Induction of Ovulation

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Chapter 37 Induction of Ovulation

PHYSIOLOGIC BASIS OF FOLLICULAR DEVELOPMENT AND OVULATION

An understanding of normal physiology is an important basis for understanding ovulation induction. Ovulation is comprehensively discussed in Chapter 3. A brief description relevant to induction of ovulation is presented here.

Folliculogenesis

Ovarian folliculogenesis is regulated by both endocrine and intraovarian mechanisms that coordinate the processes of cell proliferation and differentiation. The main follicular component of the ovarian cortex is the primordial follicle, consisting of an oocyte arrested at the diplotene stage of the first meiotic division, surrounded by a few flattened cells that will develop into granulosa cells.1 In response to an unknown signal, primordial follicles are gradually and continuously recruited to grow.

FSH Threshold

FSH concentrations must exceed a certain level before follicular development will proceed.7 When this FSH threshold is surpassed in the normal cycle, the growth of a cohort of small antral follicles is stimulated and ensures ongoing preovulatory follicular development (Fig. 37-1).8 The duration of this period in which the threshold is exceeded (the FSH window) is limited in the normal cycle by a decrease in FSH, which occurs in the early to mid-follicular phase because of negative feedback from rising estrogen levels.

Extending this window would allow the continuous development of more follicles. In the normal cycle, one follicle continues developing despite falling FSH levels because of an increased sensitivity to FSH8 while the remaining follicles respond to falling FSH levels by undergoing atresia, as shown in Figure 37-1.

When the follicle reaches a certain level of development, sustained high circulating levels of estradiol produced by the preovulatory follicle will initiate the midcycle surge in luteinizing hormone (LH) that will trigger ovulation. The surge initiates a gene cascade in granulosa cells, the products of which initiate luteinization, signal the egg to commence meiotic maturation, and lead to rupture of the follicle wall.9

OVULATION INDUCTION

CLOMIPHENE CITRATE

For more than 40 years, clomiphene citrate has been the most commonly used oral agent for induction of ovulation. Since the early 1960s, results of clomiphene citrate treatment have not changed appreciably, despite the advent of modern immunoassays for steroid hormones, advances in ultrasound technology for cycle monitoring, and the introduction of commercial ovulation predictor kits that allow accurate identification of the midcycle LH surge.

It is interesting to note that clomiphene citrate is considered pregnancy risk category X. Studies in rats and mice have shown a dose-related increase in some types of malformations and an increase in mortality. This is particularly important when considering the relatively long half-life of about 5 days to 3 weeks (depending on the isomer) and that clomiphene citrate may be stored in body fat.1618 Fortunately, studies in humans have not found an association between clomiphene citrate and congenital defects.

Pharmacodynamics and Mode of Action

Clomiphene binds to estrogen receptors throughout the body due to its structural similarity to estrogen. However, unlike natural estrogen, which only binds estrogen receptors for a period of hours, clomiphene citrate binds estrogen receptors for an extended period of time, weeks rather than hours. Such extended binding ultimately depletes estrogen receptor concentrations by interfering with the normal process of estrogen receptor replenishment.15

The antiestrogenic effect of action of clomiphene citrate on the hypothalamus, and possibly the pituitary, is believed to be its main mechanism for ovarian stimulation. Depletion of hypothalamic estrogen receptors prevents correct interpretation of circulating estrogen levels; estrogen concentrations are falsely perceived as low, leading to reduced estrogen-negative feedback on GnRH production by the hypothalamus and gonadotropin (FSH and LH) production by the pituitary.

It is believed that the hypothalamus is the main site of action because in normally ovulatory women, clomiphene citrate treatment was found to increases GnRH pulse frequency.19 However, actions at the pituitary level may also be involved because clomiphene citrate treatment increased pulse amplitude, but not frequency in anovulatory women with PCOS, in whom the GnRH pulse frequency is already abnormally high.20

During clomiphene citrate treatment, levels of both LH and FSH rise, then fall again after the typical 5-day course of therapy is completed. In successful treatment cycles, one or more dominant follicles emerge and mature, generating a rising tide of estrogen that ultimately triggers the midcycle LH surge and ovulation.19,20

Clomiphene Citrate Administration

Clomiphene citrate is administered orally for 5 days, starting on any day from the second to fifth day after the onset of spontaneous or progestin-induced menses. In anovulatory women, ovulation rates, conception rates, and pregnancy outcome are similar regardless of whether treatment is started on cycle day 2, 3, 4, or 5. Starting on day 5 has the theoretical advantage of giving more time to verify normal menses (and hopefully decreasing the chance of being pregnant) before starting therapy.

Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days, increasing by 50-mg increments in subsequent cycles until ovulation is induced. Once the effective dose of clomiphene citrate is established, there is no indication for further increments unless the ovulatory response is lost. Higher doses will not improve the probability of conception, but the risk of hyperstimulation and multiple pregnancy might increase.

Although the dose required for achieving ovulation is correlated with body weight, there is no reliable way to predict accurately what dose will be required in an individual woman. Consequently, clomiphene citrate induction of ovulation amounts to an empirical incremental titration to establish the lowest effective dose for each individual.

The effective dose of clomiphene citrate for most women ranges from 50 to 250 mg/day, although some women will be found to be sensitive to clomiphene citrate and only require doses as low as 12.5 to 25 mg/day. Most women will ovulate at the lower doses, with 52% ovulating after 50 mg/day and another 22% after treatment with 100 mg/day. Although higher doses are sometimes required, the ovulation rates are usually low at these doses, with only 12% ovulating after 150 mg/day, 7% after 200 mg/day, and 5% after 250 mg/day. Most women who fail to respond to 150 mg/day of clomiphene citrate will ultimately require alternative or combination treatments.21,22

After the lowest ovulatory dose is determined, the same dose is repeated until pregnancy is achieved or a maximum number of approximately six cycles is reached. Pregnancy rates are highest during the first three cycles of clomiphene citrate treatment. The chances of achieving pregnancy are significantly lower beyond the third treatment cycle and uncommon beyond the sixth treatment cycle (Fig. 37-2). Therefore, it is rarely advisable to continue clomiphene citrate treatment beyond six treatment cycles.21

The recommendation regarding which dose to apply is clear in cases of anovulatory infertility (increments of 50 mg until ovulation is achieved, then the dose is maintained). However, this is not clear in cases with ovulatory infertility. There are no adequate studies regarding which dose or what response (number of mature follicles) would be optimal in these women. This uncertainty is related to the individual variability in response to clomiphene citrate treatment irrespective of the dose and to the absence of a clear correlation between pregnancy rates and the number of mature follicles or amount of clomiphene citrate administered. Moreover, the value of clomiphene citrate treatment in enhancing the chance of achieving pregnancy in cases with ovulatory infertility has been questioned22 and has not been proven by large controlled studies.

Treatment Monitoring

Monitoring is required to ensure that ovulation is occurring during a clomiphene citrate treatment cycle. For most patients treated with clomiphene citrate, ovulation monitoring can often be done with any one of a number of low-cost, highly convenient methods conducted in the setting of a general obstetrician and gynecologist practice. Objective evidence of ovulation and normal luteal function are keys to successful treatment. The choice may vary and should be tailored to meet the needs of the individual patient.23

Urinary LH Detection Kit

An ovulation prediction kit can identify the midcycle LH surge in urine and more precisely defines both the interval of peak fertility (day of surge detection and the next 2 days).24 Usually the LH surge is observed from 5 to 12 days after the last clomiphene citrate tablet.25 Ovulation will generally follow within 14 to 26 hours of detection of an LH surge. Consequently, timed coitus or intrauterine insemination (IUI) on the day after the first positive urinary LH test will have the highest pregnancy rates.

Midluteal Progesterone

BBT charts and urinary LH detection kits can confirm that ovulation has occurred but do not document the quality of luteal function, which requires further tests—classically, a serum progesterone determination or endometrial biopsy.

A progesterone level above 3 ng/mL is evidence of ovulation.26 Midluteal phase progesterone concentration (7 days after BBT shift or 7 to 9 days after urinary LH surge) offers more information. Levels exceeding 10 ng/mL are usually suggestive of an adequate luteal phase.27 Endometrial biopsy and “secretory” histology that results from the action of progesterone also provides evidence of ovulation. Endometrial “dating,” using established histologic criteria, has been traditionally suggested for diagnosing luteal phase adequacy.28 However, there is still much uncertainty about the importance of luteal phase defects diagnosed by serum progesterone levels or by endometrial biopsies, reflecting our poor state of knowledge regarding the actual mechanisms involved in endometrial receptivity and implantation.29,30

More sophisticated measures to monitor the outcome of clomiphene citrate treatment, including transvaginal follicular ultrasound scans and measurements of serum estradiol and LH levels, can usually be conducted in a subspecialist reproductive endocrinology practice. Because of the cost and logistic requirements involved, the method is generally reserved for patients in whom less complicated methods fail to provide the necessary information and for women who are at a high risk for developing serious complications such as severe ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy.23

In the past, it was generally recommended that patients receiving clomiphene citrate treatment be examined before starting each new treatment cycle to ensure that there was no significant residual ovarian enlargement or ovarian follicular cysts. However, it appears that small residual follicular cysts usually do not expand during continued treatment.31 Consequently, it is unnecessary to perform “baseline” ultrasound examinations before each new treatment cycle. However, it is reasonable to withhold treatment when symptoms suggest the presence of a large cyst or gross residual ovarian enlargement.23

Adverse Effects and Risks of Clomiphene Citrate

Clomiphene citrate is generally well-tolerated. Some side effects are relatively common, but rarely are they persistent or severe enough to threaten completion of treatment. Although clomiphene citrate treatment does have intrinsic risks, they are typically modest and manageable. Adverse effects are generally divided into the side effects related to clomiphene citrate itself and the adverse effects related to induction of ovulation in general.

Congenital Anomalies

There is no evidence that clomiphene citrate treatment increases the overall risk of birth defects or of any specific malformation. Several large series have examined the question and have drawn the same conclusion.35,36 Earlier suggestions that the incidence of neural tube defects might be higher in pregnancies conceived during clomiphene citrate treatment have not been confirmed by more recent studies.37 A small study of pregnancy outcome in women inadvertently exposed to clomiphene citrate during the first trimester also found no increase in the prevalence of congenital anomalies.38

Pregnancy Loss

More than one study has suggested that pregnancies resulting from clomiphene citrate treatment are at increased risk of spontaneous abortion compared to spontaneous pregnancies. A study reviewed outcomes of 1744 clomiphene pregnancies compared to outcomes of 3245 spontaneous pregnancies.39 In this study, pregnancy loss was classified as either clinical if a sac was seen on ultrasound or if it occurred after 6 weeks’ gestation, or preclinical if a quantitative human chorionic gonadotropin (hCG) was greater than or equal to 25 IU/L and no sac was seen or abortion occurred earlier. In this study, when preclinical and clinical were considered together, the overall incidence of spontaneous abortion was slightly higher for clomiphene pregnancies than for spontaneous pregnancies (23.7% versus 20.4%). When considered separately, preclinical spontaneous abortions were also increased by clomiphene citrate overall (5.8% versus 3.9%) and for women at least 30 years old (8.0% versus 4.9%), but not for those younger than age 30 (3.7 versus 3.0%). In contrast, when clinical abortions were considered separately, clomiphene citrate did not increase the overall rate (18.0% versus 16.4%), but the rate was increased for women younger than age 30 (15.9% versus 11.2%).

More recent studies looking at rate of spontaneous miscarriage in 62,228 clinical pregnancies resulting from ART procedures initiated in 1996 to 1998 in U.S. clinics also found that spontaneous miscarriage risk was increased among women who used clomiphene citrate.40,41 However, the results of these studies are not considered to be conclusive. The pregnancy loss seen in women after clomiphene treatment may actually be related to other comorbidities in these patients, such as insulin resistance, other genetic factors related to PCOS or unexplained infertility, endometriosis, and advancing maternal age.42

Antiestrogenic Effects and Fertility

Clomiphene citrate treatment is associated with antiestrogenic effects that might have adverse effects on fertility. Because of the relatively long half-life of clomiphene citrate isomers, clomiphene citrate exerts undesirable and unavoidable antiestrogenic effects on the endocervix, endometrium, ovary, ovum, and embryo. Numerous studies in women and in various model systems have described adverse effects on the quality or quantity of cervical mucus, endometrial growth and maturation, follicular or corpus luteum steroidogenesis, ovum fertilization, and embryo development.

These adverse effects are believed to explain the “discrepancy” between the ovulation and conception rates observed in clomiphene citrate-treated patients. These effects appear to be more apparent at higher doses or after longer durations of treatment. It has been suggested that treatment with exogenous supplemental estrogen may help to minimize or negate these effects.43,44 However, there is little compelling evidence to support any beneficial effect of estrogen replacement to reverse these peripheral antiestrogenic effects.23

Clomiphene citrate treatment has been shown to affect the quality and quantity of cervical mucus production as well as the structure of the endometrium.4547 However, cervical mucus score (based on quantity and quality) has not been found to be of proven prognostic value on the treatment outcome (i.e., achievement of pregnancy).

The endometrium is believed to be one of the most important targets of the antiestrogenic effect of clomiphene citrate and may explain a large part of the lower pregnancy rate and the possible higher miscarriage rate with clomiphene citrate. Successful implantation requires a receptive endometrium, with synchronous development of glands and stroma.48

Studies have reported conflicting effects of clomiphene citrate on the endometrium45-47,4951 possibly due to different methodology used for endometrial assessment. However, a recent study has prospectively applied morphometric analysis of the endometrium, a quantitative and objective technique to study the effect of clomiphene citrate on the endometrium in a group of normal women. In this study, clomiphene citrate was found to have a deleterious effect on the endometrium, demonstrated by a reduction in glandular density and an increase in the number of vacuolated cells.51 In addition, a reduction in endometrial thickness below the level thought to be needed to sustain implantation was found in up to 30% of women receiving clomiphene citrate for ovulation induction or for unexplained infertility.45 This observation has been confirmed by other studies.46,47

Decreased uterine blood flow during the early luteal phase and the peri-implantation stage has been suggested to explain, at least in part, the poor outcome of clomiphene citrate treatment.51 Other investigators have suggested the presence of other unrecognized factors associated with clomiphene citrate treatment failure.5254 Moreover, there is some evidence for a direct negative effect of clomiphene citrate on fertilization, and on early mouse and rabbit embryo development.55,56 In addition, there have been reports of low-quality oocytes associated with clomiphene citrate treatment. However, the negative effects of clomiphene citrate in some animal studies have not been confirmed by others,53,54 and at present it is unclear if there are adverse direct effects of clomiphene citrate on human oocytes and human embryo development.

Because of the above-mentioned evidence for adverse peripheral antiestrogenic effects of clomiphene citrate treatment, several investigators tried to reverse these effects by administering estrogen concomitantly with clomiphene citrate treatment. Some investigators have reported increased endometrial thickness and improved pregnancy rates with this approach57,58; others have reported no benefit44 or even a deleterious effect of estrogen administration.59 Another approach has been to administer clomiphene citrate earlier during the menstrual cycle rather than starting on day 5,60 in the hopes of allowing the antiestrogenic effect to wear off to some extent before ovulation and implantation. In view of the long half-life of clomiphene citrate isomers, this approach is unlikely to be successful. A third method has been to combine another SERM such as tamoxifen, which has more estrogen agonistic effect on the endometrium with clomiphene citrate or to use tamoxifen as an alternative to clomiphene citrate.61 However, none of these strategies have proved to be completely successful in avoiding the peripheral antiestrogenic effects of clomiphene citrate. A more recent publication has suggested that high-dose soy isoflavones may be able to overcome the antiestrogenic effect of clomiphene citrate on the endometrium.62 This report remains to be confirmed by other investigators.

To summarize, from the available evidence and accumulated clinical experience, it is difficult to conclude the exact significance of adverse antiestrogenic effects on pregnancy outcome in clomiphene citrate-treated women. It seems that individual variability exists regarding sensitivity to the peripheral antiestrogenic effects of clomiphene citrate, likely because of the complexity of estrogen receptor replenishment and activation, and individual differences in the pharmacokinetics of clomiphene citrate. The discrepancy in the success rates in achieving pregnancy between women with unexplained infertility and women with PCOS in response to clomiphene citrate treatment (higher rates in PCOS women) suggests that PCOS women may be less vulnerable to the antiestrogenic effects of clomiphene citrate on peripheral tissues. Recent findings of differences in the expression levels of receptors (androgen receptor, estrogen receptor α and β, progesterone receptor) and cofactors in human endometrium and myometrium in PCOS patients support this hypothesis.63 For example, the p160 family of steroid receptor coactivators, known to facilitate the action of steroid receptors throughout the menstrual cycle, was found to be overexpressed in the endometrium of women with PCOS.80 However, the presence of infertility factors, rather than an increased sensitivity to the antiestrogenic effects of clomiphene citrate, in non-PCOS women may explain the less favorable outcome of clomiphene citrate treatment.

FAILURE OF CLOMIPHENE CITRATE TREATMENT

Etiologies

When considering clomiphene citrate treatment we can define two groups of treatment failures. The first group, clomiphene ovulation failure (clomiphene resistance), includes patients who fail to ovulate with clomiphene citrate treatment. The second group, clomiphene pregnancy failure, includes patients who ovulate with clomiphene citrate treatment but fail to achieve pregnancy. This second group also includes women with ovulatory infertility who do not achieve pregnancy after clomiphene citrate treatment.