Optimizing iui results

Editor's Notes

• #8: Collaborative Effort of Clinical Evaluation in Reproductive Medicine (CECERM) It is perhaps not difficult to comprehend why OH + IUI offers no added benefit in couples who have a 30 – 40% probability of a spontaneous on-going pregnancy because the cycle pregnancy rate for OH + IUI, in the best of hands, is around 15% and the cumulative PR over 3 cycles is around 30 – 40% (taking into consideration that pregnancies in most studies occurred within the first 3 cycles).
• #9: The 2012 Cochrane systematic review appeared to indicate some benefit of IUI ± OH in unexplained infertility
• #10: The conclusion of the 2007 Cochrane systematic review suggested that there is no statistically significant difference in pregnancy rates in the summary report.
• #17: Reference: 1.Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev. 2007;(2):CD005356. 2. Sinha SP. Optimization of ovarian stimulation to improve success rate in ‘ART’. Apollo Medicine 2012. 9(3): 228-238
• #18: Oral CC is inexpensive, requires little clinical monitoring and is believed to correct subtle ovulatory dysfunction. Has ease of administration, low cost and minimal side effectsIt has both estrogenic & antiestrogenic properties, competes with estrogen for estrogen receptor binding site at the level of hypothalamus. Its dose varies from 50 mg to 200 mg, can be started between 2nd to 5th day in FSH window period for 5 days However, concerns about clomifene-induced multiple pregnancies and a potential risk of ovarian cancer need consideration. Oral CC requires little clinical monitoring However, concerns about clomifene-induced multiple pregnancies and a potential risk of ovarian cancer need consideration Ref: 1.Sinha SP. Optimization of ovarian stimulation to improve success rate in ‘ART’. Apollo Medicine 2012; 9(3): 228-238. 2. Wordsworth S, Buchanan J, Mollison J et al. Clomifene citrate and intrauterine insemination as first-line treatments for unexplained infertility: are they cost-effective? Hum Reprod. 2011;26(2):369-375.
• #19: The initial dose, empirically, is 50 mg daily for five days; starting with a higher dose does not result in higher pregnancy rates. If ovulation does not occur in the first cycle of treatment, the dose is increased to 100 mg. Thereafter, the dose is increased by increments of 50 mg to a maximum daily dose of 150 mg (100 mg is the maximum dose approved by the FDA and the American College of Obstetricians and Gynecologists does not encourage the use of more than 150 mg . until ovulation is achieved, at which point the woman should attempt to conceive for four to six cycles. Most conceptions initiated by clomiphene citrate occur within the first six ovulatory cycles. Longer courses (eight days) can be considered in clomiphene-resistant women if exogenous gonadotropin therapy, the preferred therapy in this situation, is not an option (patient preference or cost. CC Resistance It is a very common used terminology and is defined as Failure to ovulate with 3 months of use at 150mg/day of 5 days. The most common cause for this is PCOS and is seen in about 20% of patients. CC Failure There are patients who ovulate but fail to conceive on CC therapy. If a patient has 3 ovulatory cycles with CC and does not conceive then she is labeled as CC failure and should be started on alternative therapy. It needs to rule out CC associated reproductive dysfunction and evaluation of other causes of infertility. This may also due to antiestrogenic effect of CC on cervical mucus and endometrium, but remains to be proven. Tamoxifen given in the dose of 20-40 mg, has similar mode of action & effectiveness as CC Letrozole is recently banned in India .. (2012) Reference: Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril 2003; 80:1302.
• #20: Reference: Lobo RA, Gysler M, March CM, et al. Clinical and laboratory predictors of clomiphene response. Fertil Steril 1982; 37:168.
• #21: CC Resistance It is a very common used terminology and is defined as Failure to ovulate with 3 months of use at 150mg/day of 5 days. Occurs in 20% of the patients. The most common cause for this is PCOS and is seen in about 20% of patients. CC Failure There are patients who ovulate but fail to conceive on CC therapy. If a patient has 3 ovulatory cycles with CC and does not conceive then she is labeled as CC failure and should be started on alternative therapy. It needs to rule out CC associated reproductive dysfunction and evaluation of other causes of infertility. This may also due to antiestrogenic effect of CC on cervical mucus and endometrium, but remains to be proven. Reference: Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril 2003; 80:1302.
• #22: Reference: 1. Emam MA. Ovarian Stimulation An overview. Accessed from website http://ebookbrowse.com/ovarian-stimulation-ppt-d152627873
• #23: Homburg R in his study showed that Clomiphene achieves about 70% ovulation and combining it with timed intercourse will achieve pregnancy of up to 25% per cycle. Ovulation induction with CC in 100 women led to delivering a singleton healthy baby in 25 women. Failure to conceive even at higher doses indicates that the peripheral antiestrogenic effects on cervical mucus and endometrium Reference Homburg R. Clomiphene citrate--end of an era? A mini-review. Hum Reprod. 2005;20(8):2043 
• #24: Injectable Gonadotropins: What To Expect? Schematic representation of the low-dose, step-up protocol of gonadotropin administration for ovulation induction. The initial subcutaneous or intramuscular dose of FSH is 37.5 to 75 IU/day; the dose is increased only if, after 14 days, no response is documented on ultrasonography and serum estradiol monitoring. Increments of 37.5 IU then are given at weekly intervals up to a maximum of 225 IU/day. Detection of an ovarian response is an indication to continue the current dose until hCG can be given to stimulate ovulation. Points to Consider Be patient! It may take 10 days or more for a dominant follicle to appear during the first treatment cycle with low-dose gonadotropin. TVUS scan before starting: if endometrium thickness >8 mm, we use progestin (medroxyprogesterone acetate, 5-10 mg/d) to induce a withdrawal bleed. Reference: White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996; 81:3821.
• #25: Injectable Gonadotropins: What To Expect? Step-down protocol — The low-dose step-down protocol of ovulation induction mimics more closely the physiology of normal cycles . Therapy with 150 int. units FSH/day is started shortly after spontaneous or progesterone-induced bleeding and continued until a dominant follicle (>10 mm) is seen on transvaginal ultrasonography. The dose is then decreased to 112.5 int. units/day followed by a further decrease to 75 int. units/day three days later, which is continued until hCG is administered to induce ovulation. The appropriate starting dose can be determined by using the low-dose step-up regimen for the first treatment cycle Reference: Imani B, Eijkemans MJ, Faessen GH, et al. Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency. Fertil Steril 2002; 77:83.
• #26: Reducing the dosage of gonadotrophins (mild ovarian stimulation) would prevent multiple pregnancies in FSH/IUI cycles questions are relevant IUI in FSH-stimulated cycles (ii) is FSH/IUI more effective than CC? and (iii) is FSH/IUI superior to IUI alone? Yet in another study where the step upand step down protocols were compared, The step-up protocol using rFSH , was more efficient in obtaining a monofollicular development and ovulation than the step-down protocol,. Although the duration of stimulation is longer, the rate of ovarian hyperstimulation is much lower using the step-up protocol. Reference: Christin-Maitre S, et al. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod. 2003 Aug;18(8):1626-31.
• #27: Reference: Verhulst SM, Cohlen BJ, Hughes E, te Velde E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2006;Art No.: CD001838.
• #28: In a meta-analysis of the remaining six trials involving 456 couples, the 5.7% difference in pregnancy rates was not significant Reference: 1. Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group. 2009;15(3):265-77.
• #29: Reference: 1. Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group. 2009;15(3):265-77
• #31: The Mechanism of Action of GnRH Antagonists Unlike GnRH agonists, the antagonists do not induce an initial hypersecretion of gonadotropins but instead cause an immediate and rapid, reversible suppression of gonadotropin secretion. The principal mechanism of action of GnRH antagonists is competitive occupancy of the GnRH-receptor.  Reference: van Loenen AC, Huirne JA, Schats R, Hompes PG, Lambalk CB. GnRH agonists, antagonists, and assisted conception. Semin Reprod Med. 2002 Nov;20(4):349-64.
• #33: Reference: van Loenen AC, Huirne JA, Schats R, Hompes PG, Lambalk CB. GnRH agonists, antagonists, and assisted conception. Semin Reprod Med. 2002 Nov;20(4):349-64.
• #34: Iatrogenic disruptions in the hypothalamic-pituitary-gonadal axis may occur during ovulation induction and controlled ovarian hyperstimulation (COH) , manifested by a shortened luteal phase with low concentrations of P. As many as 20% of women undergoing gonadotropin-stimulated ovulation induction experience luteal phase defects. Ultimately, alterations in the luteal phase create suboptimal environments for blastocysts implantation and maintenance of early pregnancy Reference: Fertil Steril. 2013 Nov;100(5):1373-80. Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis. Hill MJ1, Whitcomb BW, Lewis TD, Wu M, Terry N, DeCherney AH, Levens ED, Propst AM.
• #35: Reference: Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study. Erdem A, Erdem M, Atmaca S, Guler I. Fertil Steril. 2009 Jun;91(6):2508-13
• #36: In conclusion, the results of this systematic review and meta-analysis suggest that luteal phase P support improved the likelihood of clinical pregnancy and live birth in IUI cycles where ovulation induction was achieved with gonadotropins. Conversely, P support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction. Utilization of luteal phase P support in gonadotropin IUI cycles seems warranted. There is a need for additional large, multicenter randomized trials to confirm these findings, establish a cost benefit, and determine the duration of P that is necessary to see clinical benefit.
• #39: Most studies on OH + IUI were performed before the 5th edition of the WHO Manual on semen analysis; since 2010, the goal posts have been moved!
• #40: Studies from Asian countries were highlighted.
• #43: Evidence-based recommendations for IUI in daily practice . Middle EastFertilitySocietyJournal(2013) 18, 74–77 Considering daily practice evidence-based data indicate that the success rate of IUI is improved with an IMC above 1 million, a morphology score of more than 4% normal forms, a TMCS of more than 5 million and an initial total motility of more than 30%. In couples with cervical factor subfertility IUI in natural cycles significantly increases the probability of con- ception while the combination of ovarian stimulation and IUI is recommended in couples with unexplained subfertility. The goal of ovarian stimulation should be the development of a maximum of two dominant follicles. Sperm washing tech- niques are used to prevent partner-to-partner transmission during an AIH procedure but do not guarantee that infections are 100% removed from the post-processed sperm sample and no sperm washing technique is superior to another considering IUI outcome. Double IUI results in higher pregnancy rates compared with single IUI in couples with male factor subfertil- ity, but not in unexplained infertility cases. The optimal time- interval between HCG injection and IUI seems between 12 and 36 h and at least 10–15 min of immobilization should be ap- plied after every insemination attempt
• #44: The majority of infertile couples do not conceive after initial specific treatment and together with couples who have the original form of unexplained infertility they become eligible for empiric treatment in the form of IUI or IVF. These couples have to make many decisions: when to start treatment? What order of treatments is most sensible? When should the couple shift to more sophisticated and costly treatment? The decision-making process should not depart from the evidence, but infertility management decisions should be under the control of the couple. The best evidence reviewed in the manuscript is summarized in the following statements: † unstimulated IUI: does not significantly increase pregnancy rates; † CC/IUI: 5–7% pregnancy rate per cycle even after 7 cycles (Custers et al., 2008); † IUI/ovarian stimulation: modest effect and risks of multiple pregnancy and OHSS; † IUI/mild ovarian stimulation: the efficacy needs to be confirmed by large studies; † IVF: 7-fold higher likelihood of pregnancy (ESHRE Capri Workshop Group, 2007); † ICSI: is better that IVF only in couples with severe male infertility (ESHRE Capri Workshop Group, 2007); Reference: 1. Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group. 2009;15(3):265-77.
• #45: The majority of infertile couples do not conceive after initial specific treatment and together with couples who have the original form of unexplained infertility they become eligible for empiric treatment in the form of IUI or IVF. These couples have to make many decisions: when to start treatment? What order of treatments is most sensible? When should the couple shift to more sophisticated and costly treatment? The decision-making process should not depart from the evidence, but infertility management decisions should be under the control of the couple. The best evidence reviewed in the manuscript is summarized in the following statements: † unstimulated IUI: does not significantly increase pregnancy rates; † CC/IUI: 5–7% pregnancy rate per cycle even after 7 cycles (Custers et al., 2008); † IUI/ovarian stimulation: modest effect and risks of multiple pregnancy and OHSS; † IUI/mild ovarian stimulation: the efficacy needs to be confirmed by large studies; † IVF: 7-fold higher likelihood of pregnancy (ESHRE Capri Workshop Group, 2007); † ICSI: is better that IVF only in couples with severe male infertility (ESHRE Capri Workshop Group, 2007); Reference: 1. Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group. 2009;15(3):265-77.