Manju Puri1 and Richa Aggarwal1
Department of Obstetrics and Gynaecology, Lady Hardinge Medical College, New Delhi, Delhi, 110001, India
Worldwide, intrauterine insemination (IUI) is one of the most frequently used fertility treatments for couples with unexplained or male subfertility. IUI is widely used, often as an empirical treatment, for a broad range of indications. Contrary to IVF/ICSI methods, IUI is easy to perform and inexpensive and offers particular advantages such as the minimal equipment required, an easy to learn technique, and being less invasive when compared to IVF/ICSI. IUI can be carried out in natural cycles or in combination of ovarian stimulation. The rationale for the use of ovarian stimulation in IUI is to increase the likelihood and efficiency of ovulation and to increase the number of oocytes available for fertilization. Ovarian stimulation helps overcome subtle defect in ovulatory function and luteal phase as well as enhances steroid production, which may improve the chances of fertilization and embryo implantation. However, excessive follicular development is usually associated with very high estradiol levels which may lead to two important iatrogenic complications: ovarian hyperstimulation syndrome (OHSS) and multifetal pregnancy. Therefore the optimal ovarian stimulation protocol should maximize the probability of conception and in the mean time minimize the risk of multiple pregnancies and the occurrence of OHSS. Clomiphene citrate and gonadotropins are the two commonly used drugs for ovarian stimulation in IUI. In couples with unexplained infertility, ovarian stimulation with IUI has shown higher conception rates compared to IUI alone. In couples with male subfertility or cervical factor infertility, studies show no significant difference in the pregnancy rates with IUI alone and IUI with ovarian stimulation.
Ovarian stimulationClomiphene citrateGonadotropinsGnRH antagonistsIntrauterine inseminationUnexplained infertilityMale infertility
Intrauterine insemination (IUI) is one of the most frequently used fertility treatments for couples with unexplained or male subfertility . Ever since the first paper entitled intrauterine insemination (IUI) was published in 1962 , there has been a constant effort to improve the outcome of IUI by modifications in sperm preparation techniques, combining IUI with ovarian stimulation and optimizing the timing of IUI.
The rationale of IUI is to facilitate availability of an increased number of motile spermatozoa for fertilization of the oocyte close to the site of fertilization bypassing the cervix. Combining IUI with ovarian stimulation is based on the rationale that ovarian stimulation will further increase the number of available oocytes for fertilization with resultant increase in the probability of conception. IUI needs to be timed accurately with ovulation so that the oocyte is available when insemination is carried out. As the cervix is bypassed in IUI, the advantage of storage of spermatozoa in the cervix for 3–5 days with vaginal insemination is lost. Ovarian stimulation facilitates optimal timing of intrauterine insemination. It is also assumed that ovarian stimulation will overcome any subtle disturbance in the follicular growth or luteal phase of the menstrual cycle contributing to unexplained infertility.
Ovarian stimulation is associated with complications like ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Hence the advantages of combining ovarian stimulation with IUI need to be weighed against the potential complications and related morbidity. Milder stimulation protocols are preferred to achieve these objectives.
The goal of ovarian stimulation in anovulatory women and that undergoing in vitro fertilization (IVF-ET) is different from those planned for IUI. In anovulatory women, the aim is to induce a monofollicular growth, whereas in women undergoing IVF-ET, it is multifollicular growth so that more oocytes are available for in vitro fertilization and cryopreservation of embryos. In women undergoing IUI, the desired end point of ovarian stimulation is to have two dominant follicles so as to increase the probability of conception with a small risk of multiple pregnancy and ovarian hyperstimulation syndrome .
6.2 Basic Concepts of Gonadotropic Control of Ovarian Function
For proper understanding of the ovarian stimulation protocols for IUI, it is essential to have the basic knowledge of the gonadotropic control of the ovarian function. Follicular responsiveness to FSH and LH is developmentally regulated. FSH plays a crucial part in recruitment, selection, and dominance of the follicle, while LH contributes to dominance, final maturation, and ovulation.
At the beginning of each menstrual cycle, a cohort of follicles are recruited under the influence of increasing serum levels of FSH usually in the first 2–3 days of the menstrual cycle. The granulosa cells of these follicles undergo proliferation with expression of LH receptors. Steady serum LH levels in this phase are essential to maintain intrafollicular androgen synthesis. At a follicle size of 10 mm around day 8 of the cycle, the selection of the dominant follicle takes place. This is the follicle destined to ovulate, and this follicle has the maximum sensitivity or the lowest threshold to circulating FSH levels. This follicle starts secreting estradiol with a resultant fall in serum FSH levels due to negative feedback of the hypothalamic-pituitary axis. The growing follicles except the dominant follicle are unable to sustain their growth and undergo atresia (Fig. 6.1). The dominant follicle sustains its growth due to its reduced dependence on circulating serum FSH consequent to increased expression of LH receptors on it and its increased sensitivity to both FSH and LH. The dominant follicle continues to grow and secrete estradiol [4, 5]. Thus contrary to the conventional role of LH in triggering ovulation and supporting the corpus luteum, LH plays an important role in maturation of the dominant follicle in late follicular phase. It stimulates androgen production from the theca cells that in turn is converted in to estrogen by the FSH-stimulated aromatase activity of the granulosa cells [4, 5]. Finally when the estradiol levels reach a threshold, there is an LH surge and ovulation follows 12–24 h after LH surge.
The normal FSH window, FSH follicle stimulating hormone, LH luteining hormone
Exposure to excess of LH in early phases of follicular development can adversely affect the growing follicles. There is an LH ceiling effect, that is, high levels of circulating LH as in women with PCOS can cause atresia of the follicles and premature luteinization [4, 6]. At the same time, circulating levels of LH below the LH threshold levels also interfere with the late follicular growth and maturation of oocyte. Thus the maintenance of optimum levels of LH during ovarian stimulation is important [4, 6].
In women undergoing ovarian stimulation for IUI, the aim is to have more than one dominant follicle so that the chances of conception are increased. To achieve this, one needs to maintain FSH levels above the threshold level for a longer period than in a spontaneous cycle, that is, widen the FSH window in the recruitment phase so that more than one dominant follicle is selected (Fig. 6.2). The number of dominant follicles selected depends upon the dose of drug, that is, clomiphene, FSH, or HMG used for ovarian stimulation, and the number of days the circulating level of FSH is maintained above the threshold. As ideally ovarian stimulation in IUI aims at only two dominant follicles, the FSH levels are kept above the threshold level for a shorter period till two to three dominant follicles are selected. The chances of premature LH surge are increased if more follicles are selected as each follicle adds on to the circulating levels of estradiol, which can then reach a threshold and trigger premature LH surge even when the follicles are not yet mature. Hence the role of GnRH antagonists in late follicular phase to prevent premature LH surge and allow the follicles to mature before LH surge is triggered.
The extended FSH window, FSH follicle stimulating hormone, HMG human menopausal gonadotropin
6.3 IUI in Natural Cycle Versus Stimulated Cycle
IUI is the preferred first-line treatment for infertility due to cervical factor, mild to moderate male factor and unexplained infertility, and minimal to mild endometriosis. IUI can be carried out in natural cycles or in combination with ovarian stimulation. As ovarian stimulation is associated with an increased risk of ovarian hyperstimulation syndrome and multiple pregnancies with related maternal and perinatal morbidity and mortality, combining IUI with ovarian stimulation is justified only if it is effective. Goverde et al. found IUI combined with ovarian stimulation to result in higher pregnancy rates as compared to IUI in natural cycle . A systematic review by Verhulst et al. suggests that IUI combined with ovarian stimulation is more likely to result in a live birth than IUI in natural cycle (OR 2.0, 95 % CI 2.0–3.5) . In another systematic review of randomized controlled trials conducted by Bensdrop et al., IUI combined with ovarian stimulation has shown to result in higher pregnancy rate as compared to IUI done in natural cycle (OR 1.47, 95 % CI 0.91–2.38) . In couples with unexplained infertility and infertility due to mild or minimal endometriosis, IUI combined with controlled ovarian stimulation either by clomiphene citrate, letrozole, or gonadotropins results in significantly higher conception rate compared to IUI alone . There is no robust evidence supporting ovarian stimulation with IUI to be more effective than IUI alone for male subfertility . In isolated cervical factor infertility, IUI in natural cycles is associated with a significant increase in probability of conception; hence there appears to be no added advantage of combining ovarian stimulation to it .
6.4 Therapeutic Options for Ovarian Stimulation for IUI
The various therapeutic options available for ovarian stimulation for IUI include clomiphene citrate, aromatase inhibitors, and gonadotropins.
6.4.1 Clomiphene Citrate
18.104.22.168 Mechanism of Action
Clomiphene citrate is a nonsteroidal selective estrogen receptor modulator (SERM) having both estrogen agonist and antagonist properties. Structural similarity to estrogen allows clomiphene to compete with endogenous estrogen for nuclear estrogen receptors at sites throughout the reproductive system. However, unlike estrogen, clomiphene binds to nuclear estrogen receptors for an extended interval of time, thereby depleting receptor concentrations. Reduced negative estrogen feedback triggers normal compensatory mechanisms that alter the pattern of gonadotropin-releasing hormone (GnRH) secretion and stimulate increased pituitary gonadotropin release, which in turn drives ovarian follicular development.
Clomiphene citrate is the traditional drug of choice for ovulation induction in anovulatory infertile women with normal thyroid function, normal serum prolactin levels, and normal endogenous estrogen levels. Clomiphene citrate is not effective in women with hypogonadotropic hypogonadism. The efficacy of clomiphene treatment in women with unexplained infertility can be attributed to optimizing follicular development or to the superovulation of more than a single ovum.
22.214.171.124 Side Effects
Clomiphene citrate is generally well tolerated though minor side effects include transient hot flashes, mood swings, headache, breast tenderness, pelvic pressure, nausea, and visual disturbances like blurring, scotoma, and light sensitivity.
6.4.2 Aromatase Inhibitors
126.96.36.199 Mechanism of Action
Aromatase inhibitors act as potent, competitive, nonsteroidal inhibitors of aromatase, the enzyme catalyzing the rate-limiting step in estrogen production. They block estrogen production both in the periphery and in the brain, resulting in a compensatory increase in pituitary gonadotropin secretion that stimulates ovarian follicular development. Aromatase inhibitors do not interfere with actions of estrogen on cervical mucus and endometrial proliferation unlike clomiphene citrate.
188.8.131.52 Treatment Schedule
After a spontaneous or progestin-induced menses, letrozole is started on day 3 and continued for 5 days with a daily dose of 2.5 mg. However the use of this drug has been prohibited for ovulation induction in India.
Use of aromatase inhibitors for ovulation is controversial because of its possible teratogenicity as observed in animal models. A case series comparing the incidence of congenital malformations in 911 newborns of women who conceived after treatment with letrozole or clomiphene found no difference .
184.108.40.206 Mechanism of Action
Exogenous gonadotropins directly stimulate the ovaries leading to ovulation.
Women with hypogonadotropic hypogonadism (WHO group I) are the most obvious candidates for ovulation induction with exogenous gonadotropins. In PCOS when clomiphene citrate treatment fails to achieve ovulation, exogenous gonadotropins are used. Exogenous gonadotropins are used intentionally to stimulate the development and ovulation of more than one mature ovum in order to increase cycle fecundity in older subfertile women and those with unexplained infertility.
220.127.116.11 Side Effects
Although superovulation is intended, careful monitoring is required to avoid excessive stimulation. They are highly effective but are very costly and associated with substantial risks including multiple pregnancy and ovarian hyperstimulation syndrome. Therefore, exogenous gonadotropins should be used only by clinicians having the training and experience necessary to provide safe and effective treatment.
6.4.4 Gonadotropin-Releasing Hormone Antagonist
18.104.22.168 Mechanism of Action
GnRH antagonists act by competitive inhibition of GnRH receptors, which results in rapid decline in FSH/LH levels, thus preventing premature LH surge.
22.214.171.124 Advantages of GnRH Antagonist
Use of GnRH antagonists offers a number of potential advantages over agonists. Prolonged pretreatment to achieve pituitary downregulation is not required. Since its only purpose is to prevent a premature endogenous LH surge and its effects are immediate, antagonist treatment can be postponed until later in follicular development (after 5–6 days of gonadotropin stimulation), after estradiol levels are already elevated, thereby eliminating the estrogen deficiency symptoms that may emerge in women treated with agonists. The total dose and duration of gonadotropin stimulation required is decreased since any suppressive effects of agonists on the ovarian stimulation by gonadotropins are eliminated. By eliminating the flare effect of agonists, GnRH antagonists avoid the risk of stimulating development of a follicular cyst and OHSS. Use of antagonists allows the manipulation of follicular development so that IUI can be avoided at weekends or inconvenient timing without any detrimental effect on pregnancy rate.
126.96.36.199 Treatment Schedule
The two GnRH antagonists available for clinical use are ganirelix and cetrorelix. For both, the minimum effective dose to prevent a premature LH surge is 0.25 mg daily, administered subcutaneously. The treatment protocol may be fixed and begin after 5–6 days of gonadotropin stimulation or tailored to individual response, starting treatment when the lead follicle reaches approximately 13–14 mm in diameter.
188.8.131.52 Side Effects
The common side effects observed are injection site reactions and possibly malaise, headache, fatigue, and nausea.
6.5 Ovarian Stimulation Protocols for IUI
Ovarian stimulation protocols IUI would include stimulation with clomiphene, tamoxifen, and gonadotropins.
6.5.1 Clomiphene Citrate
This is usually the first-line ovarian stimulation protocol used in combination with IUI as this can be administered orally; it is convenient and cost effective. The risk of complications like higher-order pregnancies and OHSS is lesser compared to gonadotropins, but it is associated with adverse effects like hot flushes, visual disturbances, and antiestrogenic effect on the endometrium and cervical mucus.
Clomiphene citrate is administered orally starting on day 2–5 of onset of a spontaneous or induced cycle, usually on day 3, in a dose of 50–100 mg once daily for 5 days. A baseline scan is performed on day 2–3 to determine the antral follicle count and endometrial thickness and look for presence of any residual cyst or endometrioma. The dose of clomiphene citrate is arbitrarily decided based on antral follicle count on baseline scan. Women with a count of less than 8–10 per ovary can be started on 100 mg clomiphene citrate per day, and those with a higher count are started on 50 mg per day. If a cyst is present on the baseline scan, serum progesterone is estimated and ovarian stimulation is initiated if the serum progesterone level is <1 ng/ml. The endometrial thickness should be <6 mm on baseline scan prior to initiating stimulation protocol. Serial transvaginal ultrasound scan is performed starting on day 10 of the cycle, and 5,000–10,000 IU of human chorionic gonadotropin (hCG) or 250 μg of recombinant hCG is administered intramuscularly at a follicle size of 18 mm for triggering ovulation. IUI is done after 32–36 h of injection hCG. The couple is advised to have sexual intercourse on alternate day from 5 days after the last tablet, that is, usually from day 10 of the cycle for 10 days.
The cycle is canceled if there are more than three follicles of ≥14 mm present at the time of trigger to avoid multiple pregnancies. The couple is advised to use barrier contraception for 7–10 days. The other option is aspiration of extra follicles with or without escape in vitro fertilization (IVF-ET). This option is usually offered when ovarian stimulation is done with gonadotropins.
This is administered in the same way as clomiphene citrate in a dose ranging between 20 and 60 mg per day for 5 days. Unlike clomiphene citrate, tamoxifen has the advantage of absence of antiestrogenic effect on the cervical mucus and endometrium, hence preferred in women where the endometrial response is not satisfactory with clomiphene citrate.
After a spontaneous or progestin-induced menses, letrozole is started on day 3 and continued for 5 days with a daily dose of 2.5 mg. However the use of this drug has been prohibited for ovulation induction in India.
As the aim of ovarian stimulation in women undergoing IUI is to have two dominant follicles, mild stimulation protocol is preferred . The duration and extent of FSH above threshold level determines the number of follicles that are capable of ovulation. HMG or highly purified FSH is used in low dose of 37.5–75 IU intramuscular per day for 5 days, starting on day 3 of the onset of spontaneous or induced cycle. Close serial monitoring of the cycle is mandatory starting from day 8–10 of cycle. At a follicle size of 18 mm, 5,000–10,000 IU of hCG is administered intramuscularly to trigger ovulation and IUI is done after 32–36 h of injection hCG. As spontaneous LH surge is common in gonadotropin cycles, serum LH measurement or urinary LH detection is done to predict a natural LH surge in which case gonadotropin antagonists may be added and/or both the trigger and IUI can be preponed. Discordancy between the follicular growth and endometrial thickness and differentiation may be another indication for adding gonadotropin antagonists. The cycle has to be canceled if there are more than three follicles of ≥14 mm in diameter present at the time of trigger.
6.6 Comparison Between the Various Ovarian Stimulation Protocols for IUI
Balasch et al.  and Matorras et al.  in their respective randomized controlled trials found higher pregnancy rate when IUI was done in cycles stimulated with gonadotropins as compared to IUI done in cycles stimulated with clomiphene citrate. Cochrane review of randomized controlled trials found that there is a significant increase in the pregnancy rate per couple in women undergoing IUI and ovarian stimulation with gonadotropins compared to that with antiestrogens  (OR 1.76, 95 % CI 1.16–2.66). A meta-analysis by Hughes concluded that gonadotropins seem to be more effective compared to clomiphene citrate . Costello reviewed studies comparing clomiphene citrate with gonadotropins both combined with IUI and found a significantly higher pregnancy per cycle when treated with gonadotropins . Similarly, Eccochard et al. found IUI combined with ovarian stimulation with gonadotropin to result in higher pregnancy rate as compared to IUI combined with clomiphene stimulation . However, Dankert et al.  and Raslan  did not find any significant difference in the pregnancy rates with gonadotropin and clomiphene citrate stimulation in their respective studies.
A recent study by Mitwally and Casper showed that letrozole is as effective as clomiphene citrate in terms of pregnancy rates with the advantage of lower incidence of multiple pregnancy . A systemic review of randomized controlled trials comparing the two drugs found no significant difference in the pregnancy rates .
According to available evidence, there seems no place for GnRH agonist or antagonists in IUI programs both as regards pregnancy rate per cycle and cost-effectiveness . Eskander et al. studied 500 cases and found no significant increase in the pregnancy rate on adding GnRH agonist to cycles stimulated with gonadotropins (OR 0.67, 95 % CI 0.43–1.05) . Similarly, Bellver et al. did not find any significant increase in the pregnancy rates on adding GnRH agonist to gonadotropin-stimulated cycles . Premature LH surge occurs in 25–30 % of stimulated IUI cycles  and may interfere with timing of the IUI or result in cancelation and higher treatment failures. Although administration of a GnRH antagonist almost abolishes premature luteinization, it does not seem to considerably improve the pregnancy rate. Routine use of GnRH antagonists in women undergoing IUI and mild ovarian stimulation with gonadotropins is not warranted. In some randomized controlled trials, the average ongoing pregnancy rate was only 5.3 % greater with GnRH antagonist treatment, implying that it would take 20 cycles of GnRH antagonist administration to have one pregnancy more than without GnRH antagonist treatment [23–27].
Treatment decisions as regards IUI should be considered against the likelihood of pregnancy without treatment in a given couple, which is usually underestimated. The treatment decision depends on whether a reasonably increased chance of pregnancy with IUI in stimulated cycles justifies the increased cost of treatment, inconvenience to the patient, and the risk of complications such as multiple pregnancy and OHSS. Stimulated IUI is ineffective in male infertility and the effect on other diagnoses is small. With clomiphene citrate and IUI, the most common IUI protocol, pregnancy rates average 7 % per cycle. FSH ovarian stimulation and IUI treatment is only modestly better with a pregnancy rate of 12 % but multiple birth rates averaging 13 %. Mildly stimulated (one to two follicles) cycles might reduce the cost of treatment and multiple birth rates but may require more cycles of treatment . One should aim for a maximum of two dominant follicles in order to avoid high-order multiple pregnancies . Ovarian stimulation should be mild, and clomiphene citrate (50–100 mg per day for 5 days) remains the first-choice drug to use as it is easily available, easy to use, and less costly. If indicated hMG or recombinant FSH can be used in dosages of 50–75 IU per day. Strict ultrasound monitoring of each stimulated cycle is mandatory. One should strive for two dominant follicles larger than 15 mm, but all follicles larger than 10 mm should be measured and taken into account when defining cancelation criteria.
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