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Seconda Università degli Studi di Napoli. Dipartimento di Scienze della Vita. SUNfert. COH. Clomiphene. Fertility Center Cardito. Dr. Vincenzo Volpicelli. Citrate Clomiphene. Greenblatt et al. in 1961. remains the most commonly used drug in the treatment of infertility.

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

  2. Citrate Clomiphene Greenblatt et al. in 1961 remains the most commonly used drug in the treatment of infertility

  3. Clomiphene chemistry 2-(4-(2-chloro-1,2-diphenylethenyl) phenoxy)-N,N-diethyl-ethanamine(C26H28CINO)

  4. Clomiphene chemistry diastereomeric mixture of two geometric isomers: Enclomifene (E-clomifene) and Zuclomifene (Z-clomifene)

  5. CC pharmacokinetic data • Bioavailability: high (>90%) • metabolism: hepatic (with enterohepatic circulation) • half-life: 5-7 days * • excretion: • mainly renal • some biliary  fecal (oxide-CC, 4-OH-CC, defetyl-CC) Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ: “single-dose pharmacokinetics of clomiphene citrate in normal volunteers”. Fertil Steril 1986; 64:392-6

  6. Enterohepatic circulation • Recycling through liver by excretion in bile • reabsorption from small intestine • into portal circulation back to the liver.

  7. Enterohepatic Circulation

  8. central vein porta vein

  9. CC therapy requirements • patientfallopiantubes • Women anovulatory MAP + (WHO group II) * • integrity of pituitarygland • relativelynormal (or elevated) gonadotropinlevels • evidence of significantendogenousestrogen production • Unexplainedinfertility (?) *World Health Organization Scientific Group Report . Consultation on the diagnosis and treatment of endocrine forms of female infertility. World Health Organization Technical Report Series 514. Geneva: World Health Organization; 1976

  10. CC mode of action • non-steroidal estrogen agonist/antag drug • selective estrogen receptor modulator (SERM) • pituitary gland • hypothalamic neurons (ant & medio-basal)

  11. CC mode of action • Estrogene receptor modulator • inhibits the negative feed-back of estrogens on the in the hypothalamic neurons and gonadotrope cells ofanterior pituitary gland "Sensing" low estrogen levels • Gn-RH release is increased • FSH release is increased

  12. CC mode of action* *Huneeus A (Rev Chil Obstet Ginecol. 1994;59(6):463-8)

  13. CC increasing fecundity • increasing the number of oocytes • overcoming subtle ovulatory disfunctions • more precise timing of insemination • increasing the number of sperm in the upper female reproductive tract

  14. if forget a dose • Take the missed dose as soon as you remember it • Do not take a double dose to make up for a missed one

  15. CC administration • 50-250 mg/d • From 1°-6° cycleday • for 5-7 days • Ovulation: 5-10 daysafter last pill HCG 5.000 UI i.m. when leading follicle ≥18 mm IUI 36 hours after HCG administration HCG 2.500 UI im 6 days after the first dose of HCG Clomid, Serofene 50 mg tablets

  16. CC administration • HCG 5.000 UI i.m. when leading follicle ≥18 mm, if the LH surge was no detected • IUI 24-40 hours after HCG administration or spontaneous LH surge • HCG 2.500 UI im 6 days after the first dose of HCG Clomid or Serofene 50 mg tablets

  17. CC dose in obese • higher doses* • CC is not stored in adipose tissue • the need for an increased dose probably is due to: • a more intensive anovulatory state • higher androgen levels *Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

  18. CC time of start day of initiation (1-2° or 5° cycleday) • impact on the pregnancy rate • It is stillcontroversial

  19. CC time of administering similar in both groups * • Morphometric parameters, • histologic dating, • ultrasonographic appearance • thickness of the endometrium *Triwitayakorn A, et al (Fertil Steril. 2002 Jul;78(1):102-7)

  20. CC time of administering no differences* • in oocyte quality: • the perifollicular vascularity • inendometrial receptivity: • endometrial thickness • Doppler flow indices of ascending branches of the uterine arteries and subendometrial vessels *Cheung W, Ng EH, Ho PC: Hum Reprod 2002 Nov;17(11):2881-4

  21. CC time of administering* *Biljan MM, Mahutte NG, Tulandi T, Tan SL (Fertil Steril. 1999 Apr; 71(4):633-8)

  22. CC time of administering *Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S (2006)

  23. CC ovulation outcome 80% for cycle

  24. Pregnancy Outcome • USG pregnancy rate/cycle: 18% * • live-birth rates/cycle : 5-8% * * Published overall

  25. PO/Ovulation discrepancy • prolonged antiestrogenic effects on: • endometrial receptivity * • cervical mucus ** • uterine artery blood flow * Frydman R et al: (Fertil Steril. 1993;59:1179–1186) ** Gelety TJ, Buyalos RP. (Fertil Steril. 1993;60:471–476)

  26. CC Adverse effects* (Index Resistance) • uterine blood flow: decreases the uterine blood flow also during the early luteal phase, a periimplantation stage* *Hsu CC, Kuo HC, Wang ST, Huang KE. (Obstet Gynecol. 1995 Dec;86(6):917-21)

  27. Advantage CC vs. Gn decreased risk of complications: • injection problems • OHSS • multiple births

  28. CC Adverse effects* • Hot flashes • abdominal discomfort • visual blurring • weight gain • reversible ovarian enlargement • cyst formation • increased risk of ovarian cancer • fetal malformation * ≥1% of patients

  29. CC Adverse effects* • spontaneous abortions (~30%) • oocyte and embryo development • endometrial morphology • cervical mucus • uterine blood flow * ≥1% of patients

  30. CC increased abortion* attributed to several factors • impaired endometrial development: • integrins (down regulation), markers of endometrial receptivity • endometrial estrogen and progesterone receptors • uterine artery flow *Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

  31. CC increased abortion* • egg quality • cervical mucus *Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

  32. CC poor egg quality • CC-inducedapoptosis in granulosa cells • reducing E2 level in ovary

  33. co-administered E2 • These adverseeffects of CC wereprotected Shail K. Chaube, Pramod V. Prasad M, Sonu C. Thakur and Tulsidas G. Shrivastav: “Estradiol protects clomiphene citrate–induced apoptosis in ovarian follicular cells and ovulated cumulus–oocyte complexes” Fertility and Sterility 2005; 84,2:1163-1172

  34. CC + E2 • CC 100 mg/d on 3° cycle day • ethinyl E2 per os 0.05 mg daily on day 8 for 5-26 days • hCG 10,000 IU at least one follicle was >18 mm • A single IUI was performed 24–36 hours after the administration of hCG • progesterone 50 mg daily IM 3 days after IUI until β-hCG levels were evaluated Gerli. Intrauterine insemination. Fertil Steril 2000; 73,1:85-89

  35. EE to reverse the antiestrogenic effects of CC* E2 0.05 mg daily co-admnistration *Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

  36. EE to reverse the antiestrogenic effects of CC* ■ = CC; □ = CC + ethinyl E2. *Gerli S, Fertil Steril. 2000 Jan;73(1):85-9

  37. CC + IUI or IT • IUI: A single IUI was performed 24–36 hours after the administration of hCG • Two IUI 24 and 48 h after • Intercourse timed egg viability: 6-24 h Sperm viability: 48-72 h

  38. CC + IUI Pregnancy Outcome

  39. Pregnancy rates lower : * • over 38 years old • low ovarian reserve • poor quality sperm • endometriosis • any degree of tubal damage or pelvic scar tissue • couples with a long duration of infertility (over about 3 years) * Infertility and IVF Specialist Clinic Gurnee & Crystal Lake, Illinois

  40. luteal supplementation • Starting 3 days after IUI, • im injection of 50 mg of progesterone daily (Prontogest; AMSA). • β-hCG levels were evaluated. • Laboratory determinations • USG examinations 15-20 days after IUI

  41. COH in CC-resistant • N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. [Acta Obstet Gynecol Scand. 2007] • A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate-resistant polycystic ovary syndrome. [Fertil Steril. 2006] • A prospective, double-blind, randomized, placebo-controlled clinical trial of bromocriptine in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level. [Int J Fertil Womens Med. 2002] • Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with polycystic ovarian syndrome: a prospective randomized trial. [Fertil Steril. 2008] • Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial. [Fertil Steril. 2002]

  42. Multiple follicular recruitment and intrauterine insemination outcomes compared by age and diagnosis* • We studied the outcome of our intrauterine insemination (IUI) programme, evaluating female age and diagnosis. One-hundred-and-twenty-six patients <36 years of age (mean 30.91 ± 3.02 years) completed 306 cycles of multiple follicular recruitment (MFR) and timed IUI; 64 patients 36 years of age (mean 38.36 ± 2.08 years) completed 166 cycles (total 190 patients, 472 cycles). The male partners' semen was prepared for IUI with wash and swim-up techniques. Diagnostic groups were: male factor (n = 26), idiopathic (n = 33), endometriosis (n = 19), ovulatory disorder (n = 7), other (n = 19) and combined factors (n = 86). Pregnancy rates (% per couple, % per cycle) [overall (31.58, 12.7)] [<36 years (38.10, 15.69)] [>36 years (18.75, 7.23)] were greater in the <36 years group (P < 0.025). The probability of conception after three treatment cycles was 0.402 overall, 0.481 for age <36 years and 0.252 for age 36 years. The probability of conception for male factor and idiopathic infertility patients was 0.469 and 0.411 respectively. An age effect was found on pregnancy rates in the idiopathic group only. In conclusion, MFR + IUI is a valuable treatment especially for male factor patients and patients <36 years old, with idiopathic infertility Horbay G.L.A: Human Reproduction, Vol. 6, No. 7, pp. 947-952, 1991

  43. THE END

  44. Noyes criteria (1950) endometrial istologic changes during the menstrual cycle • Secretory glandes • Stroma • Epitelium Noyes RW, Hertig AT, Rock J: “Dating the endometrial biopsy”. Fertil Steril1950;1:3-9

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