{"paper_id":"fc46e2fc-0c2e-42da-a043-dd577a25f29e","body_text":"GUEST EDITORIAL\nIntrauterine Insemination: Fundamentals Revisited\nGautam N. Allahbadia 1\nReceived: 7 October 2017 / Accepted: 9 October 2017 / Published online: 25 October 2017\n/C211Federation of Obstetric & Gynecological Societies of India 2017\nAbout the Author\nAbstract Intrauterine insemination (IUI) is an assisted\nconception technique that involves the deposition of a\nprocessed semen sample in the upper uterine cavity,\novercoming natural barriers to sperm ascent in the female\nreproductive tract. It is a cost-effective, noninvasive first-\nline therapy for selected patients with functionally normal\ntubes, and infertility due to a cervical factor, anovulation,\nmoderate male factor, unexplained factors, immunological\nfactor, and ejaculatory disorders with clinical pregnancy\nrates per cycle ranging from 10 to 20%. It, however, has\nlimited use in patients with endometriosis, severe male\nfactor infertility, tubal factor infertility, and advanced\nmaternal age C 35 years. IUI may be performed with or\nwithout ovarian stimulation. Controlled ovarian stimula-\ntion, particularly with low-dose gonadotropins, with IUI\noffers significant benefit in terms of pregnancy outcomes\ncompared with natural cycle or timed intercourse, while\nreducing associated COH complications such as multiple\npregnancies and ovarian hyperstimulation syndrome.\nImportant prognostic indicators of success with IUI include\nGautam N. Allahbadia is the Emeritus Editor of the Journal of\nObstetrics and Gynecology of India as well as the IVF Lite (Journal of\nMinimal Stimulation IVF) and Medical Director at Rotunda—The\nCenter for Human Reproduction, Mumbai, India and Medcare\nFertility Center, Jumeira, Dubai, UAE.\n& Gautam N. Allahbadia\nivfwaladoc@gmail.com\n1 Rotunda-The Center for Human Reproduction,\nBandra, Mumbai, India\nGautam Nand Allahbadia is the Emeritus Editor of the Journal of Obstetrics and Gynecology of India as well as the IVF\nLite (Journal of Minimal Stimulation IVF). He is the Medical Director of Medcare Fertility Centre, Jumeira, Dubai, UAE, as\nwell as Rotunda—The Center for Human Reproduction, the world-renowned Infertility clinic at Bandra, Mumbai, India. He\nis a noted world authority on Ultrasound-guided Embryo Transfers and one of the pioneers in Third Party Reproduction in\nSoutheast Asia. Dr. Allahbadia was responsible for India’s first trans-ethnic surrogate pregnancy involving a Chinese\ncouple’s baby delivered by an unrelated Indian surrogate mother. He cherishes over 150 peer-reviewed publications, 140\nbook chapters, and 22 textbooks, the latest being a comprehensive text, entitled ‘ ‘Minimal Stimulation IVF,’ ’ and is on the\nEditorial Board of several International Journals. Dr. Allahbadia has recently been elected as the Vice President of the World\nAssociation of Reproductive Medicine (WARM), headquartered in Rome, and ‘ ‘Mumbai’s Top Doc’ ’ for 2012 by a peer nomination process.\nYou can read more about his work at www.gautamallahbadia.com.\nThe Journal of Obstetrics and Gynecology of India (November–December 2017) 67(6):385–392\nDOI 10.1007/s13224-017-1060-x\n123\n\nage of patient, duration of infertility, stimulation protocol,\ninfertility etiology, number of cycles, timing of insemina-\ntion, number of preovulatory follicles on the day of hCG,\nprocessed total motile sperm [ 10 million, and insemina-\ntion count [ 1 9 106 with [ 4% normal spermatozoa.\nAlternative insemination techniques, such as Fallopian tube\nsperm perfusion, intracervical insemination, and intratubal\ninsemination, provide no additional benefit compared to\nIUI. A complete couple workup that includes patient his-\ntory, physical examination, and clinical and laboratory\ninvestigations is mandatory to justify the choice in favor of\nIUI and guide alternative patient management, while\nindividualizing the treatment protocol according to the\npatient characteristics with a strict cancelation policy to\nlimit multi-follicular development may help optimize IUI\npregnancy outcomes.\nIntroduction\nDespite revolutionary advances in the field of assisted\nreproduction, such as in vitro fertilization (IVF), intracy-\ntoplasmic sperm injection (ICSI), and subzonal insemina-\ntion (SUZI), intrauterine insemination (IUI) remains an\ninexpensive, noninvasive, and effective first-line therapy\nfor selected patients with cervical factor, moderate male\nfactor, unexplained infertility, immunological infertility,\nand infertility due to ejaculatory disorders and is now also\nproposed as a therapy for endometriosis, ovarian dysfunc-\ntion, and even for tubal factor. Though the technique of IUI\nhas essentially remained the same, several advances in the\ntype of stimulation protocols, gonadotropins, sperm\npreparation techniques, and ultrasound monitoring have led\nto promising success rates with IUI.\nStrict patient selection criteria and individualized stim-\nulation protocols tailored according to the age and etiology\nof the patient with a strict cycle cancelation policy will\nhelp to reduce the associated complications, such as mul-\ntiple pregnancies and OHSS, while maximizing the overall\npregnancy outcome. Three to six IUI cycles may be offered\nbefore considering alternate therapy. However, patients\nwith advanced maternal age, severe male factor infertility,\ntubal pathology, or severe endometriosis will benefit from a\ndirect referral to IVF/ICSI.\nSemen parameters that must be considered in an IUI\nprogram include the semen processing time, processed total\nmotile sperm count, rapid progressive motility after pro-\ncessing, sperm morphology before and after processing,\ninseminating motile sperm count (IMSC), IUI insemination\ntime, and 24-h sperm survival. Delaying semen processing\nfrom 30 min up to 1 h and/or delaying IUI from 90 min up\nto 2 h after collection compromises the pregnancy outcome\nin gonadotropin-IUI cycles [ 1]. A universal threshold level\nabove which IUI can be performed with acceptable preg-\nnancy rates has not been determined yet [ 2]. However, IUI\nsuccess may be impaired in couples with processed total\nmotile sperm (PTMS) \\ 10 million [ 3], sperm survival\n\\ 70% [ 4], \\ 5% normal spermatozoa, inseminating\nmotile count (IMC) \\ 1 9 106 [ 2], and prewash IUI-se-\nmen pregnancy score (IUI-SPS) \\ 150 [ 5], necessitating\nalternative therapy. The PTMS count has been indepen-\ndently associated with fertility after IUI ( P = 0.0014) [ 3].\nPTMS C 10 9 106, their 24-h sperm survival threshold\nof C 70% [ 4], normal morphology before sperm separa-\ntion C 15.5% [odds ratio (OR) = 2.2, ( P = 0.02)], rapid,\nprogressive motility C 25.5% after sperm separation\n(P = 0.029), and curvilinear velocity (VCL) after sperm\nseparation C 102.65 lm/s ( P = 0.002) independently\npredict pregnancy outcome in patients with male factor\ninfertility [ 6]. These variables would be helpful in coun-\nseling patients for future management [ 6\n].\nDiscussion\nIn couples with a cervical factor, diagnosed by a well-\ntimed, nonprogressive, post-coital test with normal semen\nparameters [ 7], higher pregnancy rates (PRs) have been\nreported following IUI compared to expectant management\n(51 vs. 33%, respectively) [ 8] with acceptable pregnancy\nrates even without COH (9.7%) and without an increased\nrisk for multiple pregnancy compared to COH (12.7%) [ 7].\nCumulative pregnancy rates of 19.7, 36.8, and 36.8% have\nbeen reported for a maximum of three IUI cycles in\npatients with a cervical factor without superovulation [ 9].\nPregnancy rates of 12.8, 29.3, and 38.3% for a maximum of\nthree cycles have been reported in couples with a male\nfactor without superovulation [ 9], 7% per cycle following\nCOH–IUI with clomiphene citrate (CC) and 12% per cycle\nwith follicle-stimulating hormone (FSH) with multiple\nbirth rates averaging 13% [ 10]. Despite the belief that IVF\nmay be a more cost-effective primary treatment option\ncompared to IUI in lieu of the low success rates with IUI\nand the subsequent requirement for IVF in the event of\nfailure [ 11], the results of randomized controlled trials\n(RCTs) using live birth rates rather than pregnancy rates,\nand taking into account efficacy, complications, especially\nmultiple pregnancy rates, patient compliance, and cost-ef-\nficiency, suggest that the initial treatment for idiopathic\ninfertility should be IUI as opposed to IVF [ 12].\nControlled ovarian hyperstimulation with IUI is rec-\nommended in early-stage and surgically corrected\nendometriosis when the pelvic anatomy is normal, while\ncombined surgery with gonadotropin-releasing hormone\n(GnRH) analog treatment has been proposed to be a first-\nline therapy followed by IVF as second-line therapy in\n123\nAllahbadia The Journal of Obstetrics and Gynecology of India (November–December 2017) 67(6):385–392\n386\n\nadvanced cases [ 13]. Comparable clinical PRs per cycle\nhave been reported in women with minimal, mild\nendometriosis, and unexplained infertility (21 vs. 18.9 vs.\n20.5%) following COH–IUI with comparative cumulative\nlive birth rates within four cycles of COH and IUI (70.2,\n68.2, 66.5%, respectively); CPR/cycle with or without\nCOH–IUI was lower in women with surgically untreated\nminimal to mild endometriosis than in women with unex-\nplained infertility [ 14]. However, in patients with minimal\nor mild endometriosis with pathological utero-tubal trans-\nport documented by hysterosalpingoscintigraphy (HSSG),\nIUI yields poor pregnancy rates despite normal semen\nparameters and patent Fallopian tubes, necessitating\nrecourse to IVF/ICSI [ 15]. Though IVF reduces time to\npregnancy in early-stage disease compared to controls, it\ndoes not increase the chance of pregnancy after 3 years\n[16]. In patients with stage IV endometriosis and in\nwomen [ 38 years of age, significantly higher PR, fecun-\ndity, and cumulative fecundity have been reported fol-\nlowing IVF-ET compared to COH–IUI. Hence, IVF-ET\nshould be the first-line approach in the management of\ninfertility in such patients, and if COH–IUI is attempted, it\nshould not exceed 3–4 cycles [ 17].\nIUI may be contraindicated in women with sperm-im-\nmobilizing antibodies owing to antibodies secreted in the\nfemale reproductive tract that might impair sperm passage,\ninhibit fertilization, and prevent normal post-fertilization\nprocesses [ 18]. The total antral follicle number is reported\nto decrease with age. In women [ 35 years with antral\nfollicle counts (AFCs) \\ 5, the application of COH/IUI\nmay not be indicated [ 19].\nPittrof et al. [ 20] reported a significantly higher number\nof preovulatory follicles (43.6, 59.9, 12.6%, P \\ 0.0001)\nand significantly higher pregnancy rates ( P = 0.038) in\nCC/tamoxifen ? gonadotropin—stimulated cycles com-\npared to natural cycles [ 20]. However, Chen and Liu [ 21]\nconcluded that though stimulated IUI is superior to natural\ncycle IUI cycles in patients \\ 35 years, natural cycle is\npreferable for patients C 35 years. There were no signifi-\ncant differences in the abortion and delivery rates between\nthe OI and the natural cycle insemination ( P [ 0.05) [ 21].\nIUI in the spontaneous cycle carries fewer health risks than\ndoes IUI after mild hormonal stimulation and, therefore,\nshould be the first-choice treatment [ 22]. Ovarian stimu-\nlation by clomiphene citrate (CC) and IUI remains the first-\nchoice treatment for ovulatory dysfunction, unexplained\ninfertility, endometriosis, or male subfertility [ 23] with\npregnancy rates averaging 7% per cycle [ 10]. Though no\nconsensus exists about the drug of first choice to be used as\nhyperstimulation and there are no significant differences in\nclinical pregnancy (38 vs. 34.3%) and live birth rates (28.2\nvs. 26.9%) between CC and rFSH, a randomized multi-\ncenter parallel trial concluded that being less expensive,\nCC seems the more cost-effective drug and, therefore, can\nbe offered as drug of first choice [ 24].\nA meta-analysis of 43 trials involving 3957 women\nconcluded that gonadotropins might be the most effective\ndrugs when IUI is combined with ovarian hyperstimula-\ntion, yielding higher pregnancy rates compared to antie-\nstrogens, comparable PRs with different types of\ngonadotropins, no improvement with GnRH agonist or\nantagonist but increased multiple pregnancy rates and\nOHSS rates with increased doses of gonadotropins, and\nsignificantly higher multiple pregnancy rates with the\nagonist. When gonadotropins are used for ovarian stimu-\nlation, low-dose protocols are advised since pregnancy\nrates do not differ from those obtained with high-dose\nregimens, whereas the chances to encounter negative\neffects from ovarian stimulation such as multiple preg-\nnancies and OHSS are limited with low-dose gonado-\ntropins. Further research is needed for each comparison\nmade [ 25]. No significant differences have been reported\namong low-dose gonadotropin protocols that differed in\ngonadotropin dosage (4/6/8/ampoules of 75 IU FSH) or the\nmode of administration in terms of cycle parameters,\nsuggesting that an individualized and more intensive\napproach to ovarian stimulation is necessary for many\nwomen with unexplained infertility [ 26]. With regard to the\nmode of administration, daily recombinant FSH (follitropin\nbeta) stimulation has been associated with higher CPRs (42\nvs. 19%, respectively), higher total recombinant FSH dose\n(825 vs. 625 IU), and endometrial thickness (10.1 vs.\n9.3 mm) compared to alternate-day FSH stimulation in\nwomen with anovulatory or unexplained infertility for over\n12 months who had not responded to or not conceived with\nCC treatment though the duration of stimulation and the\nmedian number of follicles over 14 mm, AFC, and day-3\nserum FSH were comparable between the groups. How-\never, prospective randomized trials would be needed to\ndetermine whether this is indeed the case [ 27]. Mahani and\nAfnan [ 28] reported the highest CPRs/cycle and CPR/pa-\ntient following IUI in patients stimulated with hMG com-\npared with CC, CC ? hMG, or natural cycle.\nStudies have reported a beneficial effect of the use of the\naromatase inhibitor letrozole (2.5–5 mg/day from day 3–7\nof the IUI cycle) alone/co-administered with gonadotropins\ncompared to CC, CC ? gonadotropins, or gonadotropins\nalone in terms of comparable if not higher CPR/cycle and\ntake home baby rates. Significantly higher serum levels of\nLH, endometrial thickness, and progesterone at the time of\nhCG administration have been observed despite a signifi-\ncantly lower serum E2 level [ 29–31] with significantly\nlower costs, risks, and patient inconvenience in patients\nwith unexplained infertility [ 29, 30, 32, 33] endometriosis,\nand combined indications [ 34], and lower FSH dose\n123\nThe Journal of Obstetrics and Gynecology of India (November–December 2017) 67(6):385–392 Intrauterine Insemination: Fundamentals Revisited\n387\n\nrequirement and IUI cancelation rates in patients with\novulatory infertility [ 35] and older infertile women [ 31].\nLiang et al. investigated the influence of the time\ninterval from the end of semen processing to artificial\nintrauterine insemination with husband’s sperm (AIH–IUI)\non the rate of clinical pregnancy [ 36]. This study involved\n191 AIH–IUI cycles with the same ovulation induction\nprotocol. After Percoll density gradient centrifugation, they\ndivided the sperm into four groups based on the incubation\ntime: 0–19, 20–39, 40–59, and 60–80 min, and again into\nanother four groups according to the total progressively\nmotile sperm count (TPMC): (0–9), (10–20), (21–30),\nand [ 30 9 10\n6. They analyzed the correlation of the\nclinical pregnancy rate with the time interval from the end\nof sperm processing to AIH–IUI and with other influencing\nfactors, such as maternal age, infertility duration, and\nsemen quality. The rate of clinical pregnancy was signifi-\ncantly higher in the 20–39-min group (18.3%) than in the\n0–19-, 40–59-, and 60–80-min groups (12.7, 11.4 and\n9.1%) (all P \\ 0.05). The (10–20) 9 10\n6 group achieved a\nremarkably higher pregnancy rate (16.7%) than the (0–9),\n(21–30), and [ 30 9 10\n6 groups (0, 11.4, and 8.3%) (all\nP \\ 0.05). Logistic multivariate analysis showed that the\nrate of clinical pregnancy was decreased with the increased\nage of the women (OR 0.89, 95% CI 0.83–0.94) but sig-\nnificantly elevated in the 20–39-min group (OR 2.11, 95%\nCI 1.34–3.13) and of (10–20) 9 10\n6 group (OR 2.06, 95%\nCI 1.32–3.46). The time interval from the end of sperm\nprocessing to AIH–IUI is a significant factor influencing\nthe rate of clinical pregnancy of AIH–IUI [ 36].\nC¸ ok et al. reported on the comparison of the effect of\npreserving prepared sperm samples at room temperature or\nat 37 /C176C before intrauterine insemination (IUI) on clinical\npregnancy rate [ 37]. Clinical pregnancy rates were similar\nin IUI cycles in which prepared sperm samples were pre-\nserved at 37 /C176C and at room temperature (9.3 vs. 8.9%).\nClinical pregnancy rates in IUI cycles with two follicles\nwere higher than IUI cycles with one follicle (10.8 vs.\n7.6%) ( P = 0.002). Further statistical analysis after split-\nting data according to the number of the follicles revealed\nthat there was no statistical difference between clinical\npregnancy rates after IUI cycles in which prepared sperm\nsamples were preserved at 37 /C176C or at room temperature in\nboth one-follicle (7.6 vs. 7.6%) and two-follicle cycles\n(11.5 vs. 10.1%). Preserving prepared sperm samples at\nroom temperature had no negative effect on clinical preg-\nnancy rates when compared with preserving prepared\nsperm samples at 37 /C176C during IUI cycles [ 37].\nA modified application technique of intrauterine\ninsemination (IUI) is slow release insemination (SRI), first\ndescribed by Muharib et al. [ 38], who postulated higher\npregnancy rates with a slow release of spermatozoa for 3 h.\nTo investigate this approach, two randomized controlled,\ncrossover pilot studies were performed from 2004 to 2006\nin Israel and Germany to compare SRI with the standard\nbolus IUI. Marschalek et al. aimed to present the results\nand perform a meta-analysis on available data for SRI [ 39].\nUnivariate comparisons of pregnancy rates were performed\nusing one-tailed z tests for method superiority. For meta-\nanalysis, a fixed-effect Mantel–Haenszel weighted average\nof relative risk was performed. Fifty treatment cycles (IUI:\nn = 25, SRI: n = 25) were performed in Germany,\nachieving four pregnancies (IUI 4%, SRI 12%,\nP [ 0.05). Thirty-nine treatment cycles (IUI: n = 19,\nSRI: n = 20) were performed in Israel achieving six\npregnancies (IUI 10.5%, SRI 20%; P [ 0.05). Meta-\nanalysis of all eligible studies for SRI ( n = 3) revealed a\ncombined relative risk for pregnancy after SRI of 2.64\n(95% CI 1.04–6.74), P = 0.02). In conclusion, these\nresults lend support to the hypothesis that the pregnancy\nrate might be improved by SRI compared to the standard\nbolus technique [ 39].\nMultiple pregnancies are a recognized adverse effect of\nassisted reproductive technologies; nevertheless, there is no\nconsensus on the incremental risk associated with the\novarian stimulation (OS) used alone and intrauterine\ninsemination (IUI). The relationship between OS and IUI\nand the risk of major congenital malformations (MCM) is\nunclear. Chaabane et al. set up a study [ 40] to summarize\nthe literature and evaluate the risk of multiple pregnancy\nand MCM associated with OS used alone and IUI used with\nor without OS compared to natural conception (sponta-\nneously conceived infants without any type of fertility\ntreatments). They carried out a systematic review to iden-\ntify published papers between 1966 and 2014 in MED-\nLINE, EMBASE, and the Cochrane Central Register of\nControlled Trials. They included observational studies and\nrandomized clinical trials related to the risk of multiple\npregnancies and MCM conceived following OS alone or\nIUI compared to natural conception (spontaneously con-\nceived infants without any fertility treatments). There were\n63 studies included in this review. The systematic review\nsuggests that the use of any OS alone was associated with\nan increased risk of multiple pregnancies compared to\nnatural conception (pooled RR 8.80, 95% CI 5.09–15.20;\nP = 0.000; 9 studies). Similar increases in the risk of\nmultiple pregnancies were observed following clomiphene\ncitrate used without assisted reproductive technologies.\nCompared to natural conception, the use of IUI with or\nwithout OS was associated with an increased risk of mul-\ntiple pregnancy (pooled RR 9.73, 95% CI 7.52–12.60;\nP = 0.000; 6 studies). Compared to natural conception, the\nuse of any OS alone was associated with an increased risk\nof any MCM (RR pooled 1.18, 95% CI 1.03–1.36; 11\nstudies), major musculoskeletal malformations (pooled RR\n1.48, 95% CI 1.21–1.81; 7 studies), and malformations of\n123\nAllahbadia The Journal of Obstetrics and Gynecology of India (November–December 2017) 67(6):385–392\n388\n\nthe nervous system (pooled RR 1.73, 95% CI 1.15–2.61; 6\nstudies). Compared to natural conception, the use of IUI\nwas associated with an increased risk of any MCM (pooled\nRR 1.23, 95% CI 1.10–1.37; 10 studies), major urogenital\n(pooled RR 1.52, 95% CI 1.04–2.22; 7 studies), and mus-\nculoskeletal malformations (pooled RR 1.54, 95% CI\n1.20–1.98; 7 studies). The increased risk of multiple\npregnancy and certain types of MCM associated with the\nuse of less invasive fertility treatments, such as OS and IUI,\nfound in this review, highlights the importance of the\npractice framing [ 40].\nHeterogeneity in OS protocols, the combination with\nother fertility agents, the limited number of studies, and the\nmethodological quality differences reduce our ability to\ndraw conclusions on specific treatment. More observational\nstudies, assessing the risk of multiple pregnancy or MCM,\nas a primary outcome, using standardized methodologies,\nin larger and better clinically defined populations are\nneeded.\nRecent Advances\nThe transcriptome of spermatozoa used in homologous IUI\nreveals profound differences between expression profiles of\nsperm samples that impregnate successfully and those that\ndo not. These differences might improve the predictive\npower of sperm evaluation to estimate IUI success by\ncomplementing the basic sperm analysis [ 41]. Three-di-\nmensional (3D) and 3D power Doppler (PD) when used\nwith 2D ultrasound and color Doppler for pre-hCG follic-\nular assessment improve pregnancy rates in IUI cycles by\nenabling an assessment of the follicular volume, perifol-\nlicular resistance index, and perifollicular vascularity\nindex, all of which may influence the conception rates [ 42].\nAbdel Razik’s study evaluated the effects of nitric oxide\ndonor’s treatment on the pregnancy rate and uterine blood\nflow in patients with unexplained infertility undergoing\nclomiphene citrate stimulation and intrauterine insemina-\ntion [ 43]. A total of 120 patients were randomly allocated\nto a control group who received 100 mg clomiphene citrate\ndaily from day 5 to 9 of cycle plus placebo vaginal tablets,\nand a study group received clomiphene citrate plus\nisosorbide mononitrate 10-mg vaginal tablets. Vaginal\nultrasound was done before treatment and every other day\nstarting from day 12 of cycle to count mature follicles, and\novulation was triggered by IM injection of 10,000 IU hCG\nwhen one follicle measured 18 C mm followed by\nintrauterine insemination after 36 h. The endometrial\nthickness, uterine arteries resistance and pulsation indices,\nand endometrial vascular flow and vascular flow indices\nwere measured before treatment and at day of hCG injec-\ntion. The study group had significant higher pregnancy\nrate/cycle, higher endometrial, and lower uterine artery\nblood flow indices ( P \\ 0.05) [ 43].\nKutlu et al. assessed the relationship between the\nestrogen–progesterone alterations before and after ovula-\ntion trigger and treatment success in intrauterine insemi-\nnation (IUI) cycles (54). Two hundred and fifty-one women\nwith infertility underwent ovulation induction followed by\nIUI. For all subjects, estradiol and progesterone concen-\ntrations were evaluated on the trigger and IUI day. The\nresults were analyzed to assess the relationship between\nhormone levels and positive pregnancy test. There were 34\nwomen with a positive pregnancy test following controlled\novarian stimulation and IUI cycle. Estradiol and proges-\nterone levels on the trigger day and the day of IUI were\ncompared within groups with and without positive preg-\nnancy tests. The comparison revealed significantly\nincreased levels of progesterone after trigger in both\ngroups; however, although there were estradiol level drops\nin both groups, the drop in the group with negative preg-\nnancy tests was statistically significant. Significant drops in\nestradiol concentrations after ovulation trigger are associ-\nated with IUI cycle treatment failure [ 44].\nThe parameters measured in the standard semen analysis\nmay be insufficient for exact differentiation between fertile\nand infertile men. Therefore, Boyraz et al. assumed that the\nhigh rate of apoptotic sperm in ejaculate may play a role on\nthe etiology of unexplained infertility [ 45]. Couples with\nunexplained infertility treated by ovulation induction and\nintrauterine insemination were consecutively enrolled\n(n = 94). To determine the proapoptotic sperm rate, the\nejaculate from patients was stained with annexin V. Thir-\nteen of the 94 couples (13.8%) conceived after intrauterine\ninsemination. The annexin V-positive sperm rate was\nfound to be 20.0% in the whole group. In women failing to\nconceive, the annexin V-positive sperm rate was 20.8%\ncompared to 15.7% in patients who achieved pregnancy\n[45]. Although there is a trend toward higher preapoptotic\nsperm rate in couples failing to get pregnant with insemi-\nnation, the difference did not reach statistical significance\n[45].\nThe advanced methods for semen preparation include\nmolecular sperm selection strategies such as hyaluronic\nacid-mediated sperm selection, annexin V magnetic-acti-\nvated cell separation (MACS) that utilizes colloidal\nsuperparamagnetic microbeads (approximately 50 nm in\ndiameter) conjugated with annexin V to separate apoptotic\nand nonapoptotic spermatozoa, and annexin V molecular\nglass wool filtration [ 46].\n123\nThe Journal of Obstetrics and Gynecology of India (November–December 2017) 67(6):385–392 Intrauterine Insemination: Fundamentals Revisited\n389\n\nThe Future is Now\nSwierkowski-Blanchard conducted an observational pilot\nstudy to determine the impact of the frequency and inten-\nsity of uterine contractions (UCs) at the time of IUI on\nsubsequent fertility [ 47]. One hundred volunteer women\nscheduled for IUI between April 2011 and July 2013, in\nwhom UCs were assessed during the ultrasound before IUI\nwas included. A two-dimensional sagittal uterus elastog-\nraphy was recorded for 5 min. The elasticity index, defined\nas the mean ratio of elastographic measurements between\nthe subendometrial area (of interest) and the endometrial\narea (control), was computed. UC frequency, endometrial\nthickness and volume, and subendometrial vascularization\nwere also measured. These parameters, along with char-\nacteristics of the IUI cycle, were entered into a logistic\nregression model for predicting ongoing pregnancy. The\nelasticity index was significantly higher (2.4 ± 1.3 vs.\n1.5 ± 0.7, i.e., with stiffer myometrium), and the endo-\nmetrium was significantly less echogenic in future pregnant\nwomen. Factors closely reaching significance were age,\nprevious fertility, day 3 hormonal assessments, number of\ninseminated spermatozoa, endometrial thickness, and UC\ncount. In multivariate analysis, low UC frequency ( \\ 2.8/\nmin; odds ratio [OR] = 0.039), high elasticity index\n([ 1.7; OR 63.26), high endometrial thickness on the\novulation triggering day ( [ 8 mm; OR 28.21), and low\npatient age ( \\ 32 years; OR 0.001) were predictive of\npregnancy after IUI. A low frequency and high intensity of\nUCs at the day of IUI appear associated with a higher\npregnancy rate. Elastography provides a promising inno-\nvative tool for IUI monitoring [ 47].\nUterine contractibility is considered a powerful prog-\nnostic factor in predicting the embryo transfer outcome.\nMoreover, uterine contractions are known to be stimulated\nby prostaglandins, which are produced by cyclooxygenase\nfrom arachidonic acid. As such, suppressing the inflam-\nmatory response and contractions using anti-inflammatory\nand relaxant agents is expected to result in increased suc-\ncess rate of embryo transfer and artificial insemination.\nZarei et al. investigated the effect of piroxicam adminis-\ntration on the success rate in intrauterine insemination (IU)\ncycles in patients presenting with unexplained infertility\n[48]. This randomized, placebo-controlled clinical trial\nincluded 260 women with unexplained infertility under-\ngoing IUI cycles. Patients were randomly assigned to\nreceive either piroxicam ten mg/day on days 4–6 after IUI\nor placebo (control group). The main outcome measures\nwere number of IUI cycles, pregnancy, abortion, and\nmultiple pregnancy rates. The pregnancy rate was found to\nbe 25 (19.2%) and 16 (12.3%) in piroxicam and control\ngroups, respectively ( P = 0.039). Five patients (3.8%) in\npiroxicam group experienced twin pregnancy, whereas\nonly three patients (2.3%) in control group had twin\npregnancy ( P = 0.361). The pregnancy rate per cycle was\nalso significantly higher in those who received piroxicam\nas compared to controls (11.16 vs. 6.66; P = 0.021).\nAdministration of piroxicam after IUI is associated with\ndecreased number of cycles, as well as increased pregnancy\nrate and pregnancy rate per cycle in IUI cycles. However,\npiroxicam did not have any effect on abortion, multiple\npregnancy, and ongoing pregnancy rates [ 48].\nConclusions\nIUI is a simple, cost-effective, noninvasive first-line ther-\napy for cervical factor, anovulatory infertility, moderate\nmale factor, unexplained infertility, and immunological\ninfertility with clinical pregnancy rates ranging from 10 to\n20%. Controlled ovarian hyperstimulation with close\nmonitoring of folliculogenesis and ovulation to avoid\nadverse complications, such as ovarian hyperstimulation\nsyndrome (OHSS) and multiple pregnancies, may be used\nto obtain the adequate number of follicles. IUI is the pre-\nferred conception-enhancing technique for women\n\\ 35 years, functional tubes, short period of infertility, and\nmoderate male infertility, particularly in technology-lim-\nited settings, and four to six IUI cycles may be performed\nbefore considering alternate therapy such as IVF [ 49, 50].\nIt is the method of choice versus timed intercourse or\nnatural cycle IUI [ 51].\nReferences\n1. Yavas Y, Selub MR. Intrauterine insemination (IUI) pregnancy\noutcome is enhanced by shorter intervals from semen collection\nto sperm wash, from sperm wash to IUI time, and from semen\ncollection to IUI time. Fertil Steril. 2004;82(6):1638–47.\n2. Ombelet W, Deblaere K, Bosmans E, et al. 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