For women with polycystic ovary syndrome (PCOS), clomiphene citrate has traditionally been the standard of care for achieving ovulation.1 Clomiphene binds to estrogen receptors, causing a perceived hypoestrogenic state. This alters the pulsatile release of gonadotropin-releasing hormone from hypothalamic neurons, leading to an increase in release of follicle-stimulating hormone from the pituitary, which initiates follicular growth at the level of the ovary.2,3 The perceived hypoestrogenic state is also the cause of the side effects experienced with the administration of clomiphene, including mood swings and vasomotor flushing.4 Although visual disturbances are rare and reversible, it is recommended that treatment with clomiphene be discontinued.5
The starting dose for ovulation induction with clomiphene is 50 mg, and up to 52% of women will ovulate at this dose.6 Another 22% of remaining women will respond to 100 mg, 12% to 150 mg, 7% to 200 mg, and 5% to 250 mg clomiphene.6
Traditional protocols using clomiphene involve inducing a withdrawal bleed before increasing the dose when ovulation is not achieved.7 An alternative stair-step protocol has been shown to improve time to ovulation, wherein a higher clomiphene dose is used without inducing withdrawal bleeding.8 Although promising, the widespread adaptation of the stair-step protocol has been limited as a result of the small number of studies comparing ovulation rates and limited data on side effect profile between the traditional and stair-step clomiphene protocols, particularly at higher doses.
Our primary objective was to evaluate time to ovulation in women with PCOS undergoing ovulation induction with the traditional protocol compared with the stair-step protocol using clomiphene. Secondary outcomes included ovulation rates, clinical pregnancies, and incidence of side effects by dose.
MATERIALS AND METHODS
This is a retrospective cohort study of women with PCOS undergoing ovulation induction in a university-based county hospital infertility clinic. We included women who had undergone at least one previous cycle of clomiphene and failed to ovulate at the 50-mg dose. All women had a diagnosis of PCOS, defined by Rotterdam criteria as meeting at least two of the following three criteria: oligo- or anovulation, biochemical or clinical hyperandrogenism, and polycystic ovaries on ultrasonography (greater than 12 follicles 2–9 mm or ovarian volume of 10 mL or greater). We used International Classification of Diseases, 9th Revision code 256.4 to find all patients with PCOS in our clinic. We excluded women who did not meet criteria for PCOS and those who received other types of ovulation induction for infertility previously.9 The study was approved by the Los Angeles County Medical Center institutional review board.
We retrospectively reviewed records of all patients with PCOS resistant to clomiphene at the initial dose of 50 mg over a 2-year period from July 2012 to July 2014. In July 2013, our institution adopted the stair-step protocol as the standard of care for ovulation induction, where previously we had been using the traditional treatment protocol. Therefore, in our study, patients receiving treatment between July 2012 and July 2013 underwent ovulation induction with the traditional protocol. Those receiving treatment from July 2013 to 2014 underwent ovulation induction using the stair-step protocol.
Demographic data were abstracted from charts by residents and fellows, including age, height, weight, and ethnicity. Body mass index (BMI) was calculated as weight (kg)/[height (m)]2. We also collected data for clinical outcomes including ovulation rate, time to ovulation, pregnancy rate, and adverse effects. The database was analyzed for outlying data points. Statistical software was used to measure ranges and distributions to verify data accuracy. We excluded patients with significant missing variables.
In the traditional protocol, a dose of 50 mg was administered; if a lack of response was documented with a luteal progesterone level less than 3 ng/mL on cycle day 21 (approximately 12 days after the last dose of clomiphene citrate), the dose of clomiphene was increased to 100 mg/d after a spontaneous menses or a progestin-induced bleed. This was repeated to a maximum dose of 250 mg/d of clomiphene citrate (Fig. 1).
For the stair-step protocol, a transvaginal ultrasonogram was performed 7 days after the last dose of clomiphene to assess for follicular response. If no developing follicle greater than 10 mm was noted, the dose was increased to 100 mg/d for 5 days. An ultrasonogram was repeated 7 days after the last pill, and if there was no follicle greater than 10 mm, an escalation in dose was performed in the same fashion with an increase in 50 mg/d at each step to a maximum dose of 250 mg/d (Fig. 1).
Ovulation was demonstrated by evidence of a follicle greater than 10 mm by transvaginal ultrasonography in addition to a serum progesterone level greater than 3 ng/mL followed by menses or clinical pregnancy. Time to ovulation was calculated from the cycle start time to the date of successful ovulation. Clinical pregnancy was defined as the presence of a gestational sac and heartbeat on transvaginal ultrasonography.
Side effect data were obtained by reviewing all follow-up visits during the treatment cycles in which all patients were assessed for disorders associated with taking clomiphene. Vasomotor flushing, mood irritability, breast tenderness, and gastrointestinal side effects (nausea, abdominal distension) were classified as mild side effects. Visual disturbances or severe headaches resulting in self-discontinuation of the medication were classified as severe side effects.
Based on the Hurst study,8 which showed an approximate 50% decrease in time to ovulation, we chose a more conservative approach with our power calculation. We calculated that 44 patients were needed to a have an 80% chance of detecting a 20% difference in time to ovulation. Stata 12.0 was used to analyze data. Student t test was used to compare means for variables with a normal distribution. Results are listed as means±SD or numbers (percentage). Mann-Whitney and one-way analysis of variance were used when appropriate. χ2 and Fisher exact tests were used to compare proportions for categorical demographic data, ovulation, and pregnancy rates. Statistical significance was defined by a two-tailed test with P<.05.
From July 2012 to July 2014, we identified a total of 109 patients resistant to an initial clomiphene dose of 50 mg. Sixty-six patients (60.6%) were treated with the traditional protocol, and 43 patients (39.4%) were treated with the stair-step protocol. There was no difference in age or BMI between the traditional and stair-step patients, and the majority of patients in both groups were of Hispanic descent (Table 1).
The overall mean time to ovulation was significantly shorter in the stair-step compared with traditional group (Fig. 2). Cumulative ovulation rate was significantly higher in patients who underwent ovulation using the stair-step protocol compared with those undergoing the traditional protocol (38/43 [88%] vs 26/66 [39%], P<.05). When comparing ovulation rates by dose, ovulation rates were higher in the stair-step group at both 150 and 200 mg (Table 2).
There were no differences in pregnancy rates per ovulatory cycle in the stair-step and traditional groups (7/43 [16.3%] vs 12/66 [18.1%], P=.08; Table 2). There was one dichorionic diamniotic twin gestation in the traditional protocol and no multiple gestations in the stair-step protocol (1/12 [8%] vs 0/7 [0%]).
Patients in the stair-step group experienced a significantly greater number of mild side effects, including self-reports of vasomotor flushes, headaches, gastrointestinal disturbance (nausea), mastalgia, and changes in mood (Table 3). There was no significant difference between the groups in the incidence of severe side effects (Table 3).
The results of our study indicate that the stair-step clomiphene protocol is associated with decreased time to ovulation when compared with the traditional protocol for women with PCOS. The time to ovulation for women in the stair-step group was decreased by an average of 30 days compared with those in the traditional protocol. Although the ovulation rates for women in the two protocols were similar at 100 mg, the rates were increased in the stair-step protocol at 150 and 200 mg. Improved ovulation rates are thought to be the result of an additive effect of multiple doses. The half-life of clomiphene is 5–7 days, but may be longer resulting from variability in metabolism.10,11 When patients take their next dose, active isomers are still circulating in the system, making the total circulating concentration higher than in traditional protocols, in which previous clomiphene has time to wash out.
Data regarding alternative strategies to improve response rates to clomiphene such as metformin and dexamethasone are mixed, because some studies show improvement in ovulation in certain patients, but no improvement in live births.12–14 However, these medications may require long durations of use before a response might be observed, and the cost of continued treatment and repeated treatment failures adds to patient frustration.15,16 Laparoscopic ovarian drilling is an effective option for clomiphene resistance, but does carry the risks of surgery and potential adhesion formation.17 The stair-step protocol was introduced in 2009 as an effective way to shorten the length of time of ovulation in women undergoing ovulation induction with clomiphene citrate.8 A subsequent study from 2015 found that the stair-step and traditional protocols had similar efficacy with a shorter duration to pregnancy and minimal side effects.18 The lack of the progestin-induced withdrawal bleed is the cornerstone change that allows this protocol to lead to a faster time to ovulation. Although withdrawal bleeds have been traditionally used between doses of clomiphene, they do not lead to improved pregnancy outcomes. A study of women undergoing ovulation induction with clomiphene by Diamond et al19 showed higher live birth rates in women who did not have withdrawal bleed or preceding menses. They postulated that differences in pregnancy and live birth rates might be the result of differential expression in factors affecting endometrial receptivity, whereas others think it may be the result of decreased endometrial thickness.19,20 Because it is now considered acceptable to initiate ovulation induction during an anovulatory cycle, the case for utilizing the stair-step protocol is even stronger.
Our study reports side effects in increasing doses of clomiphene up to 200 mg using the stair-step protocol. Participants undergoing ovulation induction with the stair-step protocol did experience higher rates of mild side effects. The cumulative effect of the previous and next dose of clomiphene results in a prolonged experience of the hypoestrogenic state that stimulates symptoms such as vasomotor flushes and changes in mood. Despite a higher incidence of mild adverse effects, compliance rates with clomiphene did not decrease. Several cases of visual disturbances have been reported and are reversible with no significant sequelae.21,22 Authors conclude that visual disturbance is likely the result of the temporary effect of clomiphene on the visual cortex and not the retina. Although clomiphene may contribute to headaches, it has also been described as an alternative treatment for chronic cluster headaches as a result of its modulation of endogenous neuropeptides.23 Overall, severe adverse events with clomiphene administration are rare. The effectiveness of the stair-step protocol and benign nature of the majority of side effects make the stair-step method an acceptable and tolerable protocol for patients.
Limitations of our study include the retrospective nature, small study sample, and insufficient power to detect differences in pregnancy rates and side effects. We acknowledge that newer data suggest letrozole may be more effective first-line treatment than clomiphene for ovulation induction in PCOS.24 Given the differences between letrozole (shorter half-life and different mechanism) and clomiphene, one cannot assume that letrozole can be used in a stair-step fashion with the same benefits as seen with clomiphene. However, even if clomiphene is used as a second line, the stair-step protocol is an efficient and effective method for ovulation induction in the PCOS population.
Based on our findings, the stair-step protocol improves time to ovulation and ovulation rates at higher doses with minimal adverse effects. Although this protocol requires multiple visits in a shorter period of time and more ultrasound monitoring, it may minimize the emotional distress experienced during the time to achieve pregnancy. Given, its multiple benefits, health care providers should counsel patients regarding the advantages of this method for ovulation induction.
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