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 seminal plasma) directly into the uterus at the time of expected ovulation. However, when more than 0.2 ml of semen was injected into 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.
As early as 1982, I began to recognize the potential advantage of washing and centrifuging raw semen to separate sperm from the seminal fluid, and thereby remove prostaglandins that cause most of the problems. I subsequently introduced and reported on IUI in the journal, Fertility and Sterility (April 1984).
Reasons for Intrauterine Insemination (IUI)
- Using frozen donor sperm: To prevent the transmission of HIV and other sexually transmitted diseases, donated semen is frozen and stored for at least six months. After retesting for HIV, the thawed semen is used for insemination. Since freezing sperm can reduce its effectiveness, the semen is processed for IUI. Fertility drugs may not be needed if the recipient is ovulating normally.
- Using the husband’s sperm: If a husband has difficulty with sexual function or timing, his sperm may be collected and processed for IUI.
- Insufficient cervical mucus: Sometimes, the cervical mucus can create a barrier that prevents sperm from passing through. This can be due to physical problems with the mucus, cervical infection, or anti-sperm antibodies. In most cases, IUI can be done during natural cycles, unless the woman has problems with ovulation. However, if infertility is caused by anti-sperm antibodies in the cervical mucus, IUI will not be effective, and in vitro fertilization (IVF) should be considered.
- Abnormal ovulation: In some cases, when a woman needs fertility drugs to induce ovulation, combining IUI with the medication can improve pregnancy rates.
Selecting the Optimal Controlled Ovarian Stimulation (COS) Protocol for IUI
Oral Fertility Drugs
Oral fertility drugs like clomiphene citrate (Serophene) and Letrozole (Femara) are gentle ovarian stimulants that are typically recommended for younger women with normal egg reserves but who face issues with ovulation, mild sperm problems, or unexplained infertility. In cases of unexplained infertility, the American Society for Reproductive Medicine (ASRM) suggests starting with 3-4 cycles of ovarian stimulation and intrauterine insemination (IUI) using clomiphene or letrozole. Using clomiphene or letrozole alone, timed intercourse alone, or IUI alone does not significantly improve the monthly chance of conceiving with unexplained infertility. It is the combination of these oral stimulants with IUI that can increase the pregnancy rate.
1. Clomiphene citrate (Serophene/Clomid) is the most commonly prescribed agent for inducing ovulation in women who do not ovulate regularly, those with dysfunctional ovulation, and women with unexplained infertility. When used in young women with these issues and sufficient ovarian reserve, the viable pregnancy rate is reported to be between 6% and 10% per cycle of treatment. Clomiphene is also used to prepare women for intrauterine insemination and in vitro fertilization (IVF). Clomiphene’s popularity stems from its low cost, ease of use, and low risk of severe complications such as ovarian hyperstimulation syndrome (OHSS). The treatment usually starts with a daily oral dose of 50 mg for 5 days, but it can be increased to as much as 200 mg per day, starting on cycle day 2, 3, 4, or 5. Typically, a spontaneous LH surge occurs about 8-9 days after the last 50 mg dosage. In some cases, a trigger of 10,000 IU of hCG can be given when there is at least one ovarian follicle measuring 18-20 mm in size. Clomiphene works by inducing ovulation through its “antiestrogen effect.” By blocking estrogen receptors in the hypothalamus (a part of the brain), it tricks the brain into perceiving low estrogen levels. In response, the hypothalamus stimulates the pituitary gland to release an increased amount of follicle-stimulating hormone (FSH), which then stimulates the growth and development of ovarian follicles. This ultimately leads to a surge in pituitary LH release, followed by ovulation from one or more of the larger follicles. As the follicles grow, they release more estrogen into the bloodstream, completing the feedback loop initiated by the hypothalamus in response to the anti-estrogen effects of clomiphene. Before prescribing clomiphene to a woman, several factors should be considered carefully:
- Clomiphene is less effective than gonadotropin therapy and its effectiveness decreases with age. It is best suited for younger women (under 35 years) with normal ovarian reserve, as they are more likely to respond by producing multiple follicles. At least two sizeable follicles should develop during clomiphene treatment to ensure proper cervical mucus production and the development of a receptive uterine lining.
- Clomiphene should not be used for more than three consecutive cycles in a row. Using it for more cycles can be ineffective and even work as a contraceptive. The anti-estrogenic effects of clomiphene can affect cervical mucus and thin the uterine lining over time. After three consecutive cycles, it is recommended to have a resting cycle before considering another clomiphene cycle.
- Clomiphene is not suitable for older women or those with diminished ovarian reserve (DOR). The release of LH caused by clomiphene can lead to excessive testosterone production in the ovaries, which can hinder egg development. Women with DOR are particularly vulnerable due to the overgrowth of ovarian connective tissue, where testosterone is produced.
- About 20% of clomiphene cycles may result in “trapped” ovulation, where the egg remains stuck in the follicle despite hormone changes suggesting ovulation. This can affect the chances of a successful pregnancy.
- Women with long gaps between their periods (over 45 days) may not respond well to clomiphene and may benefit more from injectable gonadotropins
2. Letrozole (Femara) is a medication used for inducing ovulation as part of the IVF process. It works by blocking a certain enzyme called aromatase, which leads to a decrease in estrogen levels and an increase in follicle-stimulating hormone (FSH) secretion. This helps in the growth of ovarian follicles and the production of estrogen. Unlike clomiphene, another medication used for ovulation induction, letrozole does not have anti-estrogen effects on the body, so it does not dry up cervical mucus or make the uterine lining less responsive to estrogen. However, letrozole, like clomiphene, can increase the production of luteinizing hormone (LH) from the pituitary gland, which can result in higher levels of testosterone in the ovaries. While some testosterone is necessary for follicle and egg development, too much of it can hinder their growth and increase the risk of abnormal eggs. Therefore, it might not be advisable to use letrozole or clomiphene in IVF cycles, especially for older women or those with diminished ovarian reserve (DOR) who tend to have higher LH activity. Letrozole can still be used in women who have absent or dysfunctional ovulation not related to DOR, and it can be an alternative to clomiphene in some cases to avoid issues with the uterine lining. The usual starting dose of letrozole is 2.5 mg taken orally daily for 5 days, starting on day 2, 3, 4, or 5 of the menstrual cycle. The dosage can be increased to 5 or 7.5 mg if necessary. Some studies suggest that letrozole may be more effective than clomiphene for treating infertility in women with polycystic ovary syndrome (PCOS), resulting in higher rates of ovulation without significant differences in birth defects.
Common side effects of both clomiphene and letrozole: include hot flashes, sweating, nausea, tiredness, diarrhea, and joint pain.
Injectable Fertility Drugs
While the cost and risk of side effects such as severe ovarian hyperstimulation syndrome (OHSS) using injectable fertility drugs like gonadotropins to prepare for IUI are definitely far greater than when oral agents are used for controlled ovarian stimulation (COS), they are in my opinion nevertheless preferred for IUI. The success rate using such drugs is probably 20-30% higher than when clomiphene or letrozole are used. Therefore, in the hands of Physicians well-schooled in the use of gonadotropins therapy, this is by far a better approach than using oral agents.
The Risks of Multiple Births with COS in women undergoing IUI
When women ovulate normally, they usually develop multiple follicles in their ovaries, which contain eggs and supporting cells. However, only one or two of these follicles will actually mature and release an egg, while the others do not reach this stage. This natural process is called “selection.” In women who ovulate normally, the selected follicles will be larger than the others. Once these selected follicles release eggs, the remaining follicles cannot ovulate. As a result, women who ovulate normally do not have a significantly higher chance of having multiple pregnancies with three or more babies.
On the other hand, women who do not ovulate at all or have dysfunctional ovulation may develop multiple follicles at the same rate, resulting in the release of several eggs at once. This increases the chances of pregnancy but also raises the risk of multiple pregnancies. Interestingly, almost all cases of high order multiple pregnancies (more than twins) associated with fertility drug use have occurred in women who do not ovulate normally. Therefore, the risk of having high order multiple pregnancies only applies to women with absent or dysfunctional ovulation. These women should receive counseling about the potential complications of premature birth and the option of selective reduction of pregnancies during the third month. Another option to avoid this risk altogether is to choose in vitro fertilization (IVF), where the number of embryos transferred to the uterus can be controlled to limit the number of potential babies.
Intrauterine insemination (IUI) can be a valuable fertility treatment if used appropriately and selectively for the right reasons. The use of fertility drugs should not be seen as necessary for all IUI cases, and IUI itself should not be considered a mandatory step before opting for IVF.
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