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Fertility Blaze 2016 › Fertility Blaze Vol-3, No-1, 2016

Improving success rates in IUI

Introduction

Intrauterine insemination (IUI) is a technique that involves the transfer of sperms into the uterus to achieve pregnancy. It is one of the oldest techniques in reproductive medicine, with its history dating back to the 18th century. Over the last few decades, IUI has evolved through several innovations and gained popularity among couples visiting infertility clinics.1-3    It is the front-line technique for several cases of male factor infertility, mild or minimal endometriosis, and unexplained infertility. The spectrum of indications of IUI can further be extended to embrace infertility due to cervical and immunologic causes, ovulatory dysfunction, and various ejaculatory and coital problems (box 1).4,5

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Considerable clinical experience with IUI suggests that it is a simple, non-invasive, and cost-effective technique with a fairly good patient acceptance.1,2   However, its overall clinical success has remained debatable with published pregnancy rates ranging from as low as 5% to as high as 70%. Some researchers have considered IUI to be a stop-gap treatment before the application of more sophisticated procedures such as in vitro fertilization (IVF).5   The precise place and efficacy of IUI among assisted reproductive technologies (ARTs), therefore remains uncertain, underscoring the need for exploring the methods that can improve pregnancy success rates.6

It has been suggested that a comprehensive knowledge of factors predictive of IUI success outcomes can help couples as well as the clinicians arrive at a decision with regards to their treatment options and boost pregnancy outcomes.7

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Pregnancy predictors in IUI

Remarkable research in the past few years suggests that the success of an IUI cycle is multifactorial.8   A broad range of factors related to female infertility (duration of infertility, age, weight, etiology), male infertility (semen analysis), and the technique employed (type of insemination, number of cycles, number of inseminations per cycle, follicle development) influence IUI success (figure 1).9

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Several studies have been performed to recognize the predictors of pregnancy rates in IUI.10   Varying results have been obtained depending on patient selection criteria such as age, presence of different infertility factors, ovarian stimulation techniques, sperm-related and other parameters.3

Age

Several lines of evidence suggest that patient age has a statistically measurable impact on pregnancy outcomes. Yousefi et al10   revealed that maternal age negatively correlated with the number of follicles recruited, suggesting a diminished ovarian reserve with increasing age. They stated that those who conceived at a younger age had better ovarian response, with success increasing in tandem with the number of mature follicles present. Corroborating this finding, some authors11   have demonstrated an increase in spontaneous pregnancy loss with a consequent decline in live birth rates per insemination among older women.

It is believed that several inexorable age-induced changes collaborate in jeopardizing IUI success. These include progressive follicular depletion, decline in granulose function, poor oocyte quality, compromised endometrial receptivity, chromosomal abnormalities, increased frequency of anovulatory cycles, and aging of the reproductive tract.10

Duration of infertility

Emerging data illustrate that the duration of infertility is a crucial factor to assess pregnancy outcomes in IUI. Multiple publications have reported higher chances of conception corresponding to shorter periods of infertility.9   Tomlinson and colleagues12   revealed the duration of infertility to be a valuable indicator of IUI success, with pregnancy rates being particularly compromised in cases with >6 years infertility. This is in congruity with another study which demonstrated pregnancy rates to drop with increasing length of infertility duration, warranting the need for employing other ARTs after a certain period of conception failure with IUI.9

Follicular parameters

Preovulatory follicles also serve as indicators of successful pregnancy in IUI, with dominant follicles before human chorioinic gonadotropin (hCG) administration being significant independent factors to predict live birth.10   A study9   revealed that recruitment of at least two follicles boosted success rates in controlled ovarian hyperstimulation (COH) combined with IUI-by 2% for one follicle, and by 15% for two or more follicles. Likewise, cycles with a single pre-ovulatory follicle have shown poor results. In an IUI performed using a single pre-ovulatory follicle (>16 mm in diameter), the conception rate (5.7%) was significantly lower than that observed in cycles with three follicles (16.3%).13

Endometrial thickness

There is convincing evidence in literature to show endometrial thickness to be a strong determinant of IUI success. A study14   evaluated the pregnancy rates in IUI among women belonging to two age groups: >35 and 10 mm). The results showed that in all age ranges, pregnancy rate was lowest among those with thickness ≤6 mm. The findings in this study mirrored other reports15,16 whereby conception rates were high with endometrial thickness of 8 mm with a higher number of follicles (up to three), and significantly increased when the thickness was ≥ 9 mm.

It is therefore logical to suggest that clinicians providing IUI for infertile couples should pay close attention to endometrial parameters.17  Several strategies have been undertaken to circumvent thin endometrium in patients undergoing IUI cycles. Optimizing serum estrogen levels using estradiol valerate, an estrogen formulation accounts for one the important strategies.18   It is superior to other estrogens (such as conjugated equine estrogens-CEE) as it confers greater benefit without significant safety concerns.19   Li and coworkers20   demonstrated that treatment with oral estradiol valerate significantly improves ultrasonographic thickness of endometrium and enhances endometrial response by producing adequate plasma levels of estradiol without any adverse effects.

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Sperm parameters

A compelling association between sperm parameters and IUI outcomes has been observed.10   There is some evidence to suggest that sperm morphology using strict criteria and the inseminating motile sperm count (IMC) after sperm preparation are the two most crucial sperm parameters to ascertain the real impact of semen quality on IUI outcomes.21   Scores of research papers suggest IMC to independently predict pregnancy, with one study showing this count to exert the highest impact on pregnancy after IUI, among all other factors in women with infertility for >10 years.3,10

Although there is a lack of agreement with regards to the threshold whereby IUI can be performed with a satisfactory conception rate, some of the best lines of evidence suggest that success is jeopardized with insemination of

Lifestyle factors

Lifestyle and environmental factors are established contributors of reproductive failure. Hence, their identification and correction during preconception counseling of infertile couples, prior to initiation of treatment is essential.23   A high BMI or obesity is particularly known to compromise IUI success. While some studies have failed to establish an association between BMI and pregnancy rates, a majority of them have demonstrated a linear decrease in ART success with increasing BMI. This has been validated by studies showing obese patients to have poor quality oocytes, hostile intrauterine environment and deranged sensitivity to insulin and androgen.3  

Besides high BMI, cigarette smoking also has a detrimental effect on the clinical outcome of assisted conception treatments. Compared to nonsmokers, smokers require higher gonadotropin doses for ovarian stimulation, and have lower peak estradiol (E2) levels, lesser number of oocytes retrieved, lower fertilization and implantation rates, and consequently lower conception and live-birth rates.23

Lifestyle modifications such as exercise and weight loss are thereby considered to be key factors for achieving successful pregnancy in obese women contemplating IUI.9

Evaluation and technique

As described in the previous section, several male and female parameters serve as pregnancy predictors in IUI. Therefore, clinicians recommend that IUI procedure should be preceded by a complete evaluation of these parameters. The male partner is initially evaluated by obtaining a complete semen analysis and screened for sperm antibodies. Two to three semen samples provided over 1 to 2 months are screened. Antisperm antibody tests are conducted during the initial infertility evaluation, with immunobead assay being the most frequently employed technique. Immunobead assay is a quantitative assay which aids in the analysis of live sperms and provides information related to percent bound, antibody isotype, and binding location. The female partner is also required to undergo basic infertility screening, and is most often advised a hysterosalpingogram for documentation of patent tubes. Further, ovulatory function should be assessed with a urinary luteinizing hormone (LH) detection kit and midluteal serum progesterone concentrations. Presence of any clinical abnormalities or deranged laboratory values warrants additional tests so that any correctable factors can be identified and treated promptly prior to IUI procedure.

The technique of IUI involves the use of IUI catheters connected to a 2-mL syringe. The patient is kept in a dorsal lithotomy position and the cervix is visualized with a bivalve vaginal speculum. The excess vaginal fluid is cleaned from the external cervical os, and the tip of a thin flexible catheter is introduced into the uterine cavity, and the sperm sample, suspended in less than 1 mL of wash media, is gently expelled high in the uterine cavity. In case of increased resistance during injection, the catheter can be withdrawn 1 cm, and injection reattempted. After IUI, the catheter is gently removed and the patient advised to maintain supine position for at least 10 minutes if she experiences a vasovagal reaction. Some clinicians report trouble in navigating the tortuous endocervical canal with the tip of the insemination catheter. Insertion of a thin catheter (external diameter 24

Ovulation induction combined with IUI: Benefits of clomiphene and gonadotropins

Treatment by IUI may be performed either in a natural or a stimulated cycle. Most practitioners believe that the objective of IUI-which is to provide a high concentration of motile spermatozoa in the proximity of the oocyte- can be successfully achieved when IUI is combined with ovulation induction (OI). The rationale for the use of OI with IUI is both to increase the efficiency and likelihood of ovulation, and to boost the number of ova available for fertilization, thereby enhancing the probability of pregnancy. Stimulation also boosts steroid production, which may additionally serve to promote fertilization and embryo implantation.

A group of investigators documented the cumulative pregnancy rate per couple to be 33% for IUI and controlled (COH) versus 18% for IUI alone (figure 2). They asserted that COH has an independent positive effect on conception rates when combined with IUI and that in young patients without a prior pelvic surgery and good-post-wash semen quality, COH can increase IUI pregnancy rate by two-fold. Stimulated IUI has particularly been considered the firstchoice treatment, for mild male factor infertility, unexplained infertility or minimal to mild endometriosis.25-27

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A diverse range of ovarian stimulation protocols has been devised for combining with IUI, including: clomiphene citrate (CC) alone or in combination with gonadotropins and human chorionic gonadotropin (hCG); and gonadotropin-releasing hormone (GnRH) agonist or antagonist combined with gonadotropins. hCG is generally administered towards the end of the stimulation phase to attain final maturation of the oocyte(s). Most clinicians initially try CC, and switch to gonadotropins in case of no success within a few cycles of CC/IUI.26

Literature shows that CC is the most frequently employed drug for ovulation induction with remarkable efficacy. A study28   was conducted to evaluate the success rate after IUI with CC stimulation in patients with unexplained infertility. A total of 68 couples were included in the study and divided into two equal groups: group A was inducted with CC, while group B was given placebo. The investigators demonstrated pregnancy rates of 44.1% and 11.7% in group A and B respectively (figure 3) and concluded that ovulation inductions with CC, together with IUI, improves fecundity in patients with unexplained infertility and obviates the need to resort to other invasive techniques.

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To further enhance pregnancy rates, combination CC with gonadotropins is sometimes used for ovarian stimulation. A prospective study29   compared the pregnancy rate during IUI in cases of artificial insemination by husband (AIH) and artificial insemination by donor (AID). Different OI protocols including CC alone, combined CC-gonadotropins and gonadotropins alone were used. The results showed that in both AIH and AID, the conception rates were notably higher in patients receiving combined CC and gonadotropins than in those receiving either drug alone. There are several studies which specifically consider estradiol use in CC ovulation induction cycles for women contemplating IUI. This is because the adverse effects of CC on endometrium can be prevented by co-administration of estradiol, thereby improving the chances of conception.30   A meta-analysis31   demonstrated that estradiol supplementation in CC ovulation induction cycles optimizes both endometrial thickness and serum estradiol levels with a trend towards increased rates of pregnancy among infertile women undergoing IUI. These findings were corroborated in another study32   which included infertile women (aged 25 to 35 years) undergoing IUI. The women were randomized to receive either CC+placebo (group A) or CC+estradiol (group B) for the ovulation induction. The results showed that group B had greater endometrial thickness, lower risk of spontaneous abortion, and higher pregnancy rates than group A. These results could be explained by an endometrium improved with estradiol (possibly acting to balance/reverse the antiestrogenic effects of CC) that facilitated embryo implantation, leading to better pregnancy outcomes in IUI.

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Luteal phase support after ovulation induction and IUI: Focus on micronized progesterone

Luteal phase insufficiency is a clinical entity per se and a robust indicator of implantation failure in assisted conception. The growing importance of this fact has encouraged investigators to probe the role of luteal phase support after OI and IUI.33,34

Implantation and maintenance of an early pregnancy are recognized to be strongly dependent on the production of progesterone. In view of this, progesterone supplementation during luteal phase in assisted conception appears worthwhile and there is increasing consensus with regard to its beneficial role on reproductive outcomes.35   An increase in conception rates has been noted following exogenous progesterone supplementation in ART cycles.36   However, its micronized form has several advantages which include, better dissolution, better absorption, markedly increased bioavailability and desired clinical efficacy (box 2).37   Research conducted on patients with unexplained infertility undergoing hormone-stimulated IUI cycles demonstrated the clinical pregnancy rates to be notably higher in the progesterone-supported cycles as compared to the unsupported cycles.38   These findings were corroborated in a retrospective cohort analysis39   which showed luteal phase administration of micronized progesterone in CC-IUI cycles to boost endometrial receptivity and consequently clinical pregnancy rates.

Multiple publications studying the benefits of progesterone supplementation have also underlined the widespread clinical potential of its micronized, sustained release (SR) form. It is posited that the oral SR natural micronized form enables consistent tissue concentrations for endometrial support allowing once daily dosage convenience, thereby enhancing patient compliance. The pharmacokinetic profile of SR preparation is reasonably good as it reduces drug exposure to hepatic metabolic enzymes at individual time points, thereby offering sustained activity with negligible central adverse effects. Investigators have evidenced the success of IUI procedure using oral SR natural micronized progesterone 400 mg administered once a day at bedtime with good tolerability and no significant undesirable effects such as drowsiness.40,41

Based on the above-mentioned evidences, oral micronized SR formulation of progesterone can be considered beneficial in patients undergoing IUI.

Conclusion

Intrauterine insemination is an inexpensive, non-invasive and simple procedure that serves as a potential solution to several infertility problems. It can be provided easily to infertile couples in office practices and general hospitals. A range if factors such as maternal age, endometrial thickness pre-ovulatory follicles, and motile sperm fraction influence the success rate of an IUI protocol. Although there is a debate on whether or not IUI should be complemented by OI, majority of the practitioners suggest that OI does increase success rates of IUI. It increases the likelihood of ovulation and therefore the number of oocytes available for fertilization.

The most frequently employed drug for ovulation induction is CC as it boosts the success rates after IUI, particularly in patients with unexplained infertility. To further enhance pregnancy rates, combination of CC with gonadotropins is sometimes used for ovarian stimulation. Norethindrone acetate is also used for programming of ovarian stimulation in assisted conception cycles and is considered to be advantageous due to its route of administration (oral), simplicity and cost-effectiveness. In addition, since production of progesterone strongly predicts implantation and maintenance of early pregnancy, its supplementation during luteal phase appears beneficial. There is increasing evidence to support the use of its micronized form which offers better dissolution, better absorption, markedly increased bioavailability and desired clinical efficacy. Micronized progesterone is known to boost endometrial receptivity and consequently clinical pregnancy rates.

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