Intrauterine insemination (IUI), the injection of sperm into the uterus by means of a catheter directed through the cervix, has been practiced for many years. The premise of this procedure is that sperm can reach and fertilize the egg more easily if placed directly into the uterine cavity.

In the early ‘60s, physicians were injecting small quantities of raw, untreated semen, (sperm plus the seminal plasma) directly into the uterus at the time of expected ovulation. However, when more than 0.2 ml of semen was injected in to the uterus, serious and sometimes life endangering shock-like reactions often occurred. It was subsequently identified that the reason for such reactions related to the presence of prostaglandins within the seminal plasma. This led to the practice of injecting small amounts (less than 0.2 ml) of raw semen. However, the pregnancy rates were dismal, and side effects such as severe cramping and infection were rampant.

Soon after establishing the Northern Nevada Fertility Center in Reno in 1982 (the Nation’s first private in vitro fertilization (IVF) program), we began to recognize the potential advantage of washing and centrifuging raw semen, so as to separate sperm from the seminal fluid, and thereby remove the prostaglandins that cause most of the problems. We subsequently introduced and, thereupon, became the first to publish on intrauterine insemination (IUI) in the Journal, Fertility and Sterility (April 1984).

Indications for Intrauterine Insemination (IUI)

Artificial insemination using frozen (donor) sperm: The recognition of HIV infection as a sexually transmitted disease, coupled with the fact that the virus is present in semen months before it can be detected in the blood, mandates that all donors have their semen cryopreserved (frozen) and stored for at least six months, whereupon, they be re-tested for HIV infection. Only upon confirmation of a negative test should the cryopreserved semen specimen be thawed and used for insemination. Since cryopreservation inevitably reduces sperm motility and function, it is not adequate to simply thaw the frozen specimen and then inseminate the raw semen into the vagina. Rather, the semen specimen should be processed for IUI. Provided that the recipient is ovulating normally, there is no need to administer fertility drugs such as Clomiphene, Pergonal, etc.

• Artificial insemination with partner’s sperm: In cases of sexual dysfunction (impotence, retrograde ejaculation, etc.) or timing issues, the partner’s sperm may need to be collected and processed in preparation of IUI.
• Cervical mucus hostility: Sometimes the cervical mucus acts as a barrier to the activation and passage of sperm as it passes through the cervical canal. Such hostility may be due to poor physical qualities of the mucus, cervical infection, or the presence of antisperm antibodies. In all but the latter situations, IUI can readily be performed during natural cycles, unless the woman has ovulation dysfunction. However, when infertility results from the presence of antibodies in the cervical mucus, IUI will likely be ineffectual and should be replaced by in vitro fertilization (IVF).
• Absent or dysfunctional ovulation: In some cases where the woman requires the use of fertility drugs to induce normal ovulation, the concomitant performance of IUI might improve pregnancy rates.

Selecting the Fertility Drugs for Intrauterine Insemination (IUI)

Clomiphene citrate (Serophene, Clomid): Clomiphene citrate is taken orally for 5 days starting on day 2 to 5 of the menstrual cycle. Ovulation will usually occur 10 days later. In some cases, hCG is used to trigger the ovulation but this is often unnecessary. Clomiphene is a relatively inexpensive and safe method for inducing ovulation and this is why it is so commonly prescribed to women undergoing IUI. However, women receiving clomiphene have about a one third lower pregnancy rate per cycle than is the case when using injectible fertility drugs. But there are draw-backs to clomiphene citrate. Here are a few reasons why:

1. Clomiphene citrate is an anti-estrogen. Ordinarily, women who ovulate normally (without exposure to clomiphene) produce a single dominant follicle which produces enough estrogen to promote optimal cervical mucous production and an adequate endometrial lining (>9mm) However, when clomiphene is used to induce ovulation, its anti-estrogenic effect blunts this response. In fact, women on clomiphene require much more estrogen to override this effect, such that unless at least 3 large follicles develop to allow the blood estradiol levels to rise above 400pg/ml, cervical mucus production and endometrial development will usually be insufficient to allow a healthy pregnancy to occur. Younger women with normal ovarian reserve (Day-3 FSH of less than 9miu/ml)>3 follicles, whereas women over 40 years of age and those with diminished ovarian reserve (regardless of age) will rarely do so, and thus are very unlikely to achieve viable pregnancies on clomiphene.
2. Clomiphene-induced ovulation is associated with a 15-20% chance of a condition called luteinized unruptured follicle (LUF) syndrome where the hormonal changes that precede, accompany and follow ovulation (including a rise in blood progesterone level) occur, but this happens without ovulation occurring. LUF syndrome thus leads to the erroneous conclusion that an egg has been released when, in fact, it remains “trapped” in the ovarian follicle.
3. More than 3 consecutive (back to back) cycles of clomiphene will result in a very significant increase in the anti-estrogen effects referred to in 1&2 above, such that unless a break of at least 1 full menstrual cycle is taken, the likelihood of a viable pregnancy declines to less than 10%, regardless of the woman’s age or her ovarian reserve. This explains why >80% of successful clomiphene pregnancies occur within the first 3 months of treatment, and why the vast majority of clomiphene pregnancies that occur after >3 consecutive (back-to-back) cycles of treatment are lost (usually due to early miscarriages).
4. Clomiphene causes the pituitary gland to produce increased amounts of FSH and LH. FSH promotes follicle growth development while excess LH causes the ovary to produce male hormones such as testosterone. While a little testosterone is indispensable to follicle and egg development, too much testosterone can have the reverse effect and harm egg development. This effect is even more deleterious in women with diminished ovarian reserve (elevated FSH levels) and those over 40 whose ovaries tend to produce more testosterone-like hormones.

The good news is that upon discontinuation of Clomiphene for 4-6 weeks, adverse effects disappear, leaving the slate clean.

The real benefit of clomiphene lies in its oral route of administration, low incidence of side effects, and its low cost. The birth rate per clomiphene IUI is about 7-10% per cycle of treatment (about 1/3 lower than when injectible fertility drugs are used).

Letrozole(Femara): Letrozole, like clomiphene, is an oral agent used to induce ovulation that causes the pituitary gland to release large amounts of FSH as well as LH. The advantage that Letrozole has over clomiphene is that unlike the latter, it is NOT anti-estrogenic, and thus does not compromise development of the uterine lining or adversely affect the production of cervical mucus. However, as is the case with clomiphene, Letrozole causes increased LH release that can lead to overproduction of male hormones (e.g. testosterone) by the ovaries with potentially adverse effect on egg/embryo quality.

Thus, while Letrozole does have potential advantages over clomiphene, the exaggerated LH-induced testosterone effect, especially in women over 40 years of age and/or those with evidence of diminished ovarian reserve, limits its value.

Gonadotropins (Menopur, Gonal-f, Folistim and Puregon): Women with absent or abnormal ovulation who require fertility drugs in preparation for IUI should receive gonadotropins. Granted, these agents are more expensive than clomiphene, but they have no anti-estrogenic properties.

The birth rate with gonadotropin IUI in women under 35 years of age (in the absence of male infertility, where it is much lower) is about 10-15%. However, success is affected by, and contingent upon, the procedure being performed (1) for the correct indications, (2) avoiding the performance of IUI when contraindications exist (see below) and, (3) where the woman is ovulating normally on her own. Success rates decrease as a woman’s age advances. In women 35-40 years of age the birth rate is 5-10% per cycle and for over 40 years, the birth rate per cycle is under 2%, declining to less than 1% after age 43.

In Part 2 of this topic, I’ll discuss contraindications for IUI – when it is NOT recommended, and in what cases it’s unlikely to be successful. I’ll also touch on the risks of multiple gestations associated with the use of IUI.