In this article we define male subfertility, review clinical indications for the use of intrauterine insemination, evaluate insemination preparation and administration technique, and ultimately advocate for its use as a first-line therapy in the treatment of infertile couples with male subfertility.
It has been estimated in developed countries that as many as one in four couples has difficulty conceiving a child . Because infertility can be caused by male factors, female factors, or combined factors, much research and innovation have been used to determine the best treatment modality for each cohort of patients. One of the oldest reproductive technologies, which was described more than 200 years ago and is still currently in use, is artificial insemination . Since its emergence, many refinements have been made with respect to its clinical indications and use. Although significantly cheaper and technically easier than many other reproductive technologies, it is an effective tool in the armamentarium of reproductive specialists. In this article we define male subfertility, review clinical indications for the use of intrauterine insemination, evaluate insemination preparation and administration technique, and ultimately advocate for its use as a first-line therapy in the treatment of infertile couples with male subfertility.
Definition of male subfertility
When defining male subfertility, many authors use nomenclature such as normozoospermia, oligozoospermia, asthenozoospermia, teratozoospermia, and oligoasthenoteratozoospermia. Grimes and Lopez recently highlighted that these terms are actually vague because their definition and use seem to be author dependent. As a result, it is inherently difficult to construct an authoritative working definition of male subfertility and discuss its prevalence when reviewing the current body of literature. Keeping in mind the inherent challenges in such terminology and in an attempt to generate a comprehensive clinically relevant definition, we advocate adopting an approach that is based on previously published definitions stating that male subfertility is the presence of one or more subnormal sperm parameters—sperm concentration less than 20 × 10 6 /mL, motility less than 40%, or normal morphology less than 5%—in two consecutive semen analysis and in the absence of antisperm antibodies . Although we realize that no definition is perfect and that many fertile men may be diagnosed as subfertile with the aforementioned motility and morphology thresholds, leading to them being potentially “overtreated,” we believe that by stating clear parameters and avoiding confusing terminology, it is much easier to interpret the available data and integrate these findings into clinical practice. In their study population of 495 couples with semen analyses that revealed more than 2 million motile postwash sperm on day of in vitro fertilization, Keegan et al found that 55% had less than 5% normal sperm morphology, which lends credence to the idea that a large part of the population may be defined as subfertile.
Clinical indications for intrauterine insemination
Abnormal semen analysis
According to the World Health Organization guidelines for the standardized diagnosis, investigation, and management of infertile men, all couples who are unable to conceive after 1 year of unprotected intercourse warrant further investigation into the causes of their infertility . As part of this initial evaluation, semen analyses should be conducted ideally after 2 to 3 days of sexual abstinence. Standardized procedures should be followed by patients submitting semen for analysis. Research has shown that there may be variability for samples collected via masturbation versus those collected via a silastic condom . Regardless of mode of collection, we believe that it is important to conduct at least two, preferably four, separate identically collected semen samples because of the inherent variability of semen parameters in men . If the semen analyses are abnormal (as defined previously) but do not demonstrate azoospermia, the couple is a candidate for intrauterine insemination using the sperm preparation techniques discussed later.
Ejaculatory abnormalities
There are different forms of ejaculatory dysfunction, which should be defined and approached as discussed by Ohl (see the article elsewhere in this issue). More than 50 years ago, one of the earliest descriptions of successfully treated ejaculatory failure was the artificial insemination of a 24-year-old otherwise healthy woman with sperm collected from her husband’s postcoital urine . Although this patient’s retrograde ejaculation was surmised to be secondary to an inflamed ectopic right ureteral orifice opening into the prostatic urethra, there are many causes of ejaculatory failure other than anatomic aberrations . As discussed in the article by Ohl elsewhere in this issue, when ejaculatory failure is considered, it is important to formulate a wide differential, such as—but not limited to—neurologic impairments, iatrogenic causes (eg, certain surgical procedures and medications), psychologic impairment, and anatomic abnormalities . Although many of these causes may be obvious from the history, it may be necessary to conduct further diagnostic evaluation using ultrasonography. Transrectal ultrasonography may be used to evaluate for the presence of ejaculatory duct obstruction . Intrauterine insemination may be used if sufficient sperm are present in the ejaculate or in postejaculatory urine. It also may be used if sperm are obtained using ejaculation induction techniques, as described in the article by Ohl elsewhere in this issue.
Immunologic
Much controversy exists over the presence and clinical relevance of sperm autoantibodies . Unfortunately, despite the mounting body of literature that characterizes their presence, no study has characterized the type and titer that cause infertility. Although many antibodies have been found in seminal fluid and antigen/antibody complexes have been seen on sperm, the direct effects of these antigen/antibody interactions are still not known . In a recent article, the authors recommended initiating an immunologic evaluation when (1) the semen analysis displays aggregates of sperm, (2) there is low motility with other normal parameters, (3) there is a risk of autoimmune infertility (as in the case of torsion, testis injury, or vasal reconstruction), or (4) there is unexplained infertility with a normal routine semen analysis . Vasectomy has been demonstrated to induce antisperm antibodies in animal models . Patients who have undergone successful vasal reconstruction (vasectomy reversal) may experience infertility secondary to autoantibodies induced by the vasectomy.
Unexplained factors
A large volume of literature debates the use of intrauterine insemination in couples in whom there is no clearly defined cause of infertility. The true benefit of intrauterine insemination in this circumstance actually may be caused by the close monitoring of the female partner’s cycle, use of ovarian stimulating agents, or even sperm preparation . With that being said, intrauterine insemination is significantly less expensive and less invasive than in vitro fertilization and is an appropriate tool in the treatment of infertile couples.
Clinical indications for intrauterine insemination
Abnormal semen analysis
According to the World Health Organization guidelines for the standardized diagnosis, investigation, and management of infertile men, all couples who are unable to conceive after 1 year of unprotected intercourse warrant further investigation into the causes of their infertility . As part of this initial evaluation, semen analyses should be conducted ideally after 2 to 3 days of sexual abstinence. Standardized procedures should be followed by patients submitting semen for analysis. Research has shown that there may be variability for samples collected via masturbation versus those collected via a silastic condom . Regardless of mode of collection, we believe that it is important to conduct at least two, preferably four, separate identically collected semen samples because of the inherent variability of semen parameters in men . If the semen analyses are abnormal (as defined previously) but do not demonstrate azoospermia, the couple is a candidate for intrauterine insemination using the sperm preparation techniques discussed later.
Ejaculatory abnormalities
There are different forms of ejaculatory dysfunction, which should be defined and approached as discussed by Ohl (see the article elsewhere in this issue). More than 50 years ago, one of the earliest descriptions of successfully treated ejaculatory failure was the artificial insemination of a 24-year-old otherwise healthy woman with sperm collected from her husband’s postcoital urine . Although this patient’s retrograde ejaculation was surmised to be secondary to an inflamed ectopic right ureteral orifice opening into the prostatic urethra, there are many causes of ejaculatory failure other than anatomic aberrations . As discussed in the article by Ohl elsewhere in this issue, when ejaculatory failure is considered, it is important to formulate a wide differential, such as—but not limited to—neurologic impairments, iatrogenic causes (eg, certain surgical procedures and medications), psychologic impairment, and anatomic abnormalities . Although many of these causes may be obvious from the history, it may be necessary to conduct further diagnostic evaluation using ultrasonography. Transrectal ultrasonography may be used to evaluate for the presence of ejaculatory duct obstruction . Intrauterine insemination may be used if sufficient sperm are present in the ejaculate or in postejaculatory urine. It also may be used if sperm are obtained using ejaculation induction techniques, as described in the article by Ohl elsewhere in this issue.
Immunologic
Much controversy exists over the presence and clinical relevance of sperm autoantibodies . Unfortunately, despite the mounting body of literature that characterizes their presence, no study has characterized the type and titer that cause infertility. Although many antibodies have been found in seminal fluid and antigen/antibody complexes have been seen on sperm, the direct effects of these antigen/antibody interactions are still not known . In a recent article, the authors recommended initiating an immunologic evaluation when (1) the semen analysis displays aggregates of sperm, (2) there is low motility with other normal parameters, (3) there is a risk of autoimmune infertility (as in the case of torsion, testis injury, or vasal reconstruction), or (4) there is unexplained infertility with a normal routine semen analysis . Vasectomy has been demonstrated to induce antisperm antibodies in animal models . Patients who have undergone successful vasal reconstruction (vasectomy reversal) may experience infertility secondary to autoantibodies induced by the vasectomy.
Unexplained factors
A large volume of literature debates the use of intrauterine insemination in couples in whom there is no clearly defined cause of infertility. The true benefit of intrauterine insemination in this circumstance actually may be caused by the close monitoring of the female partner’s cycle, use of ovarian stimulating agents, or even sperm preparation . With that being said, intrauterine insemination is significantly less expensive and less invasive than in vitro fertilization and is an appropriate tool in the treatment of infertile couples.
Methodology
Sperm preparation
Over the last 20 years as in vitro fertilization has become increasingly more popular, improvements have been made in sperm preparation techniques such that motile viable sperm can be separated easily from the seminal plasma and dead, suboptimal spermatozoa, leukocytes, and bacteria. It is important to segregate the sperm from these potential detrimental elements and inseminate with the most concentrated sample possible. Leukocytes, dead sperm, and bacteria can produce oxygen radicals and other metabolic byproducts, which can lead to a suboptimal environment for fertilization to take place . The seminal plasma contains a high concentration of seminal prostaglandins, which can induce uterine cramps and make it uncomfortable for the patient.
Although these principles are widely held, much research has been done to investigate the optimal sperm preparation technique. After evaluating five randomized controlled trials (262 couples), a recently published Cochrane review of semen preparation techniques for intrauterine insemination found that there is a dearth of significant evidence to support gradient, swim-up, wash, or centrifugation as a superior technique over any other . There was no difference in the miscarriage rate in two studies that compared swim-up versus a gradient technique . With respect to the concentration of sperm in inseminate, Martinez et al found that pregnancies were only obtained when more than 2 × 10 6 sperm were inseminated, with the mean number of sperm in their conceptional cycles being 2.4 to 55 × 10 6 . The mean number of sperm in their nonconceptional cycles was 0.2 to 240 × 10 6 . We can surmise that if a high concentration of morphologically normal motile sperm can be collected, the choice of the preparation modality is up to the practitioner.
Ovarian stimulation
Previous authors have demonstrated that intrauterine insemination has a definite advantage over timed intercourse . Although many researchers would agree with these findings, because the sperm has been prepared and refined as stated previously, much controversy still exists over the use of ovarian stimulation in conjunction with intrauterine insemination in treating couples with male subfertility. For example, Cohlen and colleagues found that when a moderate to severe semen deficit is noted, there is no advantage to using controlled ovarian hyperstimulation; however, when there is a mild semen defect (> 10 × 10 6 spermatozoa), controlled ovarian hyperstimulation can improve the chances of conception. In a systematic review of 5214 cycles reported in 22 trials, researchers found that when stratifying the results of a couple with 2 years of unexplained secondary infertility, their untreated cycle fecundity would be approximately 4%, when treated with follicle stimulating hormone it would be 8%, and when used in conjunction with intrauterine insemination it could be as high as 20% . A more recent study demonstrated that intrauterine insemination did not improve pregnancy rates in couples with unexplained or mild male factor subfertility. In the mildly hyperstimulated group (follicle-stimulating hormone) there was a significantly higher rate of multifollicular development and subsequent multiple pregnancies . Taken together, the literature shows that the use of controlled ovarian hyperstimulation is of added value when used in an appropriately selected patient population.
We advocate a step-wise approach to intrauterine insemination starting without an ovulation-inducing agent, using clomiphene citrate, which is lower in potency than injectable gonatropins, progressing to low-dose gonadotropins, and ultimately using higher dose injectable medications over progressive cycles. As discussed later, as with any procedure, ovulation induction is not without risk. It requires close monitoring and a practitioner who is committed to canceling a cycle if the patient is at any potential risk for multiple pregnancy, ovarian hyperstimulation syndrome, or other known complications.
Timing and number of inseminations per cycle
In patients undergoing natural cycles with insemination, it is our practice to monitor a patient’s serum luteinizing hormone levels as a marker of ovulation and perform serial sonograms to look for correlating follicles of an ideal size of 18 to 20 mm. In patients undergoing a natural cycle, a patient is inseminated approximately 24 hours after the luteinizing hormone surge is noted. With patients undergoing ovarian stimulation, human chorionic gonadotropin is administered to induce ovulation once the luteinizing hormone surge is detected; a patient is subsequently inseminated approximately 24 hours later.
The number of inseminations per cycles also may influence pregnancy rates after intrauterine insemination. In a review of 18 randomized and prospective trials that compared two inseminations versus one insemination per cycle (1156 intrauterine insemination cycles), researchers found that although the pregnancy rate per cycle was higher in the group that received two insemination per cycle (14.9% versus 11.4%), there was no significant difference . The authors noted that there was considerable heterogeneity regarding the ovarian management and timing of the insemination, but more research is needed to further elucidate the use of multiple inseminations per cycle. In our practice we only administer a single, appropriately timed insemination per cycle.
Technique of insemination
As opposed to in vitro fertilization, in which extensive research has been done on the success rates of different catheters at the time of embryo transfer, fewer studies have compared the catheters used during intrauterine insemination . With respect to those used for in vitro fertilization, soft catheters, regardless of manufacturer, were found to be superior to rigid catheters . Although speculative, the prevailing thought is that endometrial trauma at the time of transfer may induce uterine contractions, which could lead to a suboptimal environment for implantation . In a systematic review and meta-analysis of intrauterine insemination catheters, researchers found that catheter choice does not influence outcome. The authors hypothesized that because fertilization takes place in the fallopian tube, even if uterine trauma occurred, it would be potentially healed by the time of implantation days later . More studies are needed to elucidate any potential differences between rigid and soft catheters, however.
Another area of controversy regarding intrauterine insemination techniques relates to insemination delivery technique. A randomized cross-over study demonstrated that the pregnancy rate was three times higher after slow-release intrauterine insemination compared with the bolus technique . Unfortunately, the aforementioned study was limited to patients diagnosed with cervical hostility, and the applicability to the patient subpopulation of subfertile men has yet to be determined. The authors described their slow-release method as requiring a patient to lie in bed with a continuous infusion of spermatozoa (3 × 10 6 /hr) for 3 hours. Although we find this method of insemination to be of academic value, we believe that it is less than practical because it requires a patient to endure a significantly longer period of discomfort during the insemination process and lends itself to an increased risk of introducing pathogens into the uterine canal.
Risks of intrauterine insemination
In a review of 38 reported series of intrauterine insemination, it was found that 5 of the 3129 couples studied experienced an infectious complication . The prevalence of infectious complications was estimated to be 1.83 per 1000 women undergoing intrauterine insemination, and this rate was not altered by semen washing with antibiotics or by the administration of prophylactic antibiotics to the women.
Beyond the risk of infection in the setting of an undiagnosed infection, there is a risk for multiple pregnancies. When ovulation-inducing agents are administered, the risk of multiple pregnancies increases significantly, as seen in Table 1 , which was adapted from an analysis of 17 studies evaluating the outcomes of more or less aggressive stimulation protocols . Finally, in a recent Cochrane review of intrauterine insemination for male subfertility, the authors stated that there was insufficient data available to statistically evaluate adverse outcomes, such as miscarriages, ovarian hyperstimulation syndrome, and ectopic pregnancies, which are all potentially life-threatening conditions . When counseling patients about their specific treatment plan, it is important to note that intrauterine insemination is not without risk and that with increasing potency of stimulating agents there is a well-recognized risk of multiple pregnancies and other untoward outcomes.
Related posts:
Hormonal Evaluation of the Infertile Male: Has It Evolved?
Assessing Sperm Function
Anejaculation and Retrograde Ejaculation
Ejaculatory Duct Obstruction
Reassessing Reconstruction in the Management of Obstructive Azoospermia: Reconstruction or Sperm Acquisition?
Intracytoplasmic Sperm Injection (ICSI) – What are the Risks?
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