html xmlns=”http://www.w3.org/1999/xhtml” xmlns:mml=”http://www.w3.org/1998/Math/MathML” xmlns:epub=”http://www.idpf.org/2007/ops”>
Introduction
Polycystic ovary syndrome (PCOS) is one of the most common causes of ovulatory dysfunction and identifiable causes of infertility. Clomiphene citrate, aromatase inhibitors such as letrozole, metformin, the combination of metformin and clomiphene citrate, and gonadotropins are the most commonly used medications for ovulation induction in patients with PCOS. The following chapter discusses the background and indications for use of each of these medications.
Clomiphene citrate
Clomiphene citrate, a selective estrogen receptor modulator, has been used as a first-line medical ovulation induction agent since 1967. Clomiphene citrate is administered for 5 days beginning on any spontaneous or progestin-induced menstrual cycle day from 2 to 5, starting with 50 mg/day and increasing to 150 mg/day if anovulatory. If ovulation cannot be achieved at doses of 150 mg/day, the patient is deemed to have clomiphene citrate resistance. The dose of clomiphene citrate can be increased up to 250 mg. If pregnancy cannot be achieved after six ovulatory cycles, then the patient is deemed a clomiphene citrate failure. Most conceptions occur within the first six ovulatory cycles and at doses of less than 150 mg a day, but the fecundity rate decreases dramatically with age (<4% at >41 years of age) [1–3].
Studies with clomiphene citrate have shown an ovulation rate of 60–85% and a pregnancy rate of 30–50% after six ovulatory cycles, with an increased risk of multiple pregnancy of 5–7% [4]. A Cochrane systematic review and meta-analysis of three randomized controlled trials comparing clomiphene citrate with placebo demonstrated that clomiphene citrate improves both ovulation and pregnancy rate [5] The addition of an ovulatory trigger dose of human chorionic gonadotropin (hCG) to clomiphene citrate ovulation induction therapy does not improve ovulation, pregnancy, or miscarriage rates [6].
Aromatase inhibitors
Aromatase inhibitors were first proposed as ovulation-inducing drugs in anovulatory women in 2001 [7]. There are concerns regarding the potential teratogenic effect of letrozole for infertility treatment [8], but two subsequent publications did not find an increased risk of fetal anomaly [6,9,10]. Letrozole is typically prescribed at a starting dose of 2.5–5 mg and can be increased by increments of 2.5 mg, but the optimum dose range has not been established. Letrozole may have a better side effect profile than other aromatase inhibitors and result in fewer multiple pregnancies [1,11].
There are no published randomized controlled trials (RCTs) comparing aromatase inhibitors with placebo or no treatment in therapy-naive PCOS women. A single RCT comparing letrozole with placebo in clomiphene citrate-resistant (CCR) PCOS women found no difference in pregnancy or live birth rate per patient [12]. Two recent systematic reviews and meta-analyses of six RCTs comparing letrozole with clomiphene citrate in PCOS women who were therapy naive, CCR, or where the type of PCOS women was not reported, demonstrated a higher ovulation rate per patient with letrozole, but no difference in ovulation rate per cycle or pregnancy rate per patient [6,13]. Individually, the RCTs in either therapy-naive or CCR PCOS women demonstrated no difference in pregnancy rates between letrozole and clomiphene citrate [6].
A study by Nahid and Sirous [14] showed that the effects of letrozole and clomiphene citrate on ovulation were almost the same, though clomiphene citrate caused endometrial thinning more often than letrozole. Also the side effects reported by patients in the group receiving clomiphene citrate were higher, while in the group receiving letrozole no complication was reported. Based on these findings, letrozole can be considered an appropriate alternative for clomiphene citrate, especially with a decreased side effect profile.
One disadvantage of clomiphene citrate is depletion of the estrogen receptors throughout the body and its long half-life. In contrast, an aromatase inhibitor blocks the conversion of androgens to estrogens in the ovarian follicles, peripheral tissues, and in the brain. This results in a decrease in circulating and local estrogens and a rise in intra-ovarian androgens. The fall in estrogen levels releases the hypothalamo-pituitary axis from the negative feedback of estrogens. Thus, there is a surge in follicle-stimulating hormone (FSH) release, which results in follicular growth. Since the feedback mechanism is intact, normal follicular growth, selection of dominant follicle, and atresia of smaller growing follicle occurs, thereby facilitating monofollicular growth and ovulation [15–21].
Another likely mechanism of action of the aromatase inhibitors is by the increasing intra-ovarian androgens. This likely increases the follicular sensitivity to FSH. Recent data shows the role of androgens in early follicular development by augmenting FSH receptors and stimulating insulin-like growth factor (IGF)-1; FSH and IGF-1 act synergistically to promote follicular growth [15,22–24].
Metformin
Treatment with insulin-sensitizing agents, such as metformin, thiazolidinedione, and D-chiro-inositol, has been suggested to be useful for ovulation induction in some women with PCOS [25–31]. The proposed mechanisms of action are similar to those observed with weight loss, such as a decrease in insulin levels, which may indirectly decrease ovarian androgen production, and a potential direct effect on the hypothalamus [32].
Pharmacology and dosing
Metformin is a biguanide antihyperglycemic agent approved by the United States Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. It reduces blood glucose levels by decreasing hepatic gluconeogenesis and intestinal absorption of glucose, as well as enhancing peripheral glucose uptake and use by increasing insulin sensitivity [33]. It is rapidly absorbed from the small intestine, with peak plasma levels occurring 2 hours after ingestion. Food decreases the rate of drug absorption as well as peak drug concentration. Metformin is not metabolized and is largely excreted in the urine; its plasma elimination half-life is approximately 6 hours.
When used in anovulatory women with PCOS, it acts to decrease insulin levels and luteinizing hormone (LH). This decrease in insulin and LH levels subsequently leads to an increase in the levels of sex hormone-binding globulin (SHBG), resulting in a decreased level of androgens. The decrease in androgens is in part because of the increased level of SHBG, but also because of the decrease in LH levels. Women with PCOS also benefit from metformin, because it typically causes a slight reduction in weight [34–36], which results in decreased serum testosterone concentration, resumption of ovulation, and pregnancy [37–40]. Studies have found that approximately 50% of women with PCOS or anovulatory cycles resume regular menses after taking metformin for 6 months.
The optimum dose of metformin to restore ovulatory menses has not been determined. The target dose, in anovulatory patients, is typically 1500–2500 mg in divided daily doses. Its most common adverse effects are gastrointestinal in nature, including diarrhea, nausea, emesis, flatulence, indigestion, and abdominal discomfort. The reported discontinuation rate is 5%, secondary to side effects [33]. These side effects can be sometimes diminished or avoided by a gradual dose escalation, beginning treatment with 500 mg taken with a meal, and if tolerated, increased to 500 mg twice daily with meals and then three times daily with meals. One to two weeks should elapse between increases in dose [41]. Another alternative is to switch to metformin XL or the liquid form, which typically have fewer side effects, before abandoning metformin therapy [42].
After initiating metformin therapy, it may take up to 6 months for ovulatory cycles to ensue. During the initial phase of oligomenorrhea, it may be difficult to determine whether ovulation has taken place. Although cumbersome, measuring serum progesterone every 10 days may be one approach to identify whether ovulation has occurred following initiation of metformin therapy [41].
Precautions and monitoring
Metformin therapy may have hepatic toxicity or be complicated by lactic acidosis; as such, liver and renal functions must be evaluated before treatment and monitored periodically thereafter. Metformin should not be prescribed in patients with conditions that may increase the risk of lactic acidosis, such as renal insufficiency, congestive heart failure, or sepsis.
Caution must be taken when patients taking metformin are undergoing intravascular contrast studies with iodinated materials, as this may lead to changes in renal function and has been associated with lactic acidosis. Per FDA current recommendations, metformin should be discontinued at the time of or prior to any contrast procedure and withheld for 48 hours after the procedure, and resumed only after renal function has been shown to be normal [41].
Metformin should also be temporarily suspended for all surgical procedures that involve restriction of fluid intake and should not be restarted until normal fluid intake has resumed and renal function has been shown to be normal.
Indications
As previously mentioned, the only FDA-approved indication for metformin is for type 2 diabetes mellitus; however, it has been used “off-label” to treat or help prevent several clinical problems associated with PCOS.
For women with oligomenorrhea due to PCOS, endometrial protection from hyperplasia is needed, and estrogen-progestin contraceptives are considered first line, followed by continuous or cyclic progestin-only when combined contraceptives are contraindicated. Metformin can also be used as a second-line therapy, restoring ovulatory menses in approximately 50% of women with PCOS [43,44]. However, when metformin is used, cyclic progestin therapy is added for the first 6 months of metformin treatment until regular cycles are established. Metformin has not been proven to be endometrial protective.
In one trial, 23 women with PCOS were randomly assigned to receive metformin, 500 mg three times per day, or placebo for 6 months [43]. Approximately 50% of the women achieved normalization of menstrual function, which was confirmed by intermenstrual interval and luteal phase serum progesterone monitoring. In a meta-analysis of 13 trials, women treated with metformin had a fourfold higher chance of ovulating when compared to placebo [45]. A similar increase was seen for the combination of metformin plus clomiphene versus clomiphene alone. Although metformin may restore ovulation in some women, it appears to be less effective than clomiphene for pregnancy and live birth rates.
In women with hirsutism secondary to PCOS, an estrogen-progestin contraceptive, as recommended by the 2008 Endocrine Society Guidelines, is the first line of treatment. If after 6 months the response is suboptimal, an antiandrogen is then added. Several clinical trials have studied the effects of metformin and other insulin-lowering agents on circulating androgen concentrations. Even though metformin has been shown to cause improvement in plasma insulin and insulin sensitivity, with a reduction in serum free testosterone and an increase in serum HDL cholesterol, there has not been a significant reduction in hirsutism, despite the lower free serum testosterone concentration. The best available evidence comes from a meta-analysis of nine placebo-controlled trials of insulin-lowering drugs [46]. When the eight metformin trials were analyzed separately, no significant benefit was seen in hirsutism when compared to placebo. Based upon these findings, the Endocrine Society Clinical Practice Guidelines suggest against the routine use of metformin for the treatment of hirsutism [47].
Anovulatory infertility is one of the main concerns for patients with PCOS. A structured approach is warranted for its treatment, starting with low-cost interventions and advancing to high-resource interventions. As such, the initial management steps are weight loss through caloric restriction and increased exercise for women with a body mass index (BMI) >27 kg/m2, followed by medical therapy [41].
In 2003, a meta-analysis of studies involving treatment with metformin in women with PCOS concluded that its efficacy was similar for treating anovulatory infertility when compared to clomiphene [48]. However, subsequent randomized multicenter trials comparing both metformin and clomiphene, alone and in combination, have found clomiphene clearly superior to metformin and observed that combined treatment offers no significant additional benefit [49–51].
The Pregnancy in Polycystic Ovary Syndrome I (PPCOS I) trial, a large multi-center RCT that evaluated the use of metformin versus clomiphene, versus both combined, shows a significantly lower live birth rate with metformin compared with clomiphene, only offering an advantage when added to clomiphene in women with BMI over 35 kg/m2 [50].
In the largest trial, clomiphene yielded a significantly higher live birth rate than metformin (22.5% vs. 7.2%). Results for combined therapy, with metformin and clomiphene, were not significantly better (26.8%), when compared to clomiphene alone (22.5%) [50]. A few small studies, however, involving clomiphene-resistant anovulatory patients with PCOS, have shown that combined treatment has increased ovulation and pregnancy rates over those achieved with clomiphene alone [52–55].
Patients that fail to ovulate in response to clomiphene, clomiphene failure or clomiphene resistant, may respond to supplemental or combination treatment regimens. Some of the options include adjuvant treatment with glucocorticoids, exogenous hCG, aromatase inhibitors, and metformin. These alternatives are helpful as many couples may be unable to pursue the obvious alternative of gonadotropin treatment due to associated costs, and others may be reluctant to do so once fully advised of the risks [56].
Combined metformin and clomiphene citrate
In women with PCOS and anovulatory infertility, clomiphene citrate is recommended as the first-line pharmacological therapy as previously described. If ovulation cannot be achieved with clomiphene citrate administration, and resistance is reached, other agents are recommended such as metformin, aromatase inhibitors, or gonadotropins [56].
The combination of metformin and clomiphene citrate seems to be an effective supplementation in clomiphene-resistant women. In Nestler and colleagues’ study, sixty PCOS women with a mean BMI of 32.3 were randomized to metformin (500 mg 3 times daily) versus placebo [31]. Women who failed to ovulate on metformin or placebo were given clomiphene citrate (50 mg on days 5 to 9). After addition of clomiphene citrate to metformin, 90% of the women ovulated versus 8% of the women who received clomiphene citrate plus placebo. Two high-quality reviews found that a combination of metformin and clomiphene citrate was better than clomiphene citrate alone for ovulation and for pregnancy rate in women with clomiphene citrate resistance [57].
In a few small studies involving clomiphene-resistant anovulatory women with PCOS, combined treatment with metformin and clomiphene increased ovulation and pregnancy rates over those achieved with clomiphene alone [52,53,55]. A 2008 meta-analysis, including 17 randomized trials, concluded that combined treatment achieves higher ovulation and pregnancy rates than treatment with clomiphene alone [27]. Although there is no convincing evidence that combined treatment with metformin and clomiphene can increase live birth rates over those achieved with clomiphene alone [57], it seems like a reasonable attempt for women who have few alternatives besides ovarian drilling or treatment with exogenous gonadotropins.
Limited evidence indicates that combined treatment with metformin or clomiphene and rosiglitazone is no more effective than metformin alone [29,58]. Also, the safety alert issued by the FDA concerning a possible increased risk of ischemic cardiovascular events in patients receiving treatment with thiazolidinediones argues against their adjuvant use for ovulation induction [59].
In a recent Cochrane review from 2012, analyzing insulin-sensitizing drugs in women with PCOS, when comparing metformin combined with clomiphene citrate, there was a significant effect when combined versus clomiphene alone (18 RCTs, number of cycles = 3265; OR 1.74, 95% CI 1.50–2.00), with a moderate degree of heterogeneity (I2 = 62%). The analysis was stratified based on sensitivity to clomiphene and BMI. A significant heterogeneity was observed in a group of trials when the status of clomiphene sensitivity was not defined (I2 = 67%); in contrast, as might be expected, the clomiphene-resistant group appeared to be homogeneous (I2 = 0%) [57].
We recommend that metformin is used in combination with clomiphene citrate, primarily in women with PCOS who are also clomiphene resistant, to aid in ovulation, pregnancy, and live birth [60]. This combination deserves consideration in women who prove clomiphene resistant, before proceeding to ovarian drilling or treatment with gonadotropins [56].
Gonadotropins
Gonadal function regulation is mediated by gonadotropin-releasing hormone (GnRH) and by the two gonadotropins, LH and FSH, which are biosynthesized in and secreted by gonadotropes in the pituitary. Placentally derived hCG also plays a role in regulation. These three gonadotropins regulate reproductive endocrinology, including steroid production, follicle and sperm maturation, ovulation, as well as maintenance of early pregnancy.
Structurally, these three gonadotropins exist as heterodimers; they all share a common alpha subunit and have a homologous hormone-specific beta subunit. They are secreted and circulate as such, having different bioactivity and pharmacokinetics based on varying degrees of glycosylation and sulfonation [68]. These circulating isoforms are present in different proportions in the different available commercial preparations [62,63].
Since their introduction into clinical practice in 1961 [49,50], exogenous gonadotropins have played an important role in ovulation induction. They have been used particularly in women who fail to respond to other forms of treatment as well as women who are gonadotropin deficient. Gonadotropins are highly effective, but are also associated with potentially serious complications including ovarian hyperstimulation syndrome and multiple pregnancies. They have a high cost, require close monitoring with ultrasound and determination of estradiol levels, and lack an oral formulation, reasons for which gonadotropins are considered a second-line treatment for PCOS patients with infertility.
Gonadotropin preparations
Gonadotropin preparations have significantly evolved since their initial discovery and first use. The initial crude preparations, obtained from postmenopausal female urine, have been gradually refined to highly purified urinary extracts; and finally, since 1996, the recombinant preparations we have available today [64,65].
These recombinant preparations are easier to administer, subcutaneous versus intramuscular, and have a higher grade of purity and consistency of preparation when compared to earlier forms. They have also made it possible to increase our understanding of their specific actions in follicular development and oocyte maturation, as well as allowing us to tailor stimulation regimens to the needs and requirements of individual patients in an attempt to optimize cycle outcomes [66].
Indications for gonadotropin treatment
The choice of gonadotropin preparation and treatment regimen will vary according to the type of ovulatory disturbance the patient has. The World Health Organization (WHO) has adopted a classification system for the causes of anovulation that provides a practical guide to appropriate therapeutic intervention.
The WHO classification system comprises group I: hypogonadotropic, hypogonadal anovulation; group II: normogonadotropic, normoestrogenic anovulation; and group III: hypergonadotropic, hypoestrogenic anovulation, and hyperprolactinemic anovulation. Gonadotropin treatment is indicated for WHO groups I and group II, for patients who have failed to ovulate or conceive with clomiphene citrate. For the purpose of this review we will focus on the latter as it pertains to the PCOS patient population.
When clomiphene citrate treatment, alone or in combination (glucocorticoids, exogenous hCG, aromatase inhibitors, or metformin), fails to achieve ovulation, gonadotropins become a suitable option. Ovarian stimulation with clomiphene citrate followed by gonadotropins in patients with clomiphene resistance in PCOS patients showed a cumulative live birth rate of 60% at 1 year and 78% at 2 years [67].
However, failure with other treatments is not a prerequisite for use of gonadotropins, rather it is a logical stepwise approach, as use of gonadotropins implies an increase in costs, risks, and logistical demand. A recent RCT evaluating clinical outcome of gonadotropin versus clomiphene citrate as first-line therapy for ovarian stimulation for ovulation induction showed a higher pregnancy and live birth rate with low-dose FSH [68].
Clomiphene-resistant anovulatory women with PCOS usually have a normal range of gonadotropin concentration, and many patients will have elevated LH levels. These patients benefit from exogenous gonadotropins. Theoretically, purified FSH preparations do not affect or impact endogenous LH production, thus avoiding further worsening of the ongoing LH hypersecretion. However, there is no evidence to support this theory and both human menopausal gonadotropin (hMG) and FSH may be used.
A meta-analysis including 14 RCTs comparing purified urinary FSH versus hMG for ovulation induction in clomiphene-resistant PCOS patients found that the only advantage of FSH over hMG is a reduced risk of ovarian hyperstimulation syndrome (OR = 0.20, 95% CI = 0.08–0.46) [69]. When comparing FSH forms, recombinant versus purified urinary, or different treatment regimens, there was no difference in the rates of ovulation, pregnancy, miscarriage, multiple pregnancy, or in the incidence of ovarian hyperstimulation syndrome [70,71].
The doses needed to achieve the desired response are relatively low; in fact, some patients might be extremely sensitive to gonadotropins and even subtherapeutic doses can cause ovarian hyperstimulation syndrome. This requires frequent adjustments in dosage and careful monitoring. Even though unifollicular ovulation is the goal, this might not be the case in many patients, and the risk of multiple pregnancy is high. These patients will seldom require luteal phase support, as women with PCOS usually have elevated endogenous LH, which provides adequate support. For those patients that exhibit poor luteal function and require support, progesterone therapy is preferable over hCG as the latter increases the risk for ovarian hyperstimulation syndrome [67].
Monitoring and administration
Monitoring during gonadotropin stimulation to predict adequate, but not excessive response is essential. Gonadotropin treatment regimens in patients with PCOS should start conservatively, since the risk of developing ovarian hyperstimulation syndrome, or having a multiple pregnancy, is high in these patients. Proper monitoring for these patients requires integration of hormonal and physical data. Follicle size during a treatment cycle needs to be followed with serial ultrasounds and response needs to be assessed with serum estradiol measurements.
Circulating estradiol levels peak approximately 12 hours after the preceding dose of gonadotropins, therefore times for drug administration and serum evaluation should be standardized, usually in the evening. Estradiol level is typically obtained in the morning, so the results can be interpreted by the afternoon and any dose changes can be communicated to the patient before her administration of medication in the evening. The estradiol levels should sustain a constant rise during stimulation, doubling every 2–3 days.
Ultrasound monitoring for follicular size and endometrial thickness should occur concomitantly with the serum estradiol measurements. Uniform follicular growth should be seen with constant growth. Follicles have a greater chance of ovulating as they increase in size; virtually all large follicles (>20 mm) will ovulate. Follicles 14 mm or smaller still have approximately a 40% chance of ovulating.
Typical monitoring for WHO group II patients includes an estradiol level and ultrasound on day 5 of stimulation. Monitoring these patients on the third day of stimulation is also an option for earlier adjustments if subsequent dosing is expected. Repeat assessment is dictated by the rate of rise in estradiol and growth of the developing follicles from ultrasound examination. The therapeutic window for patients with PCOS is notoriously narrow. The high cohort of available follicles in these patients can lead to a greater follicular responsiveness [72]. Development of ovarian overstimulation syndrome can occur with gonadotropin doses that start too high or are increased too frequently. Low initial doses of gonadotropin with small increases is a safe strategy for eliciting follicular response in these patients [73–77].
Low-dose step-up protocols typically start with a dose of 75 IU or less and dosing increments are increased as needed in 37.5 IU intervals [78–80]. hCG is injected when the leading follicle is >18 mm in diameter [81]. Ovarian hyperstimulation syndrome (1.4%) and multiple pregnancy rates (5.7%) have been reported to be very low with this regimen [89]. Another treatment regimen for PCOS patients is the step-down protocol. The FSH starting dose is 150 IU/day until a follicle of >10 mm is seen. The dose is decreased by 37.5 IU/day and further to 75 IU/day 3 days later until hCG is administered [83].
Ovarian hyperstimulation syndrome is one of the major risks of ovulation induction. It refers to a combination of ovarian enlargement due to multiple ovarian cysts and an acute fluid shift out of the intravascular space.
Exogenous gonadotropins administered for ovarian stimulation will override normal feedback mechanisms, thereby resulting in recruitment of multiple antral follicles, as opposed to monofollicular development that occurs in spontaneous cycles. These large numbers of follicles release vasoactive substances that are secreted during maturation and luteinization, causing increased capillary permeability. This will subsequently lead to fluid shifts out of the intravascular space, hemoconcentration, and third-space accumulation of fluid. Clinical symptoms usually appear 5–10 days following the first dose of the ovulatory trigger. Some serious complications include renal failure, hypovolemic shock, thromboembolic episodes, acute respiratory distress syndrome, and death [83,84].
Some patients can be identified as being at higher risk for ovarian hyperstimulation syndrome and in this way changes in stimulation regimens can be made and preventative measures can be implemented. Risk factors include young age, previous ovarian hyperstimulation syndrome, sensitivity to gonadotropins, PCOS, high basal anti-müllerian hormone, and high antral follicle count (>14) [85,86]. Even though complete prevention is still not possible, identifying risk factors can significantly reduce its incidence.
Prevention strategies are divided into two types: primary prevention for those patients identified to be at higher risk based on the presence of previously mentioned risk factors on initial screening, and secondary prevention for patients in whom risk factors arise from excessive response to stimulation protocols. Primary prevention strategies include reducing exposure to gonadotropins by reducing the dose as well as duration of exposure, addition of GnRH antagonists, avoidance of hCG for luteal phase support and use of progesterone instead, in vitro maturation, and use of insulin-sensitizing agents [87–90]. Secondary prevention strategies include coasting, cryopreservation of embryos for reimplantation when the patient’s serum hormone levels are not elevated, alternative trigger agents, and lastly, cycle cancellation.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
