Fig. 6.1
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.
Fig. 6.2
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 [7]. 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) [8]. 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) [9]. 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 [10]. There is no robust evidence supporting ovarian stimulation with IUI to be more effective than IUI alone for male subfertility [11]. 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 [12].
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
6.4.1.1 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.
6.4.1.2 Indications
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.
6.4.1.3 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
6.4.2.1 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.
6.4.2.2 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.
6.4.2.3 Complications
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 [13].
6.4.3 Gonadotropins
6.4.3.1 Mechanism of Action
Exogenous gonadotropins directly stimulate the ovaries leading to ovulation.
6.4.3.2 Indications
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.
6.4.3.3 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
6.4.4.1 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.
6.4.4.2 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.
6.4.4.3 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.
6.4.4.4 Side Effects
The common side effects observed are injection site reactions and possibly malaise, headache, fatigue, and nausea.
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