Welcome to chapter 10. The following chapter is called "Ovulation Induction for Intrauterine Insemination (IUI)". The author is Dr Mark Bowman. 1
The learning objectives of this chapter are: To know the indications for intrauterin insemination (IUI), To learn the most appropriate stimulation regimens for both ovulatory and anovulatory women undertaking gonadotropin stimulation-iui, and To maximize the pregnancy rates from stimulated-iui whilst also keeping the risk of multiple pregnancy to a minimum. 2
Intrauterine insemination (IUI) is a popular treatment for infertility around the world. The return from treatment, like most fertility treatments is dependent upon the etiology and the age of the woman. The laboratory techniques and equipment required for IUI are less intensive than that required for IVF. Hence, particularly in countries where there is only modest or no health fund reimbursement for fertility treatment, IUI is usually the first-line choice for assisted conception. There is evidence that additional ovarian stimulation improves pregnancy rates beyond IUI in the woman s natural ovulation cycle, and results are highest when gonadotropin ovarian stimulation is employed (Guzick et al., 1998). This module will focus primarily on gonadotropin stimulation for IUI, but will deal briefly with other forms of ovarian stimulation (clomiphene and letrozole). 3
There are two reasons why ovarian stimulation might be added to an IUI regimen. The first is obvious if the woman does not ovulate then ovulation induction must be a component to achieve success. Of course, if ovulation disorder is the only apparent fertility problem then the women could simply have ovulation induction, or OI, (using whichever regimen is deemed appropriate) and rely on timed intercourse rather than IUI. There are no randomized controlled trials comparing pregnancy rates from combination ovarian stimulation-iui to simple OI alone, in women with polycystic ovary syndrome (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group). In ovulatory women, the addition of ovarian stimulation to an IUI treatment improves pregnancy rates either by correcting some effects of subtle ovulatory disorders or though inducing multiple follicular development (and hence the release of more than one egg) but at a risk of multiple pregnancy. 4
Irrespective of ovarian stimulation, IUI has its greatest return when the fallopian tubes are normal and sperm parameters are very normal. Mild inhibitions of sperm parameters (e.g. concentration between 10 and 20 million/ml, or impaired motility) may be overcome with IUI, but in general the return is low with moderate sperm parameter changes and IVF/ICSI will instead be required. IUI in combination with ovarian stimulation is of value in cases of endometriosis without obstruction, probably by overcoming subtle defects of ovulation, improving sperm accessibility to oocyte(s) and through better endometrial development. With or without ovarian stimulation, IUI will assist in cases where regular intercourse is proving problematic or there is suspected cervical factor. IUI in the absence of ovarian stimulation has only a marginal benefit over regular intercourse in cases of unexplained infertility there is, however, a proven increase in pregnancy rates from gonadotropin IUI in cases of unexplained infertility (Practice Committee of ASRM). 5
Clomiphene citrate and letrozole are oral agents that encourage a higher production of pituitary gonadotropins (in particular FSH). As a result these agents have an indirect effect upon ovarian follicular development. In contrast, injected gonadotropins have a direct stimulatory effect upon follicular development. Gonadotropins may be urinary derived (human menopausal gonadotropin or hmg) or manufactured using recombinant DNA technology (recombinant FSH or rfsh). The latter is more expensive per unit dose but has been reported to have greater purity and, therefore greater efficacy of action. hmg also contains a degree of LH activity and some researcher claim that additional LH effect leads to better follicular/oocyte development and as a result, higher pregnancy rates compared to rfsh. However, there is no published evidence for this, particularly in IUI cycles where there is background pituitary production of FSH and LH. This is in contrast to ovarian stimulation for IVF where there is often concomitant pituitary down regulation using GnRH analogues. Recombinant LH is also available for assisting ovarian stimulation but there is no evidence that this is required in stimulated IUI cycles unless the woman is truly LH deficient with associated anovulation/amenorrhea. This problem can be functional and secondary to lifestyle problems (e.g. excessive exercise, anorexia) or rarely secondary to hypothalamic/pituitary pathology (e.g. pituitary 6
Clomiphene is a non-steroidal estrogen agonist-antagonist the preparation contains a racemic mixture of trans (enclomiphene) and cis (zuclomiphene) isomers in a 3:2 ratio. The cis isomer appears to have greater ovulation inducing properties (Yen and Jaffe). Clomiphene and related compounds (e.g. tamoxifen) have both pre-estrogenic and anti-estrogenic properties and are termed selective estrogen receptor modulators (SERMs). Clomiphene probably induces ovulation by binding to hypothalamic estrogen receptors leading to a hypo-estrogenic state in the hypothalamus and inducing a higher production of FSH and LH (Yen and Jaffe, pp 967-968). Clomiphene is usually given at a dose of 50-100mg per day for five days in cases of stimulation for ovulation induction, occasionally higher doses are given (up to 200mg per day) in non-ovulatory women. There is no difference in pregnancy rate whether clomiphene is commenced on day 2, 3, 4 or 5 of the cycle, although there is perhaps a tendency to multiple follicular development the closer the agent is commenced to menses. 7
Letrozole is a synthetic agent that has a reversible inhibitory effect upon the p450 enzyme responsible for conversion of androgen to estrogen (Yen and Jaffe pp 148-150). In turn, a relative estrogen lack leads to increased pituitary production of endogenous gonadotropins. Like clomiphene, letrozole is used early in the menstrual cycle in induce ovulation or boost the ovulatory process. However, it appears that letrozole has less hypo-estrogenic consequences on the reproductive tract with better endometrial development and less impact upon cervical mucous than is seen in clomiphene cycles. In many countries including Australia, letrozole has not been approved for use as an ovulation induction agent as it has been associated with an increased risk of miscarriage and fetal anomalies. The author has no experience with this agent for ovulation induction. 8
This slide summarizes the important basic concepts of ovarian stimulation for IUI. Following natural menses (or induction or menses with the use of a progestagen or the oral contraceptive pill), FSH treatment is commenced between 2 and 5 days into the woman s cycle. The half life of gonadotropins (whether hmg or rfsh) is not longer that 24 hours, so a daily dose is given. Most preparations are subcutaneous and as a result, the majority of patients can be taught to self-administer their drugs. The response to ovarian stimulation is quite variable (both in terms of an overand under-response) and as a result, regular intermittent assessment of response is required. Ideally this is in the form of both hormone assessments and transvaginal ultrasound follicular measurements. When an appropriate follicular response has been attained, ovulation is induced with a single dose of human chorionic gonadotropin (hcg). This agent mimics the LH surge that is required for follicular/oocyte maturation and subsequent ovulation. Ovulation can also be induced (or triggered ) with a single dose of recombinant LH or with a GnRH agonist, but hcg is relatively inexpensive, simple to administer and effective. Now, let s examine these issues in more detail firstly for ovulatory, then nonovulatory women. 9
What is the best day to commence FSH? Given background pituitary function in ovulatory women, there will be some endogenous follicular recruitment and selection and this occurs quite early in the menstrual cycle usually before it is apparent on follicular scanning. As a result, waiting for a few days after menses will lower the risk of an unacceptably high number of co-dominant follicles and hence lower the risk of multiple pregnancies. In Australia, most workers would commence stimulation on days 3-5. What is the ideal dose of recfsh or hmg? There is no evidence that doses above 112 IU per day improves the pregnancy rate from stimulation IUI, rather there is a significant increase in higher order multiple pregnancy (HOMP) at higher doses. This data will be reviewed later in this chapter. What is the best form of monitoring? As an absolute minimum, monitoring of follicle number and size is essential to ensure an adequate response and particularly to ensure that the woman is not over responding and producing too many leading follicles and, is therefore at risk of HOMP. Additional estrogen assessment has other advantages: A low estrogen in the presence of apparently appropriate follicular development suggests that what is being visualized on ultrasound is not in fact 10
Monitoring close to hcg trigger is best individualized and should include LH and progesterone as discussed in the previous slide. Should a spontaneous LH surge occur, IUI can be undertaken within 24 hours of the point when the surge was first detected. A fall in estrogen in comparison with prior assessments combined with a modest rise in progesterone from baseline suggests that ovulation is likely occur within 24 hours of the serum assessment. Due to the fact that bloods are usually drawn in the morning, such a pattern would indicate that IUI is best undertaken on the afternoon of the hormone estimation. In contrast, a still-rising estrogen level combined with a baseline progesterone level and a rising LH, indicates that IUI can be deferred to the next morning. In the absence of a spontaneous LH surge (and this will be the large majority of occasions), hcg is administered with a plan for IUI 34 37 hours later.. It is expected that ovulation would usually occur around 39 hours after hcg administration; additionally washed/prepared sperm will be most viable for the first few hours after insemination. 11
hcg is usually self administered by subcutaneous injection with the IUI undertaken 34-37 hours later. Either urinary-derived hcg 5,000 IU or recombinant hcg 250microgram (which approximates to about 6500 IU) can be used. There is no evidence that either is more or less efficacious and no evidence that a higher dose of hcg (as is often used in IVF cycles) is necessary. 12
The hoped for outcomes of a gonadotropin-iui cycle are shown above, including: Starting FSH stimulation on day 3 A modest dose of FSH (75 IU) per day Appropriate intermittent monitoring The development of two follicles only above 10 mm hcg trigger when the leading follicle(s) at 17+ mm Luteal support A positive hcg that is suggestive of a singleton pregnancy Note the estrogen assay is pmol/l, NOT pg/ml. 13
Some extra attention is required when using gonadotropins for anovulatory women. These principles are the same as those described for women undergoing pure ovulation induction. Most physicians employ the use of a low dose, step-up regimen of ovulation induction similar to that described by Franks and others (Messinis, 2005). Following induction of menses with either progestagens or the oral contraceptive pill, FSH or hmg is commenced 2-3 days later at a dose no higher than 50-75 IU per day. The dose is not altered until an estrogen (and often ultrasound assessment) around 7 days later. If there is any evidence of an estrogen rise above baseline (even if no follicular development is seen), the existing dose is maintained and further assessment with ultrasounds and hormones are undertaken every 2-3 days. A rising estrogen level indicates follicular development. When there are 1-2 follicles, 17 mm in diameter or larger and the estrogen level is about 1,200 pmol/l or 350 pg/ml, hcg 5,000-10,000 IU is administered. If no rise of estrogen above baseline is seen after 7 days of FSH/hMG, the dose can be cautiously increased by 25-50 IU per day above the previous dose. The process of further assessment 5-7 days later can be repeated, with further increases in FSH/hMG only being necessary in the absence of a estrogen/follicular response. 14
It is generally considered that luteal support is of value, even when the patient has an intact hypothalamic-pituitary axis and there is background pituitary function for example in the use of gonadotropin stimulation for IUI without the additional use of GnRH agonists or antagonists. This may relate to the artificial triggering of ovulation with hcg. Soliman et al performed a meta-analysis of available trials investigating luteal support in 1994. They found: That the use of progesterone for luteal support significantly improved pregnancy rates compared to untreated controls, and That there was no significant difference in outcome when comparing the use of hcg and progesterone 15
To avoid HOMP one should be strict about cancelling cycles where there is an exaggerated response to gonadotropins. Cycles should always been cancelled when there are more than two leading follicles, but there is also evidence (see papers from Dickey later in this module) that suggest that all follicles above 10mm have a risk of producing competent oocytes and, therefore, should always be considered in a decision for cancellation. The level of estrogen should also be considered a mature competent follicle usually correlates with an estrogen of around 300 pg/ml (around 1,000 pmol/l). Therefore, excessive levels of estrogen, even in the presence of apparently appropriate follicle growth, is still considered to be a risk for multiple pregnancy if the IUI is undertaken. 16
Gonadotropin-IUI is a successful treatment but the greatest risk lies with multiple pregnancy, as a result of multiple follicular development. The aim of treatment is to develop one leading follicle but many times there are other smaller follicles. Additionally, most physicians would accept two codominant follicles as an appropriate result for triggering of ovulation. As a result, twin pregnancies are relatively common and represent about one fifth of all ongoing pregnancies. Unlike clomiphene, where pituitary FSH is initially stimulated and then gradually falls in serum level towards midcycle, gonadotropin injections maintain a constant level of serum FSH throughout the follicular phase. As a result the normal process of dominant follicle selection is overridden and even middle sized follicles can contain an oocyte with the capacity to cause pregnancy. This leads to a higher risk of not only twins but also higher order multiple pregnancies (HOMP). There is a correlation between FSH dose and multiple pregnancy. Within this chapter published reviews that examine other risk factors for multiple pregnancy will be summarized. 17
Why worry about multiple pregnancy? Don t our patients want twins? The simple fact is, there is a significant risk of morbidity from twin pregnancies (particularly for the fetuses) and these risks become worse in HOMP. The risks of twinning are often unknown by our patients and often ignored by doctors working in fertility. As an example, The AIHW National Perinatal Statistics Unit of Australia noted that in Australia in 2006, 55.5% of all babies in multiple gestations were delivered premature, and there is a significant increase in the risk of long term morbidity for babies born prematurely. Also, the fetal death rate for multiple pregnancies increases with increasing plurality (Laws and Hilder, 2006). There is also a significant cost burden to the patients and to society from premature birth. The average hospital admission cost of a singleton birth is approx $AUD10,000 but this rises to $AUD30,000 per baby for twins and $AUD117,000 per baby for triplets and the latter figures are much higher when there is a prolonged admission to neonatal intensive care. It has been estimated that over $AUD15 million in hospital admission costs have been saved in Australia over recent years by transferring a single embryo in Australian IVF practice (Chambers G, 2009). 18
Dickey et al., reviewed a large data set from his own unit/practice in 2005 to determine risk factors for multiple pregnancies. The methods of the study like the usual dosages and hcg trigger criteria, along with summary findings for pregnancy rate and the prevalence of multiple pregnancy are summarized on this slide. The results will be presented on the next slides. 19
The study shows useful trends that represent risk factors for HOMP, particularly with gonadotropin use. The risk of HOMP was increased in younger women, where multiple follicles were seen (including those above 10mm but not often considered to be significant or competent) and peak estrogen levels were above 1,000 pg/ml. Overall, the incidence of HOMP was increased threefold when the peak estrogen was >1,000 pg/ml. There were no cases of HOMP in women over 37 years of age or in women with only 1-2 follicles noted above 10mm on ultrasound. However, adopting a strict cancellation policy would have led to a high percentage of cancelled cycles. For example if all cycles in which multiple follicles above 10 mm were seen in women < 38 years were cancelled, then 26% of all cycles would have been cancelled. If all cycles where 3-6 follicles were seen were cancelled, this would have meant withholding hcg for 55% of cycles. 20
Dickey also undertook an extensive literature review of multiple pregnancies after stimulated-iui and the proposed strategies to reduce this. These potential strategies were summarized in the table from the paper. 21
Dickey s review proposed that all patients undergoing stimulated-iui should use clomiphene before moving to gonadotropin IUI. This had the opportunity to successfully treat many women who were at the greatest risk of HOMP with hmg/fsh. If gonadotropin IUI is employed, minimal doses should be used. Almost no HOMP occurs when 75 IU per day is employed, but the risk increases to significant levels at 150 IU per day. Cancelling cycles when there are three or more follicles above 10 mm significantly reduces the risk of HOMP. Dickey states that the failure to count follicles less than 14 mm is the principal reason that attempts to prevent HOMP have been unsuccessful. There is no clinically safe level of estrogen below which HOMP does not occur. But the risk progressively rises as the peak estrogen increases from a range of 500-1000pg/ml to above 1000pg/ml. Dickey also reviewed other proposed strategies to reduce HOMP that have been reported and the paper is recommended by this author to all physicians intending to use stimulated-iui as part of their regular fertility practice. 22
In 2003 Healy et al. reported on their experience of gonadotropin-iui in a context of keeping multiple pregnancy to a minimum. This paper was published in response to a literature based debate which arose out of a paper from Gleicher et al., which reported a high number of multiple pregnancies. Whilst the twin rate was exceedingly low, this was at the expense of a low livebirth rate per cycle. In contrast Gleicher et al. (2000) reported an ongoing pregnancy rate (i.e. viable to beyond the second trimester) of 9% of 3137 gonadotropin-iui cycles, although their overall multiple pregnancy rate was 28.9% (20% of ongoing pregnancies were twins, 5% triplets, 2.3% quadruplets, 1.1% quintuplets and 0.5% sextuplets). 23
The published outcomes from gonadotropin-iui demonstrate the principle difficulty with this treatment: There is a direct correlation between increased pregnancy rates and increased multiple pregnancy rates. The close monitorization of the cycle is fundamental to allow the production of a sufficient and controlled number of follicles. Many physicians would argue that this tradeoff is unacceptable and, therefore, if appropriate resources and funding are available, that IVF with single embryo transfer offers a greater return in terms of live-birth rate with minimal multiple pregnancies, compared with gonadotropin-iui. 24
In contrast to IVF (where hospital admission rates for OHSS can range from 0.5% to 2% of IVF stimulation cycles), OHSS should be a relatively rare event from stimulated-iui. This is because the risk of OHSS is directly correlated to the number of follicles and oocytes that develop. Additionally, OHSS does not develop until hcg trigger is given (or until a natural LH surge occurs). As a result: The gonadotropin dose for stimulation-iui is lower than for IVF, as the aim is only to attain 1-2 mature follicles Cycles will be canceled prior to hcg if there is an excessive response There remains a risk of OHSS from either clomiphene or gonadotropins in association with cycle cancellation as a spontaneous LH is possible postcancellation. In this situation it is critically important that the couple abstain from intercourse to avoid the risk of HOMP. Additionally, conception will also exacerbate any developing OHSS. 25
An extensive review and meta-analyses of the various types of ovarian stimulation for IUI was published by Cantineau and Cohlen in 2009. For many subgroups there were limited numbers and unfortunately few studies reported live birth rates. However, the most important features to emerge from the review were: An increase in pregnancy rates when gonadotropins were used compared to anti-estrogens see table this slide No clear difference in pregnancy rates from the use of anti-estrogens or aromatase inhibitors Adding GnRH agonists (to reduced the risk of a spontaneous LH surge) does not appear to improve the pregnancy rates from gonadotropin-iui There appeared to no difference in miscarriage rates across the various types of ovarian stimulation. There is a trend towards a higher rate of OHSS with gonadotropins although this did not reach statistical significance. Finally, as with all forms of ART, pregnancy rates are most significantly influenced by female age. 26
Five suitable trials comparing aromatase inhibitors and anti-estrogens for stimulated-iui were identified in the meta-analysis. None of the trials nor the final combined data showed a difference in the chance of pregnancy between these two groups of drugs. 27
Different types of gonadotropins used for stimulation prior to intrauterine insemination were compared in nine different studies. The results were combined in a meta-analysis by Cantineau and Cohlen (2009). The presented table shows the overview of the studies, comparing pregnancy rates per couple for different types of gonadotropins. It is important to mention that none of the studies, which were included in the meta-analysis, reported live birth rates; and only one study Pares 2002 reported ongoing pregnancy rates. Most studies only stated pregnancy rates per couple and/or per cycle, number of multiple pregnancies and number of miscarriages. The studies of Filicori 2001, Filicori 2003 and Gerli 1993 compared hmg with FSH, with no significant difference suggesting to favor one of these two types of gonadotropins over the other. The same statistically insignificant results were obtained in the four studies by Gerli 2004, Gerli II 2004, Matorras 2000 and Pares 2002, which compared the use of r-fsh with u-fsh. Finally, the study of Gurgan and the co-workers in 2004 compared hmg versus u-fsh versus r-fsh, reporting no significant differences as well. A recently published analysis of 280.394 stimulated IVF/ICSI cycles, registered in the German IVF Registry between 1998 and 2008, revealed different results (Bals-Pratsch et al, 2010). Mean pregnancy rates in cycles stimulated with recombinant FSH were significantly higher than in cycles stimulated with 28
When comparing the dosage of the gonadotropins used for stimulation, published papers agree on the fact that patients require lower total dosage of rfsh compared with ufsh (Balasch J. et al 1998, Bergh C. et al 1997, Daya S. 2002, Frydman R. et al 2000, Revelli A. et al 2006). The necessary duration of treatment with rfsh is also significantly shorter compared with the duration of ufsh treatment. Most studies of the meta-analysis, which were presented in the previous slide, used a lower rfsh dosage compared with ufsh. Two studies, however, used similar dosage of both gonadotropin types and reported slightly better results in rfsh groups (Matorras 2000, Pares 2002). Besides, higher numbers of oocytes/embryos were retrieved when using rfsh for ovarian stimulation (Nyboe-Andersen et al. 2005 ). Other points to consider when comparing rfsh with ufsh are the lacking reports on the outcomes for the frozen-thawed IVF cycles. Many published studies (for example Al-Inany H. et al. 2003, Bergh C. et al. 1997, Frydman R. et al. 2000) were not able to detect a significant difference between rfsh and ufsh when only fresh transfers were taken into consideration. It must be re-emphasized that the most relevant endpoint is the cumulative pregnancy rate, calculated as the total pregnancy rate combining the outcomes from fresh and frozen-thawed transfers with embryos from the same cycle of stimulation. It is important to bear in mind that if rfsh stimulation results in higher number of embryos per cycle, then more embryos will be available for transfer, especially if fresh transfer fails to cause a pregnancy. Finally, it should be mentioned that the purity of ufsh and rfsh is an important point of issue. Most urinary preparations of gonadotropins used for ovarian stimulation contain various contaminant proteins. Due to modern techniques, recombinant gonadotropins are classified as 99% pure. Preparations of urinary derived gonadotropins, although their purity has improved significantly in the last years, still contain up to 30% of contaminant proteins from which 39 were already identified, including prions. The risks associated with these proteins are considered to be extremely low; nevertheless it cannot be averted completely. 29
To summarize the chapter: Stimulated-IUI is a useful treatment for many forms of subfertility/infertility. Gonadotropin-IUI leads to higher pregnancy rates compared to other forms of ovarian stimulation, but there is a significant risk of multiple pregnancy. Higher order multiple pregnancy represents serious morbidity and as a result low stimulation doses, careful monitoring and prudent cancellation of at-risk cycles is essential. Pregnancy rate of 10% to 20% per cycle can be attained with stimulated-iui, but up to 20% of cycles may need to be cancelled. 30
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