 3.75 mg in one dose on 21stdayonlyofpreviouscycle or • Gn-Rh-alow-dosedaily on the 21stdayofpreviouscicleto HCG day: • Buserelin (Suprefactfl 5.5 ml) 0.3 ml fl s.c. • Buserelinnasally 1 buff x 3/d (300 μg) • Leuproreline (Enantonediefl s.c.) 0.2 ml/day • Triptoreline (Decapeptyldiefl s.c.) 0.2 ml or • on anydaywhen: • LH <0.5 • E2 <30 • No ovariancyst >10 mm

  11. Gn-RH-a long protocol 2 Fertility Center Cardito • r-FSH/HMG 300-650 IU/day on 2ndcycleday to HCG day • HCG 10.000 IU on the leasttwofollicles >18 mm • Pick-up after 33-36 hours • P4 supplementation • HCG 5.000 IU sixdaysafter E-T

  12. Gn-RH-a long protocol

  13. Gn-RH-a long protocol

  14. Short (flare-up) protocol • Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day 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 • HCG (+ P4)

  15. Gn-RH-a flare low dose protocol • EE-P for 1-2 cycles • on 1st cycle day at HCG day: • Triptoreline (decapeptyl die) 0.2 ml (0.1 mg) s.c. daily • Leuproreline acetate (enantone die) 0.2 ml (1 mg) s.c. daily • Buserelin (Suprefact flac 5.5 ml) 0.3 ml s.c. • Buserelin nasally 3 buff/day (300 μg) or • on any day when: • LH <0.5 • E2 <30 • No ovarian cyst >10 mm • r-FSH/HMG 300-650 UI/d on 3rd cycle day After administration s.c. enantone die reachs a serum peak of 32.3 mg/ml in 0.6 h

  16. Gn-RH-a ultrashort protocol • on 2nd cycledayforthreedays: • Triptoreline 0.2 ml s.c • Leuproreline 0.2 ml s.c. • Buserelin 0.5 ml s.c. • Buserelinnasally 3 buff/day or • on anydaywhen: • LH <0.5 • E2 <30 • No ovariancyst >10 mm • r-FSH/HMG on the 2ndcycleday

  17. 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

  18. HCG low-dose long protocol • Granulosa cells in ovarianfollicles of largersize (>10–12 mm) normally express the LH/hCGreceptor and become sensitive to LH activitystimulation(1). • For a long time it was thought that thisphysiologicphenomenon was finalized to make mature folliclessusceptible to the midcycle LH surge and thus ovulate. • Nevertheless, GCs LH/hCGreceptorsmayalsobehighlyrelevant to permitcontinueddominantfolliclegrowth in the spontaneousmid-latefollicularphase, at a timewhen the physiologicserum FSH declinemaycurtailadequate GC support and growth. • At thistimeLH appearscapable of exertingvirtuallyall the physiologicactions 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

  19. 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

  20. 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 (200IU/d), corresponding to roughly 1,200 IU/d of LH • The hCG is also drastically less expensive than recombinant FSH or hMG . • 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 • 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

  21. 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 alone until the end of COH or variable amounts of r-FSH and low-dose (10-50) IU hCG • reduced r-FSH/hMG consumption • outcome comparable to traditional COH regimens; • reduced number of small preovulatory follicles; • did not cause premature luteinization; • more estrogenic intrafollicular environment (1) 1. Filicori M: Fertil Steril 2005: 84, 2:394-401

  22. gonadotropin 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±1.24.3±0.6 <.001 • hCG (IU/L) 0.4±0.2 8.1±0.5 <.001 • E2 (pg/mL) 2.358±2343.235±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

  23. Clinical outcome Filicori M: Fertil Steril 2005: 84, 2:394-401

  24. 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 8 • r-FSH continueduntil HCG day (if LH ≥5 mUI/ml) or • HMG on 9thuntil HCG day (if LH < 1 mUI/ml) Ye H: Fertil Steril 2006;86,3S:S420-S421

  25. r-FSH/HMG Long protocol 21° Gn-RH-adepot or low dose long protocol

  26. r-FSH/HMG Long protocol

  27. Antagonists (1990s) • They bind immediately to the receptor • Receptor target • this leads to immediate pituitary down-regulation • and do not activate classic postreceptor events; • no “flare-up” *Orgalutran, Cetrotide 0.25 mg fls.c

  28. Gn-RH Antagonists

  29. Antagonistsprotocol • on 1° days Gn stimulation • on 5°-6° days • on leading follicle ≥14 mm • HMG or r-FSH + LH added Fixed and early start of the antagonist is probably more effective than an individualized and late start.

  30. advantages: Prevention surge LH larger cohort of follicles Avoidance of adverse effects of agonists More friendly stimulation protocol  OHSS disavantages LDP  peak E2 on HCG day  mature follicles  oocytes  embryos  PR Gn-RH Antagonist

  31. LH 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? Fertil Steril 20003;79:253–5.

  32. LH added • Granulosa cells in ovarian follicles of larger size (>10–12 mm) normally express the LH/hCG receptor and become sensitive to LH activity stimulation * • Campbell et al. showed that pulsatile LH administration in sheep maintained elevated ovulatory rates despite FSH withdrawal ** • 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 * * * Zeleznik AJ , Hillier SG .: Clin Obstet Gynecol . 1984;27:927–940 * * Campbell BK , Dobson H , Baird DT , Scaramuzzi RJ .: J Reprod Fertil . 1999;117:355–367

  33. LH ADDED target • LH <1 UI/ml at the start of Gn stimulation • Gn-RH-a flare protocol (LH suppression) • Gn-RH antagonist during stimulation • >35 years • Poor responders • High responders (LH prevalence activity decrease n. small follicles and OHSS risk)

  34. LH added target

  35. LH 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

  36. LH added target

  37. LH added target • FSH: earlier cycle follicular phase: • follicles recruitment • Follicles growth • LH: late cycle follicular phase: • mature oocytes • Ovulation • LH: Luteal cycle phase: • corpus luteum, LDP * Filicori 2003

  38. 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

  39. 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 testosterone under LH stimulation, and FSH induces granulosa cell 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 iperandrogenismo in PCOS)

  40. LH Added protocol 15 leuprolide acetate 1 mg daily, sc, from menstrual day 21 for 14 days (+ 7 days) excluded from further treatment if E2 >20 pg/ml and/or LH >2,5 IU after 21 days leuprolide LH <2.5 IU/L andE2 <20 pg/mL r-FSH starting at 150 IU sc daily at 07.30 h. for 4 days • 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 maintained at 150 IU/day • r-LH 375 IU twice a day (7.30 and 19.30 h) for the last 2 days of COH or • Leading follicle ≥14 mm *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” J Clin Endocrinol Metab . 1999;84:228–232 .

  41. LH added vs. HMG in over 38 * *Gomez-Palomares J. L. ; Acevedo-Martin B. ; Andres L. ; Ricciarelli E. ; Hernandez E. R.; Reproductive biomedicine online   ISSN 1472-6483; 2008

  42. Luteal supplementation in agonists/antagonists protocols • Pituitary depletion • Pituitary desensitization • Negative estrogen feed-back • Compulsory supplementation E/P HCG supplementation absolutely necessary !!!

  43. P4 secretion *P4 serum level:4 ng/ml is low level; 40 ng/ml is high

  44. luteal P4 supplementation • Few studies in the last 20 years • Currently, no reliable method for specific diagnosis of P4 deficiency in luteal phase • Regimens often determined by clinical experience • The rationale for P4 supplementation: • Aspiration of the granulosa cells • Presence of high levels of E2 • Analogues  poor luteal function(due to residual suppression of pituitary LH secretion) • ASRM Practice Committee: “Exogenous progesterone supplementation” Fertil Steril 2008;89,4:789-792.

  45. luteal P4 supplementation • P4 50 mg/d i.m. Or • 200-600 mg/day vaginally • Starting: • 3 days after IUI or • at E-T day • Prontogest fl im 100 mg

  46. luteal P4 supplementation Higher pregnancy rate * Lack of evidencein literature * * Increased of hypospadias (progestins derived from androgens and that bind to androgen receptors) * * * * Yovich JL et al: “Early luteal serum progestyerone concentration are higher in pregnancy cycles”. Fertil Steril 1985;44:185-189. ** Ziad R. Hubayter: “luteal supplementation in in vitro fertilization: more question than answers”. Fertil Steril 2008; 89,4:749758. • ***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;159:957

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