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Ovulation rate and cycle characteristics in a subsequent clomiphene citrate cycle after stair-step protocol

  • Tara H. Budinetz
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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  • Claudio A. Benadiva
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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  • Daniel W. Griffin
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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  • Lawrence L. Engmann
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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  • John C. Nulsen
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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  • Andrea J. DiLuigi
    Correspondence
    Reprint requests: Andrea J. DiLuigi, M.D., Center for Advanced Reproductive Services, University of Connecticut Health Center, 263 Farmington Avenue, Dowling South Building, Farmington, Connecticut 06030-6224.
    Affiliations
    Center for Advanced Reproductive Services, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut
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      Objective

      To determine the ovulation rate after ovulation induction with clomiphene citrate (CC) in women who had previously been ovulatory after a stair-step (CC-SS) ovulation induction.

      Design

      Retrospective cohort.

      Setting

      University–based tertiary fertility center.

      Patient(s)

      61 anovulatory patients <40 years of age with polycystic ovary syndrome who underwent ovulation induction with a CC-SS protocol and a subsequent CC cycle.

      Intervention(s)

      Ovulation induction with CC.

      Main Outcome Measure(s)

      Ovulation rates and cycle characteristics.

      Result(s)

      Of 61 patients who underwent a subsequent CC cycle, 15 (25%) failed to ovulate at the previously ovulatory dose. Of those 15 patients, 13 (86.7%) ovulated after an increase in dose. The total number of follicles ≥15 mm (2.8 ± 1.2 vs. 1.6 ± 0.7) and peak estradiol (E2) levels (604 ± 272 pg/mL vs. 447 ± 218 pg/mL) were statistically significantly higher in the CC-SS cycle compared with the subsequent CC cycle, respectively. The endometrial lining was statistically significantly thinner in the CC-SS than the CC cycle (7.8 ± 1.8 vs. 9.2 ± 2.7, respectively).

      Conclusion(s)

      The majority of patients who ovulate after a CC-SS protocol will ovulate after taking the previously ovulatory CC dose in a subsequent cycle. Those who do not ovulate will likely ovulate with a further increase in CC dose.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/budinetzt-ovulation-clomiphene-citrate-stair-step-protocol/
      Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women and the most common cause of anovulatory infertility (
      • Sirmans S.M.
      • Pate K.A.
      Epidemiology, diagnosis, and management of polycystic ovary syndrome.
      ,
      • Perales-Puchalt A.
      • Legro R.S.
      Ovulation induction in women with polycystic ovary syndrome.
      ,
      • Norman R.J.
      • Dewailly D.
      • Legro R.S.
      • Hickey T.E.
      Polycystic ovary syndrome.
      ). Clomiphene citrate (CC) is often the initial treatment of choice in this population because it is readily available, inexpensive, well-tolerated, safe, and efficacious (
      • Palomba S.
      • Orio F.
      • Zullo F.
      Ovulation induction in women with polycystic ovary syndrome.
      ,
      • Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
      Consensus on infertility treatment related to polycystic ovary syndrome.
      ). As a selective estrogen receptor modulator, CC acts by binding to estrogen receptors and inhibiting the negative feedback of estrogen on the hypothalamus (
      • Perales-Puchalt A.
      • Legro R.S.
      Ovulation induction in women with polycystic ovary syndrome.
      ,
      • Practice Committee of the American Society for Reproductive Medicine
      Use of clomiphene citrate in infertile women: a committee opinion.
      ). This causes a compensatory increase in follicle-stimulating hormone levels, thereby stimulating follicular development and subsequent ovulation (
      • Perales-Puchalt A.
      • Legro R.S.
      Ovulation induction in women with polycystic ovary syndrome.
      ,
      • Practice Committee of the American Society for Reproductive Medicine
      Use of clomiphene citrate in infertile women: a committee opinion.
      ). Although CC is known to have a relatively long half-life, approximately 85% of the drug is excreted from the body after 7 days (
      • Mikkelson T.J.
      • Kroboth P.D.
      • Cameron W.J.
      • Dittert L.W.
      • Chungi V.
      • Manberg P.J.
      Single-dose of clomiphene citrate in normal volunteers.
      ). However, some CC remains in the circulation and continues to be excreted for at least 6 weeks (
      • Mikkelson T.J.
      • Kroboth P.D.
      • Cameron W.J.
      • Dittert L.W.
      • Chungi V.
      • Manberg P.J.
      Single-dose of clomiphene citrate in normal volunteers.
      ).
      A commonly used CC protocol for ovulation induction involves a starting dose of 50 mg per day for 5 days during the follicular phase. If ovulation does not occur, the dose is often increased by 50 mg in the next cycle after a progesterone-induced withdrawal period (
      • Sirmans S.M.
      • Pate K.A.
      Epidemiology, diagnosis, and management of polycystic ovary syndrome.
      ,
      • Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
      Consensus on infertility treatment related to polycystic ovary syndrome.
      ). The alternative option is to use a stair-step protocol (SS), which consists of increasing the CC dose in an incremental fashion within the same cycle when ovulation does not occur, rather than inducing a progesterone withdrawal bleed (
      • Hurst B.S.
      • Hickman J.M.
      • Matthews M.L.
      • Usadi R.S.
      • Marshburn P.B.
      Novel clomiphene “stair-step” protocol reduces time to ovulation in women with polycystic ovarian syndrome.
      ). It has been shown that patients treated with the CC-SS protocol have a shorter time to ovulation (
      • Hurst B.S.
      • Hickman J.M.
      • Matthews M.L.
      • Usadi R.S.
      • Marshburn P.B.
      Novel clomiphene “stair-step” protocol reduces time to ovulation in women with polycystic ovarian syndrome.
      ).
      Given the long half-life of CC, it is possible that the CC-SS protocol works due to a cumulative effect of the multiple doses of the medication. We therefore hypothesized that patients undergoing the CC-SS ovulation induction cycle would have a higher follicular response than in a subsequent CC cycle. To date, there are no published studies regarding a possible cumulative effect of the CC-SS protocol. Our study determined the ovulation rate and cycle characteristics in women undergoing ovulation induction with CC using the dose of CC that was effective in inducing ovulation in a prior CC-SS cycle.

      Materials and methods

       Study Design

      We retrospectively studied a cohort of anovulatory patients with PCOS aged younger than 40 years who underwent ovulation induction with CC-SS protocol followed by a subsequent CC cycle between January 2010 and December 2013. This study was conducted at the Center for Advanced Reproductive Services at the University of Connecticut Health Center in Farmington, Connecticut, and was approved by the University of Connecticut Health Center Institutional Review Board.

       Participants

      Initially, 103 women who were <40 years of age with a diagnosis of PCOS based on the Rotterdam Criteria (
      • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
      Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.
      ) were reviewed. Of those, 61 women did not conceive in the initial CC-SS protocol and underwent a subsequent CC cycle. Forty-two patients who did not undergo a subsequent cycle after the initial stair-step cycle were excluded (Fig. 1). Reasons for not undergoing a subsequent cycle included achievement of pregnancy, undergoing ovulation induction with injectable gonadotropins paired with intrauterine insemination or in vitro fertilization, and self-discontinuation of treatment.
      Figure thumbnail gr1
      Figure 1Flowchart of patients in the clomiphene citrate stair-step protocol program.

       Treatment Protocol

      The CC-SS protocol was adapted from Hurst et al. (
      • Hurst B.S.
      • Hickman J.M.
      • Matthews M.L.
      • Usadi R.S.
      • Marshburn P.B.
      Novel clomiphene “stair-step” protocol reduces time to ovulation in women with polycystic ovarian syndrome.
      ). Patients were started on CC at 50 mg, 100 mg, or 150 mg for 5 days in the follicular phase. This initial starting dosage was chosen by the treating physician based on patient age, body mass index (BMI), and prior response. Transvaginal ultrasound scans and measurements of serum estradiol (E2), serum luteinizing hormone (LH), and serum progesterone were obtained on day 11–14 to assess the patient's response. If no response was noted (no follicle >10 mm, E2 <70 pg/mL, and progesterone <1.0 ng/dL), a higher dose of CC was immediately initiated for 5 days (CC dose increased by 50 mg to a maximum dose of 200 mg). An ultrasound was then performed 1 week after the CC dosage increase to assess the follicular response and endometrial thickness. In addition, serum E2, LH, and progesterone concentrations were measured. These steps were continued and the CC dose increased by 50-mg increments until a response was noted or a maximum dose of 200 mg had been reached. Once a response was documented, the patients were monitored daily for an LH surge via urinary LH predictor testing or serum LH levels. Patients then timed their intercourse or underwent intrauterine insemination on the day after the LH surge. Serum human chorionic gonadotropin (hCG) levels were obtained 16 days later.
      Nonpregnant patients undergoing a subsequent CC ovulation induction cycle were prescribed a starting dosage of CC equivalent to the previous ovulatory dose from the CC-SS cycle. Transvaginal ultrasound scans and measurements of serum E2, LH, and progesterone concentrations were obtained on days 11–14 to assess follicular development and endometrial thickness. If no response was noted, the CC dose was increased in 50-mg increments until a response occurred or a maximum dose of 200 mg was reached. This was followed by monitoring with blood testing and ultrasound, as previously described. Once a response was documented, daily LH monitoring occurred previously described. Patients then either had intercourse or underwent intrauterine insemination on the day after the LH surge.

       Outcome Variables

      The primary outcome was the ovulation rate in the subsequent CC cycle. Secondary outcomes included the number of follicles ≥20 mm, number of follicles ≥15 mm, peak E2 levels, and endometrial thickness in the subsequent CC cycle when compared with the prior CC-SS cycle. Pregnancy outcomes including the clinical pregnancy rate, the ongoing pregnancy rate, spontaneous abortion, ectopic pregnancy, and the multiple gestation rate were also assessed only in the subsequent cycle. Clinical pregnancy rate was defined as the presence of a gestational sac on ultrasound scan. The ongoing pregnancy rate was defined as a pregnancy continuing after 12 weeks gestation.

       Statistical Analysis

      Statistical analyses was performed using the SPSS 20 for Windows package (release 6.0; SPSS Inc.). A paired t test was used for continuous variables and the chi-square or Fisher's exact test for categorical variables. P<.05 was considered statistically significant. All P values were two-sided.

      Results

      Figure 1 depicts the study's patient flow. A total of 103 patients underwent ovulation induction using the CC-SS protocol. Forty-two patients were excluded because they did not undergo a subsequent CC cycle. The reasons for not undergoing a subsequent CC cycle included achieving pregnancy (19.0%; 8 of 42), undergoing other treatment types such as ovulation induction with injectable gonadotropins paired with intrauterine insemination (23.8%; 10 of 42) or in vitro fertilization (in vitro fertilization) (45.2%; 19 of 42), or self-discontinuation of treatment (11.9%; 5 of 42).
      Thus, 61 patients underwent another CC cycle and were included in the study. Of those patients, 16 (75%) of 61 underwent a subsequent traditional CC cycle and ovulated at the previous ovulatory dosage in the CC-SS cycle. However, 15 (25%) of 61 were not ovulatory. Of those who did not ovulate, 13 (86.7%) of 15 were found to be ovulatory after an increase in CC dose using the CC-SS method a second time. A small number of patients (13.3%, 2 of 15) were unable to take an increased CC dose because they had reached the maximum dosage of 200 mg. Baseline characteristics are shown in Table 1. This patient population consisted of mostly young, nulliparous women with PCOS who were undergoing their first cycle of ovulation induction with CC. Additionally, all 61 patients undergoing the subsequent CC cycle did so with the menses immediately after the CC-SS cycle. Therefore, there were no patients who took time off between cycles.
      Table 1Baseline characteristics of the women in the clomiphene citrate stair-step study.
      Patient characteristicValue (n = 61)
      Age (y)31.4 ± 3.8
      BMI (kg/m2)32 ± 7.9
      Nulliparous (%, n)73.8 (45)
      AMH (ng/mL)6.8 ± 4.6
      Day-3 E2 (pg/mL)44.2 ± 15.1
      Day-3 FSH (mIU/mL)6.7 ± 1.5
      Day-3 LH (mIU/mL)5.4 ± 3.7
      Basal antral follicles (n)31 ± 17
      Basal ovarian volume (cc)11.9 ± 5.5
      No. of prior cycles0.2 ± 0.5
      Note: Values are expressed as either percentages or mean ± standard deviation. AMH = antimüllerian hormone; BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
      Most patients were stair-stepped from 50 mg of CC to 100 mg in the initial cycle, and were started on 100 mg in the subsequent cycle (45.9%; 28 of 61). In 16 (26.2%) of 61 patients, an initial CC dosage of 100 mg stair-stepped to 150 mg was used in the first cycle followed by a starting dosage of 150 mg in the subsequent cycle. Fewer patients (11.5%; 7 of 61) were started on 150 mg of CC and increased to 200 mg in the initial stair-step cycle and were started on 200 mg of CC in the subsequent cycle. Of the 61 patients who were stair-stepped in the initial cycle, 51 (83.6%) of 61 required only one incremental dose increase of 50 mg (a “step”). However, 9 (14.8%) of 61 required two steps, and 1 (1.6%) of 61 required three steps. Of those patients requiring two stair-steps, 3 (4.9%) of 61 started at 50 mg and were increased to 100 mg, followed by 150 mg. The remaining 6 (9.8%) of 61 patients requiring two stair-steps were started at a dosage of 100 mg, increased to 150 mg, followed by 200 mg. The patient who required three stair-steps was started at a dosage of 50 mg, increased to 100 mg then 150 mg, and finally to 200 mg. The 13 patients who were stair-stepped in the subsequent cycle only required one step.
      The cycle characteristics of patients who underwent the CC-SS cycle and were ovulatory in the subsequent CC cycle are shown in Table 2. The number of follicles ≥20 mm did not statistically significantly differ between the CC-SS cycle and subsequent CC cycle. The number of follicles ≥15 mm was statistically significantly higher in the CC-SS cycle compared with the subsequent CC cycle (2.8 ± 1.2 vs. 1.6 ± 0.7, respectively; P<.01). The peak E2 level was also statistically significantly higher in the CC-SS cycle than the subsequent CC cycle (604 ± 272 vs. 447 ± 218 pg/mL, respectively; P≤.01). The endometrial stripe thickness was statistically significantly thinner in the CC-SS cycle compared with the subsequent CC cycle (7.8 ± 1.8 vs. 9.2 ± 2.7 mm, respectively; P≤.01).
      Table 2Cycle characteristics in patients who were ovulatory in the subsequent cycle.
      Cycle characteristicCC stair-step cycle (n = 46)Subsequent CC cycle (n = 46)P value
      No. of follicles ≥20 mm (n)1.4 ± 0.51.2 ± 0.5.14
      No. of follicles ≥15 mm (n)2.8 ± 1.21.6 ± 0.7<.01
      Peak E2 (pg/mL)604 ± 272447 ± 218<.01
      Endometrial stripe (mm)7.8 ± 1.89.2 ± 2.7<.01
      Note: Values are expressed as mean ± standard deviation. CC = clomiphene citrate; E2 = estradiol.
      Overall, in those who were initially stair-stepped prior to exclusion, the cumulative clinical and ongoing pregnancy rates were 25.2% (26 of 103) and 23.3% (24 of 103), respectively. The mean time to conception from inception of treatment was 52.5 ± 12.4 days. The pregnancy outcomes for the 61 patients undergoing a subsequent CC cycle are depicted in Table 3. The multiple gestation rate was 10.5% (2 of 19); both of these were twin pregnancies occurring in patients who did not ovulate on the previously ovulatory CC dose and had to be stair-stepped again.
      Table 3Pregnancy outcomes for the subsequent clomiphene citrate cycle.
      Pregnancy typePregnancy rate (N = 61), %, n
      Clinical pregnancy rate31.1 (19)
      Ongoing pregnancy rate27.9 (17)
      Spontaneous abortion1/6 (1)
      Ectopic pregnancy1.6 (1)
      The clinical and ongoing pregnancy rates were similar in subsequent cycles of patients whether they had responded to the previously ovulatory dose or had to be stair-stepped again. The clinical and ongoing pregnancy rates in the 46 patients who had responded to the previous ovulatory stair-step dose were 32.6% (15 of 46) and 28.3% (13 of 46), respectively. In those who were stair-stepped again, the clinical pregnancy rate and ongoing pregnancy rate were 30.8% (4 of 13) and 30.8% (4 of 13). There were two patients who did not respond to the maximum dose of 200 mg in the subsequent cycle; as expected, no pregnancies resulted. Those undergoing a subsequent cycle using the previous ovulatory CC dose without the use of CC-SS did not experience any multiple gestations. In those who had to be stair-stepped again in the subsequent cycle, 2 (50%) of the 4 clinical pregnancies were twin gestations. No pregnancies were triplets or greater.

      Discussion

      This study demonstrates that the ovulatory dose of CC in a CC-SS protocol is effective in inducing ovulation in most patients in a subsequent CC cycle. Therefore, once the ovulatory dose is determined, it is reasonable to start at that dose in a subsequent CC cycle. However, some patients may fail to ovulate after taking this dose. One potential explanation could be that the decreased sensitivity of a particular cohort of antral follicles to follicle-stimulating hormone in response to CC may vary from cycle to cycle (
      • Hannoun A.
      • Abu Musa A.
      • Awwad J.
      • Kaspar H.
      • Khalil A.
      Clomiphene citrate challenge test: cycle to cycle variability of cycle day 10 follicle stimulating hormone level.
      ). This could also be due the loss of a possible cumulative effect of CC in the SS-protocol. However, most patients will ovulate after a further increase in the CC dose. This finding may be helpful when counseling patients undergoing treatment.
      In our study, we observed that the CC-SS cycles had more follicles ≥15 mm, a higher peak E2, and a thinner endometrial stripe than the subsequent CC cycles (Table 3). This suggests that the CC-SS protocol may act through a cumulative effect of the CC. Clomiphene citrate consists of two geometric isomers mixed in an approximate 3:2 ratio: enclomiphene and zuclomiphene, respectively (
      • Practice Committee of the American Society for Reproductive Medicine
      Use of clomiphene citrate in infertile women: a committee opinion.
      ,
      • Dickey R.P.
      • Holtkamp D.E.
      Development, pharmacology and clinical experience with clomiphene citrate.
      ). Enclomiphene is more potent than zuclomiphene and is primarily responsible for ovulation induction, although it has a relatively short half-life (
      • Mikkelson T.J.
      • Kroboth P.D.
      • Cameron W.J.
      • Dittert L.W.
      • Chungi V.
      • Manberg P.J.
      Single-dose of clomiphene citrate in normal volunteers.
      ,
      • Clark J.H.
      • Guthrie S.C.
      Agonistic and antagonistic effects of clomiphene citrate and its isomers.
      ,
      • Van Campenhout J.
      • Borreman E.
      • Wyman H.
      • Antaki A.
      Induction of ovulation with cisclomiphene.
      ,
      • Young S.L.
      • Opsahl M.S.
      • Fritz M.A.
      Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.
      ). Zuclomiphene, has been shown to persist for weeks and may even gradually accumulate after several cycles (
      • Mikkelson T.J.
      • Kroboth P.D.
      • Cameron W.J.
      • Dittert L.W.
      • Chungi V.
      • Manberg P.J.
      Single-dose of clomiphene citrate in normal volunteers.
      ,
      • Young S.L.
      • Opsahl M.S.
      • Fritz M.A.
      Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.
      ). It is possible that the zuclomiphene is responsible for the cumulative effect of the CC-SS protocol though there is no evidence that the remaining zuclomiphene has any clinical significance (
      • Young S.L.
      • Opsahl M.S.
      • Fritz M.A.
      Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.
      ).
      In our study, the higher number of follicles and peak E2 that was observed in the CC-SS group would suggest that there may be an increased risk of multiple pregnancies. As we compared the CC-SS cycle to the subsequent CC cycle in the same patient, we were unable to statistically compare pregnancy rates. We did, however, obtain pregnancy rates in the subsequent CC cycle. Our ovulation (75%), clinical (31.1%), and ongoing pregnancy (27.9%) rates in the CC subsequent cycle are consistent with prior published data (
      • Homburg R.
      Clomiphene citrate—end of an era? A mini-review.
      ).
      It has also been shown that almost 50% of patients will not respond to CC at an initial dose of 50 mg (
      • Hurst B.S.
      • Hickman J.M.
      • Matthews M.L.
      • Usadi R.S.
      • Marshburn P.B.
      Novel clomiphene “stair-step” protocol reduces time to ovulation in women with polycystic ovarian syndrome.
      ). This information may be helpful in setting expectations when counseling patients who are initiating CC treatment. In our study, there were no multiple pregnancies in the subsequent CC group. In patients who failed to ovulate and had to be stair-stepped again in the subsequent cycle, the clinical and ongoing pregnancy rates were similar to those who were not stair-stepped again. The overall multiple pregnancy rates in patients who conceived were low and within the range that has been reported in the literature (
      • Ahlgren M.
      • Kallen B.
      • Rannevik G.
      Outcome of pregnancy after clomiphene therapy.
      ,
      • Schenker J.G.
      • Yarkoni S.
      • Granat M.
      Multiple pregnancies following induction of ovulation.
      ,
      • Correy J.F.
      • Marsden D.E.
      • Schokman F.C.
      The outcome of pregnancy resulting from clomiphene-ovulation.
      ). Nevertheless, in patients who were stair-stepped again in the subsequent cycle, 50% of the ongoing pregnancies were twin gestations. Although these numbers are small, this could be related to a higher number of follicles and a higher peak E2 level in the CC-SS cycles.
      We observed a thinner endometrial stripe in the patients undergoing CC-SS than in those undergoing a subsequent CC cycle. A thin endometrial stripe could raise concerns about implantation and clinical pregnancy rates. It is possible that although the difference in the endometrial stripe thickness was statistically significant, the effect was not large enough to be clinically significant. Additionally, it has been suggested that endometrial shedding may have negative effects in women with PCOS undergoing ovulation induction with CC. It has been previously shown that conception and live-birth rates are lower in women with PCOS undergoing either spontaneous or progesterone-induced menses before starting CC (
      • Diamond M.P.
      • Kruger M.
      • Santoro N.
      • Zhang H.
      • Casson P.
      • Schlaff W.
      • et al.
      Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome.
      ). Therefore, the CC-SS method offers an incremental increase in CC dose without the potential negative effects of endometrial shedding in the PCOS population.
      It has been previously shown that in anovulatory women the CC-SS protocol may decrease the time to ovulation from inception of treatment compared with serial non-SS cycles with interval progesterone-induced withdrawal bleeding followed by increased CC doses (
      • Hurst B.S.
      • Hickman J.M.
      • Matthews M.L.
      • Usadi R.S.
      • Marshburn P.B.
      Novel clomiphene “stair-step” protocol reduces time to ovulation in women with polycystic ovarian syndrome.
      ). This is a benefit of the CC-SS protocol, which offers patients an alternative option to the progesterone-withdrawal bleed. The CC-SS protocol may also be helpful in establishing an ovulatory dose for potential additional CC cycles.
      The limitations of our study include the retrospective study design and the small sample size. Although the sample size was small, statistically significant differences were found. Nevertheless, these results should be interpreted cautiously as further prospective studies are needed to validate these findings and assess pregnancy rates.
      In conclusion, the CC-SS protocol provides another treatment option in PCOS patients who are not responsive to the initial treatment dose. The previously effective ovulatory dose in the CC-SS protocol is effective in most patients although 25% of patients may not respond. Nevertheless, most patients who fail to ovulate with the previously effective CC dose will still ovulate after an incremental increase in CC dose.

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