DEFINITION
The deposition of spermatozoa in the uterus at any point above the internal os is considered as intrauterine insemination (IUI).
RATIONALE
The rationale of IUI performed using either husband's or donor spermatozoa is to overcome the problems of (i) Vaginal acidity; (ii) Cervical mucus hostility and (iii) Deposition of a good number of highly motile and morphologically normal sperms in the uterus near the fundus at the anticipated time of ovulation.
INDICATIONS OF INTRAUTERINE INSEMINATION
Unexplained Infertility
In this condition, there is no definite cause for infertility, even after subjecting the patient to complete workup. The complete workup includes routine lab investigations, hormonal investigations (T3, T4, TSH, prolactin, T, DHEAS, day 2 LH, FSH and E2 and day 21 progesterone) semen analysis, assessment of tubal status (HSG or laparoscopy-hysteroscopy) and assessment of ovulation (serial vaginal USG, daily urinary LH or day 21 progesterone). The average incidence of unexplained infertility is around 10–15%.
The pregnancy rates in these patients are as follows:
- Natural cycle + IUI: 6%
- Clomiphene (CC) and/or gonadotropins + IUI: 18–19% Zeyneloglu et al. demonstrated that superovulation with IUI gave the best chance of pregnancy.
A Cochrane systematic review in 2016 did not find conclusive evidence of a difference in live birth or multiple pregnancy in most of the comparisons for couples with unexplained subfertility treated with intrauterine 2insemination (IUI) when compared with timed intercourse (TI), both with and without ovarian hyperstimulation (OH). There were insufficient studies to allow for pooling of data on the important outcome measures for each of the comparisons.1
Cervical Factor
The following are some common causes of cervical factor:
- Insufficient mucus production
- Altered quality of mucus
- Abnormal cervix: Stenosis, injury, malformation, infection, erosion
- Abnormal postcoital test (the general consensus is that PCT has nonpredictive value in terms of pregnancy).
The pregnancy rate is as follows:
- Natural cycle + IUI: 14%
- CC and/or HMG/FSH: 17%.
Male Factor
Zayed et al2 reported a PR of 19% per cycle in patients with mild male factor.
Mild male factor was defined as follows:
- Patient with only one abnormal male parameter
- Total motile sperm concentration of more than 5 million and morphology greater than 5%.
Sperm quality has to be one of the main determinants to predict IUI success. Clinical practice would benefit from the establishment of threshold levels for sperm parameters above which IUI pregnancy outcome is significantly improved and below which a successful outcome is unlikely. There is a lack of standardization in semen-testing methodology and the huge heterogeneity of patient groups and IUI treatment strategies. The four sperm parameters most frequently examined were: (i) inseminating motile count after washing: cut-off value between 0.8 million and 5 million; (ii) sperm morphology using strict criteria: cut-off value >4% normal morphology; (iii) total motile sperm count in native sperm sample: cut-off value of 5–10 million; and (iv) total motility in native sperm sample: threshold value of 30%.3 Patients with severe male factor infertility should go directly for IVF/ICSI.
Ejaculatory Failure
Causes
Anatomical: Severe hypospadias: In this the semen is collected by masturbation and IUI is performed.
Neurological: Retrograde ejaculation and paraplegics: In retrograde ejaculation, urine is centrifuged and then washed to isolate sperms and IUI performed. In paraplegics, the semen is collected by electroejaculation. In electroejaculation, a probe is inserted into the rectum and a stimulus is given 3to the seminal vesicles to bring about ejaculation. The semen is collected and IUI performed. In both these conditions, the sperm quality especially its motility is hampered. Good results are obtained in whom the progressive motility is more than 20–30%.
Psychological conditions: Impotence and erectile dyfunction: In this, the patient is given sex-psychotherapy. Drugs such as viagra, muse, or papaverine may be given to bring about a good erection. Some patients benefit with the use of mechanical vibrators. Very occasionally the patients may have be subjected to general anesthesia and electroejaculation. Following this IUI may be performed.
Immunological
Infertile couples suffer infertility by immunological mechanisms mainly by the presence of antisperm antibodies (ASA) in blood, semen or cervicovaginal secretions; the formation of ASA in men and women may be associated with disturbance in immunomodulatory mechanisms that result in functional impairment of sperm and thus its inability to fertilize the oocyte. Immunological infertility caused by ASA is the result of interference of these antibodies in various stages of fertilization process, inhibiting the ability of interaction between sperm and oocyte.4
Endometriosis
Patients with mild to moderate endometriosis have good pregnancy rates of between 7% and 18% with IUI. However, as the pregnancy rates (3–5%) are very low with severe endometriosis, it is best to opt for IVF/ICSI.
Donor Semen IUI
When there is azoospermia due to testicular failure and high FSH.
When there is obstructive azoospermia but the couple does not want to undergo ICSI with sperm extraction.
Severe Oligoasthenospermia
Single woman or those are in a homosexual relationship. The following etiological factors of intrauterine insemination are elaborated in Figure 1.1.
PREREQUISITES FOR INTRAUTERINE INSEMINATION
- Age less than 40 years.
- Patient capable of spontaneous or induced ovulation.
- Sperm count of more than 10 million/mL prewash or a postwash count of >5 million motile sperms.
- Easy access to the uterine cavity via a negotiable cervical canal.
Fig. 1.1: Etiological factors of intrauterine insemination
Note: Total does not equal 100% due to rounding.
Intrauterine Insemination: Steps
- Patient selection and workup
- Ovarian stimulation
- Semen wash
- Insemination
- Luteal support.
Patient Selection and Workup
The patients are selected based on their tubal, hormonal and seminal status. For further details one can look up the section on indications.
Patient Workup
- Routine investigations of both husband and wife
- Hb, CBC, ESR, VDRL, HBSAG, HIV, HCV, blood sugars
- Investigations of the husband
- Semen analysis after 3–4 days of abstinence
- Optional tests: Semen culture
- Kruger sperm morphology
- Sperm antibodies: Immunobead and MAR test
- Scrotal Doppler to rule out varicocele, FSH, testosterone, prolactin
- Hormonal investigations of the wife
- In case of patients suspected to be poor responders, one can do additional tests:
- Anti-mü llerian hormone (AMH): AMH levels seem to have a positive correlation and patient's age and LH levels had a negative correlation with the outcome of IUI and controlled ovarian stimulation with gonadotropins. AMH concentration was significantly higher and LH was significantly lower in patients with a clinical pregnancy after three cycles of IUI treatment compared with those who did not achieve pregnancy.5
- Serum inhibin-B test which is >45 pg/mL in poor responders
- Clomiphene challenge test: CC 100 mg/day from day 5 to day 9 and FSH on day 10. A high FSH indicates poor response and poor prognosis.Nowadays, inhibin and CC challenge test are rarely done.
- Serum prolactin and T3, T4, TSH
- In case of patients with PCOS diagnosed by USG, or symptomatology or having features of androgen excess one can do the following tests:
- Fasting serum insulin level (>10 mIU/mL is significant)
- Fasting and postprandial blood sugar
- DHEAS, androstenedione and testosterone.
- In obese patients a follicle phase 17-OHP level (to rule out congenital adrenal hyperplasia) and dexamethasone suppression test (to rule out Cushing's syndrome) should be carried out.
- Rarely, serum alanine transaminase level is done in patients who are intolerant to metformin treatment and who need to be placed on Rosiglitazone
- In women with past history of renal disease on metformin treatment, serum creatinine and/or 24 hour creatinine clearance may have to be done.
- For screening and academic purposes a C peptide assay may be performed to pick up latent diabetes.
- Tests to rule out tuberculosis: These are especially important in developing countries.
- CBC
- ESR
- Mantoux test
- Serum IgG and IgM for tuberculosis
- Plain X-ray of chest
- Sputum acid fast bacilli on three consecutive days.
- TMA or PCR on any tissue suspected of having tuberculosis
- Guinea pig inoculation and culture
- An USG of the abdomen and pelvis should be done. It is preferable to perform a transvaginal USG.
- Hysterosalpingography (Immediately after the menstrual period)
- It is normally indicated in the early phase of treatment when the couple has just started trying for a pregnancy. It is a relatively simple, 6minimally invasive test which can give us a lot of information, however, it is painful. If HSG is normal, one can offer the couple few cycles of CC with planned relations. If that fails to achieve pregnancy, one can try few cycle of CC plus IUI before going for a thorough investigation by performing a laparoscopy, hysteroscopy and endometrial biopsy. It is prudent not to subject the patient to too many CC cycles before doing laparoscopy, as too many stimulation cycles may predispose to long term effects of increased incidence of ovarian cancer in the sixth and seventh decade of the patients life.
- It can also be performed in patients who have already undergone laparoscopy in the past. It can be done to rule out any gross abnormalities in the uterus prior to starting IUI treatment.
- It can also be done as a therapeutic procedure of fallopian tube recanalization (FTR) where the tubal blocks could be opened by guide wire under image intensifier HSG control. One of the prerequisites of this procedure is blocked tubes without having any major pathology seen on Laparoscopy.
- Diagnostic cum operative laparoscopy—hysteroscopy—endometrial biopsy—histopathalogy
- Tests for classifying patients ovulatory status (ovulatory or anovulatory)
- Basal body temperature (Rarely done nowadays)
- Serial vaginal ultrasound follicular scan in spontaneous cycle
- Serum progesterone on Day 21 of cycle >4 ng/mL indicates ovulation and >10 ng/mL indicates adequate luteal phase
- Endometrial biopsy—secretory premenstrual biopsy indicates ovulation.
REFERENCES
- Veltman-Verhulst SM1, Hughes E, Ayeleke RO, Cohlen BJ. Intrauterine insemination for unexplained subfertility. Cochrane Database Syst Rev. 2016;2:CD001838.
- Zayed F, Lenton EA, Cooke I. Comparison between stimulated in vitro fertilization and stimulated intrauterine insemination for the treatment of unexplained and mild male factor infertility. Hum Reprod. 1997;12(11):2408–13.
- Ombelet W1, Dhont N2, Thijssen A3, Bosmans E2, Kruger T4. Semen quality and prediction of IUI success in male subfertility: a systematic review. Reprod Biomed Online. 2014;28(3):300–9.
- Restrepo B1, Cardona-Maya W. Antisperm antibodies and fertility association. Actas Urol Esp. 2013;37(9):571–8.
- Bakas P1, Boutas I1, Creatsa M1, Vlahos N1, Gregoriou O1, Creatsas G1, Hassiakos D1. Can anti-müllerian hormone (AMH) predict the outcome of intrauterine insemination with controlled ovarian stimulation? Gynecol Endocrinol. 2015;31(10):765-8. doi: 10.3109/09513590.2015.1025381. Epub 2015 Aug 18.