Intrauterine Insemination Ghumman Sindhu Surveen
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Indications and Patient Selection for IUIChapter One

Surveen Ghumman Sindhu
2
Appropriate patient selection is one of the most important factors which determine success of an IUI programme. Many times treatment is empirical, but it is possible to deduce a section of people in whom this treatment is going to be useful. The basis of treatment is to improve the quality and quantity of gametes available for fertilization, and to bring them closer by bypassing factors which depend on deposition of sperms in vagina and transport through cervical mucus to upper genital tract. There are several indications for IUI which may be because of male, female or combined factors (Fig. 1.1).
Before taking up the patient for IUI, a complete workup is required to reach the diagnosis, and rule out any contraindications. If any one of the contraindications is present IUI success rates may be poor (Table 1.1). The cause of infertility must be established to give a diagnosis to the patient, which is essential to decide if IUI is appropriate therapy. Patients must be counseled on success rates, other options and risks of IUI.
 
INSEMINATION WITH HUSBAND'S FRESH SPERM
 
Male Factor
 
Retrograde Ejaculation
With retrograde ejaculation, there is reflux of semen backwards from the posterior urethral valve and into the bladder at the time of ejaculation. These sperms lose their viability due to toxic effects and acidity of urine.3
zoom view
Figure 1.1: Indications and Patient Selection for IUI
Table 1.1   Contraindication of IUI
Contraindications
1. Bilateral tubal block
2. Very severe oligoasthenospermia
3. Genital tract infection
4. Pregnancy contraindicated in female partners
5. Unexplained genital tract bleeding
Relative contraindication
1. Tubal pathology
2. Genetic abnormality
3. Pelvic mass
4. Older women
5. Multiple infertility aetiologies
6. Pelvic surgery
7. Severe illness in one or both partners
8. Recent chemotherapy or radiotherapyContraindications
4
IUI has been used in these cases when medical therapy fails especially where there is a good sperm motility.
 
Cause
  • Diabetes mellitus
  • Multiple sclerosis
  • Damage to innervation of bladder neck can occur during surgery, like transurethral resection of the prostate and retropubic prostatectomy
  • Drugs—alfa adrenergic blockers, phenothiazines.
 
Diagnosis
Demonstration of sperm or detection of fructose in urine following an orgasm.
 
Goal of Management
Alkalinize urine and retrieve sperms, as soon as possible, after ejaculation.
 
Treatment
  1. Patient is asked to ejaculate on full bladder. The urinary continence with full bladder entails closure of bladder neck sphincters and this prevents reflux of ejaculated semen into bladder especially when patient is in upright position.
  2. The sperms can be collected from urine for IUI.1
  3. Surgical treatment is aimed at restoring sphinteric control.
  4. Medical therapy is also possible and aims at increasing sympathetic discharge, or decreasing 5parasympathetic activity at the bladder neck. Alfa adrenergic agents, such as phenyl propanolamine hydrochloride, synephrine and nidodrin and anticholinergic drugs like brompheniramine, have been tried.
 
Impotence or Ejaculatory Dysfunction
There are a number of reasons for impotence or ejaculatory dysfunction (Table 1.2). The quality of semen is generally poor in men, who are continent for long periods. The motility is low despite high sperm density. Debris, inflammatory cells, and bacteria may be found in the sample. They may have recurrent urinary tract infections, which spread on to the genital tract. The success of treatment depends on sperm quality. In patients with progressive sperm motility of more than 20-30 per cent, the results of IUI are good. A fecundity rate of 9-36.8 per cent has been reported.2
Table 1.2   Causes of impotence or ejaculatory dysfunction
• Psychogenic
• Organic
• Spinal cord injury
• Diabetes mellitus
• Multiple sclerosis
• Atherosclerosis
• Hypo and hyperthyroidism
• Epilepsy
• Renal failure
• Damaged hypogastric nerves during surgery, such as abdominoperineal resection of rectum, retroperitoneal lymph node dissection and aortoiliac surgery
• Drug
6
 
Treatment
  1. Treat the cause.
  2. Intracavernosal injection:
    • Papavarine hydrochloride
    • Phenoxybezamine
    • Phentolamine mesylate
    • Prostaglandin.
  3. Surgical methods:
    • Epidydimal sperm aspiration
    • Hypogastric sperm aspirator
    • Sperm reservoirs.
  4. Penile vibrator.
  5. Rectal electrostimulation.
Autonomic hyper-reflexia may occur in men with spinal cord injury, leading to a raised blood pressure following orgasm. This can be treated by drugs. Retrogade ejaculation is occasionally seen, hence culture medium should be instilled into the bladder prior to the procedure. Urine must be collected and processed.
Penile vibrator or electrostimulator: The penile vibrator or electrostimulators are effective and safe. Electro-ejaculation, with stepwise application of ART, is effective in treating anejaculatory infertility. Intrauterine insemination, with the least expensive monitoring protocol, should be used for most couples, as use of more expensive monitoring has not shown improved results. Female management protocol, and etiology of an ejaculation does not affect results. Patients undergoing IVF had higher cycle fecundity (37.2%), than did those undergoing IUI.(32.5%) It is cost-effective 7to bypass IUI and proceed directly to IVF, in men who require anesthesia for electro-ejaculation, and in those with a total inseminated motile sperm count < 4 million.3
Per cutaneous vasal sperm aspiration (PVSA): In a study IUI was performed in 26 men with anejaculation after percutaneous vasal sperm aspiration. A pregnancy rate of 73.1 per cent was achieved. Values for sperm variables were acceptable and as follows: motility, 78.6 per cent; progressive motility, 60.4 per cent; density, 37.6 × 106 cells/mL; total count, 35.2 × 106 cells; and abnormal sperm, 18.6 per cent. Percutaneous vasal sperm aspiration may obtain high motility sperms, and combined with IUI, is an effective treatment for male infertility with an ejaculation.
 
Hypospadias
Here deposition of semen occurs outside the vagina or much away from the os. However, hypospadius is usually repaired in infancy.
 
Hypospermia
The term should only be used if the volume is consistently less, and it is ensured that there is no spillage. Low volume could be because of inadequate sexual stimulation, in which case the semen may be collected from home.
Need for IUI in such cases exists because:
  1. The very small volume of ejaculate may be deposited away from the cervix.8
  2. Small volume of seminal plasma is inadequate to change pH of upper vagina, and the acidic pH of vagina destroys the sperms.
 
Non Liquefying or Highly Viscous Semen
Increased viscosity impedes the escape of sperms from the ejaculate into the cervical canal before destruction by vaginal acidity occurs. Enzymatic digestion of mucus is possible by plasmin or chymotrypsin. Mechanical methods may be employed to break tenacious mucus threads while preparing sperms. After adding culture medium, the sample is repeatedly aspirated and expelled through a hypodermic needle of 18 G size. Alternatively a pipette can be used. However, there may be portions of highly viscous ejaculate which have normal viscosity.
The overall pregnancy rate, when viscosity was increased, was 14 per cent vs 11.8 per cent for normal semen. However 62.5 per cent pregnancies miscarried in the first trimester; with no miscarriage in the normal semen group. The high miscarriage rate, in couples with semen hyperviscosity, may be attributed to biophysical alterations or chemical changes of the ejaculate that could impact sperm quality, despite normal sperm parameters on semen analysis.4
 
Subnormal Semen Parameters
The cause of infertility in oligoasthenospermia is decreased availability of motile sperms required for fertilization.
Oligospermia: In patients with oligoasthenozoospermia the normal motile sperm fraction is selected out during 9the preparation and is selectively deposited in the uterine cavity. They bypass the vaginal acidity and cervical mucus and reach the fallopian tube in numbers greater than what would have been otherwise possible.
Teratospermia: With teratozoospermia the motility is decreased because of abnormal morphology. Also the ability of sperm to bind to the zona may be altered. Sperm preparation and insertion into the uterine cavity is not going to improve the fertilization rates unless adequate amount of normal motile sperms are selected out while preparing the sample. Sperm preparation with more than 1 × 106 motile sperms is needed.
Patients with severe male factor infertility like sperm count of less than 5 million, or more than two abnormal parameters, have poor results.5 With mild male factor infertility, the pregnancy rates of IUI are comparable to IVF.6
 
HIV Infection
Recently insemination of HIV negative women with processed semen sample of HIV positive partners has been carried out to reduce the risk of transfer. Sperm washing can significantly reduce the virus load7 However, documentation of testing of sperm preparation by PCR on each sample is a must before insemination. In a recent study 740 serodiscordant HIV positive couples no seroconversion of female partner was observed with IUI or ICSI.810
 
FEMALE FACTOR
 
Cervical Factor
The cervical mucus plays an important role in fertility.
  • The preovulatory cervical mucus is receptive and allows entry of sperms into the uterus
  • It protects the sperm from vaginal acidity
  • It serves as a sperm reservoir, from which there is continuous slow release of sperms, which remain available for the egg
  • There is initiation of capacitation of sperms in the cervical mucus.
At microscopic levels the cervical mucus appears to be a loose network of fibres with fluid filled interstitial spaces. These spaces are small, compared with the sperm, so the sperm must be motile to push its way through the mucus. Cervical mucus limits the passage of motile sperms, filters out the non-motile cells and debris, and prevents passage of seminal plasma into the uterus. If the cervical mucus is scanty or hostile, due to immunological factors, the sperm may not ascend into the uterine cavity. This could occur if there is:
  • History of cervical cone biopsy or amputation
  • Radical cauterization
  • Tumors of cervix
  • Severe cervical stenosis
  • Chronic endocervicitis
  • Inspissated cervical mucus.
IUI helps to bypass these hostile factors. It has been observed that only 0.1 per cent of the sperms placed in the vagina are present in the cervical canal one hour 11after insemination.9 Direct deposition of motile sperms in the uterine cavity can reverse this situation, and increase the chances of pregnancy. It resulted in a 14 per cent fecundity rate, which increased to 17 per cent with controlled ovarian stimulation (COS). Ongoing pregnancy rates were only marginally better when controlled ovarian stimulation is used (9.7% vs 12.7%).10 COS does not give an advantage with cervical factor infertility according to recent study.11 However, the predictive value of postcoital test is questionable, hence raising doubts about the existence of cervical factor.12
 
Ovulatory Dysfunction
Results of pregnancy improve if IUI is performed instead of timed intercourse, along with controlled ovarian stimulation, in women with ovulatory dysfuncion.
 
Endometriosis
IUI with ovulation induction can be tried in mild endometriosis. However, in these patients the success rate of IUI remains poor in comparison to IUI done for indications like mild male factor or unexplained infertility. The mean fecundity rates remain between 7-18 per cent depending on the severity of endometriosis. In patients with severe endometriosis, results of IUI are poor because of tubal factor and it is recommended that IVF be done directly. The clinical PR per cycle was comparable in women with minimal, or mild, endometriosis treated laparoscopically 12(21% and 18.9%, respectively), and in women with unexplained infertility (20.5%), when COS and IUI was done.13
COS and IUI should be the second line of treatment after surgery, in the absence of specific indication for IVF. The financial and psychological strain is significantly more with IVF. Attempts at IUI should be limited to 3 to 6 cycles as success rates decrease thereafter. Those with severe endometriosis should directly be taken up for IVF as results of COS and IUI are poor.
 
FACTORS COMMON TO BOTH MALE AND FEMALE
 
Immunological Infertility
In the males antisperm antibodies are found in the serum and seminal fluid, while in the females they can be found in serum, cervical mucus, tubal fluid, follicular fluid and peritoneal fluid. There is an increased incidence of these antibodies in infertility.
 
Causes
Causes in men are usually testicular trauma or obstruction to the male genital tract. In women a break in the vaginal epithelium, peritoneal instillation, or anal and oral intercourse, may cause development of antibodies. Local antibodies are more important in causing infertility than the ones found in the serum. These antibodies can prevent binding of sperm to zona pellucida. They also impair sperm movement.
Various treatments, like prolonged use of condoms, immunosuppression with steroids and laboratory 13procedures, to wash sperms to remove antibodies from the surface of the sperms have been tried without too much success.
Both IUI and IVF yielded unexpectedly high pregnancy rates in this selected group of patients, with long-standing infertility due to sperm surface antibodies (predominantly IgG). Since cost benefit analysis comparing superovulation IUI with IVF may favour a course of four IUI cycles, superovulation IUI is advocated as the first line therapy in male immunological infertility.14 If antibodies are found in cervical mucus IUI helps to bypass them.
 
Unexplained Infertility
Unexplained infertility is a diagnosis made when a couple fails to establish pregnancy despite there being no obvious cause. The diagnostic protocol should show a normal laboratory assessment of ovulation, evaluation of tubal patency and semen analysis. It is diagnosed as cause of infertility in 15 per cent couples.
 
Rationale of Treatment
Since these patients have reduced reproductive capacity, it may take longer for them to conceive. Their monthly fecundity is 3 per cent compared to 20 per cent for normal fertile couples. Thus most couples of unexplained infertility will conceive, given time. Their chance of successful pregnancy, without any intervention, is as high as 60 per cent in 3 years. Viewed from this aspect, the rationale of treatment in unexplained infertility is to increase the monthly 14probability of pregnancy, hence reducing time interval for conception and identifying, early, couples who may not respond to treatment. Superovulation with intrauterine insemination, and in vitro fertilization (with or without intracytoplasmic sperm injection), have been known to increase the chance of pregnancy.
The therapy consists of three basic management principles:
  1. Increasing availability of gametes by ovulation induction and IUI.
  2. Improving gamete quality.
  3. Bringing gametes together by IUI and IVF.
Defects in folliculogenesis, gamete development, fertilization and embryo implantation may be responsible for unexplained infertility. The rationale of empirical therapy is to reduce, or bypass, as many causative factors, as possible. ART techniques are used to overcome known deficiencies, such as using IVF to circumvent damaged fallopian tubes. Because these techniques are based upon enhancement and/or substitution, they can be applied to unexplained infertility patients, with the hope that what is being enhanced or substituted, is the element responsible for the infertility. To enhance the decreased reproductive capacity in couples with unexplained infertility the number of gametes can be increased. Ovulation induction, besides increasing number of gametes, helps in removing subtle defects of ovulation which may be responsible for unexplained infertility. Increasing density of motile sperms in semen, prepared for IUI, might increase probability of pregnancy. Hence the ovulatory and male factors are enhanced while the cervical factor is bypassed.15
COH, with clomiphene, combined with intrauterine insemination, is tried in cases of unexplained infertility. Since clomiphene is a safe drug, a 3 month trial with clomiphene is recommended.
Efficacy of IUI: Controlled ovarian hyperstimulation (COH), without IUI, leads to success in unexplained infertility, but success rates improve when combined with IUI. It is well established that IUI gave better pregnancy rates than timed intercourse (TI), both in stimulated and natural cycle.15
In a retrospective analysis of 45 published reports, success rates were analysed as pregnancy rate per initiated cycle (Table 1.2). Addition of IUI to superovulation improved results. Use of gonadotropins, in place of clomiphene citrate improved pregnancy rates from 8.3 per cent to 17 per cent16 (Table 1.3).
Table 1.3   Efficacy of treatment in unexplained infertility
Treatment
Combined pregnancy rates perinitiated cycle (%)
No treatment
1.3%
IUI
3.8%
CC
5.6%
CC with IUI
8.3%
HMG
7.7%
HMG with IUI
17.1%
IVF
20.7%
Gonadotropins may be preferred in older patients, or where clomiphene has failed, as it produces greater number of follicles. It is also free from antiestrogenic effect of clomiphene. Three cycles of gonadotropins, combined with intrauterine insemination, may be tried.16
However, controversy exists as to whether the success is attributable to ovarian stimulation and close monitoring of the cycle. Of all the etiologies of infertility, unexplained infertility gave the best results with IUI in terms of overall fecundity of 22 per cent.17
 
Insemination with Husband's Frozen Semen
Freezing of husband's semen is indicated in the following conditions:
  1. Absentee husband.
  2. Anti neoplastic treatment.
  3. Vasectomy.
  4. Poor semen parameters.
  5. Drug therapy: Drugs that are detrimental to testicular function—Alcohol, cocaine, colchicines, niridazole, methadone, heroin, lead, diethylstil-besterol, sulphasalazine, tobacco, trinitrotoluene.
 
INSEMINATION WITH DONOR SPERMS
The use of cryopreserved sperms in donor insemination, is now mandatory to minimize transmission of HIV.
The indications are:
  1. Azoospermia.
  2. Severely subnormal semen parameters.
  3. Persistent IVF/ICSI failures.
  4. Hereditary disease in father.
  5. Rhesus isoimmunization.
  6. Patient unable to afford the cost of IVF.
Obstructive azoopsermia can now be treated with ICSI after recovering sperms from testis or epidydimus by TESA or MESA.17
Hereditary disease: Recent advances have introduced preimplantation genetic diagnosis which enables embryo biopsy in cases with family history of genetic disease like hemophilia and cystic fibrosis. Hence, donor insemination can be avoided.
Patients must be properly selected for IUI. It is important that patients are appropriately counseled about success rates, multiple pregnancy and ovarian hyperstimulation before they are taken up for IUI. Male subfertility has been the most controversial indication for IUI. Although pregnancy rate in the presence of severe male factor and endometriosis is low with IUI the procedure should not be rejected outright without considering cost effectiveness when compared with IVF.
REFERENCES
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  1. 18 Zhao Y, Vlahos N, Wyncott D, Petrella C, Garcia J, Zacur H, Wallach EE. Impact of semen characteristics on the success of intrauterine insemination. J Assist Reprod Genet 2004; 21(5):143–8.
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  1. 19 Ombelet W, Vandeput H, Janssen M, Cox A, Vossen C, Pollet H, Steeno O, Bosmans E. Treatment of male infertility due to sperm surface antibodies: IUI or IVF? Hum Reprod 1997; 12(6): 1165–70.
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