Arch Gynecol Obstet DOI 10.1007/s00404-014-3398-y
GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE
Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial Canan Dura Deveci • Berfu Demir • Ozlem Sengul • Berna Dilbaz • Umit Goktolga
Received: 8 April 2014 / Accepted: 22 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To evaluate the efficacy of the stair-step protocol using clomiphene citrate (CC) and to assess the uterine and systemic side effects in patients with polycystic ovary syndrome (PCOS). Methods A total of 60 PCOS patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle were randomly allocated to the control (traditional protocol) and study (stair-step protocol) groups. In the stair-step protocol,patients were treated with CC 50 mg/day for 5 days and then in nonresponsive patients, the dosage was increased to 100 mg/day for 5 days in the same cycle. Patients who failed the 50 mg/day CC treatment in the previous cycle were stimulated with 100 mg/ day CC and were accepted as the control group. Ovulation and pregnancy rates, duration of treatment and uterine and systemic side effects were evaluated. Results Ovulation and pregnancy rates were similar between the stair-step and the control group (43.3 vs. 33.3 %, respectively) (16.7 vs. 10 %, respectively). The duration of treatment was significantly shorter in stair-step compared to traditional protocol (20.5 ± 2.0 vs. 48.6 ± 2.4 days, respectively). There were no significant This study was presented as an oral presentation at the American Society of Reproductive Medicine 67th Annual Meeting, 2011. C. D. Deveci Ankara Training and Research Hospital, Ankara, Turkey B. Demir (&) O. Sengul B. Dilbaz Etlik Zubeyde Hanım Women’s Health Teaching and Research Hospital, Ankara, Turkey e-mail: [email protected] U. Goktolga Bahceci Fulya IVF Center, Istanbul, Turkey
differences in the systemic side effects between the groups. Uterine side effects were evaluated with endometrial thickness and uterine artery Doppler ultrasound; no significant differences were observed in stair-step compared to traditional protocol. Conclusions The stair-step protocol was determined to have a significantly shorter treatment period without any detrimental effect on the ovulation and pregnancy rates. Keywords Clomiphene citrate Stair-step protocol Traditional protocol Polycystic ovary syndrome
Introduction According to the Rotterdam criteria, polycystic ovary syndrome (PCOS) is characterized by two of the following three criteria: oligo-anovulation, ultrasonographically defined polycystic ovaries and clinical or biochemical signs of hyperandrogenism with the exclusion of other androgen excess disorders [1]. Chronic anovulation is one of the most common causes of infertility in women with PCOS. Oocyte quality or endometrial and implantation abnormalities also may contribute to the pathogenesis of infertility in PCOS [2]. Infertile anovulatory women who want to conceive are candidates for ovulation induction. Clomiphene citrate (CC) is the first drug of choice in the management of infertility in PCOS [3]. Although CC treatment is usually initiated indays 2–5 of menstruation, it may be initiated at any time in patients with oligo-amenorrhea. However, clinicians usually prefer to begin CC treatment following spontaneous or progesterone-induced menstruation in these patients. Generally 50 mg CC for 5 days is used in the first cycle. In cases of anovulation, CC dose is increased by 50 mg in the
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subsequent cycle. With this protocol, it has been reported that 52 % of patients ovulate with a CC dose of 50 mg/day, 22 % with 100 mg/day and 12 % with 150 mg/day [4, 5]. A meta-analysis has suggested that only 46 % will respond to 50 mg/day, a further 21 % will respond to 100 mg and another 8 % will ovulate with 150 mg/day [6]. Approximately 20 % of the patients are refractory to CC regimen [7]. Although the maximum dose of CC is 250 mg/day, clinicians prefer not to use doses above 150 mg/day and these patients are regarded as CC resistant [8]. A new protocol is the stair-step protocol in which the increasing daily CC dose is administered without intervening menses between the dosages. The important point is that ultrasonographic monitoring is required during the stimulation. The potential advantage of stair-step protocol is the lack of a waiting period until the next menstruation. Potentially adverse effects of the cumulative doses in the same cycle on the endometrium and on systemic side effects may be disadvantages of stair-step protocol. The aim in this study was to evaluate the efficacy of the stairstep protocol in PCOS patients and to assess the uterine and systemic side effects of cumulative doses within a single cycle.
Materials and methods Sixty women diagnosed as PCOS according to the Rotterdam 2003 criteria were enrolled inthis prospective study. The exclusion criteria were confounding factors such as any other reasons for infertility such as tubal pathology, endocrinological disorders, previous gynecological operation, woman’s age C35 years’ old or male infertility. The demographic characteristics of the patients were obtained from the history and body mass indices (body weight (kg)/ body height (m))2 and day 3 serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactine and thyroid stimulating hormone (TSH) levels of the women were recorded. The study was carried in the infertility division of hospital between January 2010 and September 2010. The study was approved by the Ethics Board of the hospital. Informed consent was obtained from all the cases enrolled in the study. Computer-based randomization was applied using a block randomization scheme. Patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle were allocated to the control and study groups. In the stairstep protocol (n = 30), CC was administered at 50 mg daily for 5 days following the onset of a spontaneous or progestin-induced menses. Follicular response was monitored with transvaginal ultrasonography starting on day 8. When the mean diameter of the follicle size was below 11 mm on
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cycle day 14, the dosage was increased to 100 mg daily for 5 days. Then on cycle day 19, the evaluation by transvaginal ultrasonography was restarted. When the mean diameter of the leading follicle reached 17 mm, human chorionic gonadotrophin (hCG) was administered. Intrauterine insemination (IUI) was performed at 36 h after the hCG administration. When no follicular response was observed on cycle day 23, the cycle was cancelled. The daily dosage of CC was not increased to 150 mg daily because of the potentially adverse effects of the cumulative doses. In the control group (n = 30), CC was administered 100 mg daily for 5 days after the onset of a progestin-induced menstruation. Follicular response was monitored with transvaginal ultrasonography starting with day 8. When the mean diameter of leading follicle reached 17 mm, hCG was administered. IUI was performed at 36 h after the hCG administration. When no follicular response was observed on cycle day 20, the cycle was cancelled (Fig. 1). The duration of stimulation was calculated only in patients undergoing IUI and in the control group; this period was calculated from the beginning of the first treatment cycle. Serum progesterone and hCG were measured 7 and 14 days after the IUI, respectively. Ovulation was defined as a serum progesterone level greater than 10 ng/ml. Uterine side effects of the CC were evaluated with the measurements of the endometrial thickness and uterine artery Doppler ultrasonography. The measurement of Doppler ultrasound was performed between 8 and 12 am to exclude the effect of circadian rhythm on blood flow [9]. In the study protocol, the first uterine artery Doppler ultrasound was performed on the day of CC increment and on the first day of CC in the control group. The second examination was performed on the day of IUI both groups. The amounts of change on the pulsatility index and resistivity index were calculated in each group then compared. Systemic side effects were evaluated with a questionnaire. It was composed of six scales including hot flushes, mood disturbance, pelvic pressure, nausea, pelvic pain, and breast tenderness. Each parameter was evaluated as none, mild, moderate, and severe. The aim of this study was to evaluate the efficacy of the stair-step protocol using CC and to assess the uterine and systemic side effects in patients with PCOS. If the primary outcome was accepted as pregnancy rate, 10 % difference with 80 % power was required 401 sample size. A multicenter based study would be required for the collection of such large sample size. Therefore, the sample size of this prospective study failed the required power. The statistical analyses were performed using the Statistical Package for Social Sciences, version 18 (SPSS Inc., Chicago, IL, USA). Distribution of continuous variables was tested by using the Kolmogorow–Smirnov test.
Arch Gynecol Obstet Fig. 1 Consort diagram of the selection and treatment of the patients
Women who were diagnosed as PCOS according to the Rotterdam 2003 criteria who failed to respond to 50 mg/day for 5 days of CC treatment were enrolled to study (n=68) Patients who have any reasons for infertility except as oligo-anovulation like -tubal pathology, -endocrinological disorders, -previous gynecological operation, -women’s age ≥35 years’ old, -male infertility, were excluded the study (n=8). A total of 60 patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle ( If follicle size was below 11 mm on cycle day 14) were randomly allocated to the control (traditional protocol) and study (stair-step protocol) groups.
Stair-step protocol (n=30) the dosage was increased to 100 mg daily for 5 days.
Traditional protocol (n=30) CC was administered 100 mg daily for 5 days after the onset of a progestin-induced menstruation.
On cycle day 19, the evaluation by transvaginal ultrasonography was restarted.
Ultrasonographic monitorization was started with day 8.
Mean diameter of the leading follicle was reached 17 mm, hCG was administered. Intrauterine insemination was performed at 36 hours after the hCG administration. No follicular response was observed on cycle day 23, the cycle was cancelled.
Student’s t test was used for variables with normal distribution. After testing the skewed distribution, comparisons between the groups were tested using the Mann–Whitney U test. The Chi-square test and Fisher’s exact test were used to analyze nominal variables. Continuous variables were expressed as mean ± standard deviation. A value of p \ 0.05 was accepted as statistically significant.
No follicular response was observed on cycle day 20, the cycle was cancelled.
Table 1 The demographic characteristics of the groups Stair-step gr. (n = 30)
Control gr. (n = 30)
p value
Age (years)
23.1 ± 3.7
24.9 ± 3.5
0.86
The duration of infertility (months)
22.4 ± 11.7
28.2 ± 19.7
0.17
BMI (kg/m2)
25.2 ± 3.6
27.1 ± 4.0
0.06
5.5 ± 1.2
5.7 ± 1.2
0.51
Day 3 FSH (IU/l)
Results The demographical characteristics of the groups were comparable (Table 1). The duration of ovulation hyperstimulation was significantly shorter in the stair-step group compared with the control group (p = 0.0001). There was a trend for a higher ovulation rate and clinical pregnancy rate in the stair-step protocol group compared to the traditional protocol group, although this difference did not reach statistical significance (Table 2).
Day 3 LH (IU/l)
10.7 ± 4.6
9.7 ± 4.6
0.38
Day 3 E2 (pg/ml) Day 3 TSH (mIU/ml)
47.3 ± 11.9 1.9 ± 1.0
43.7 ± 11.4 2.1 ± 0.9
0.23 0.58
Day 3 PRL (ng/ml)
12.8 ± 6.8
11.9 ± 6.8
0.61
There was no statistically significant difference between the stair-step and control groups in endometrial thickness (8.3 ± 2.1 vs. 9.3 ± 2.4 mm, respectively) on the day of hCG. The changes in uterine artery pulsatility index and resistivity index were similar between the groups (Table 3).
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The distribution of the systemic side effects according to the severity of the symptoms was similar between the groups. Although there were no statistically significant differences between the two groups in systemic adverse effects, rates of hot flushes, pelvic pressure, pelvic pain and breast tenderness were slightly higher in the stair-step group (Table 4).
Discussion The present study demonstrated that ovarian hyperstimulation using the stair-step protocol revealed shorter time period to reach to ovulation and/or decision resistance to CC without any detrimental effect on the ovulation and Table 2 The stimulation results of the groups Stair-step gr. (n = 30)
Control gr. (n = 30)
p value
Duration of treatment (days)
20.5 – 2.0
48.6 – 2.4
0.0001*
Ovulation rate/cycle (%)
43.3
33.3
0.64
Cycle cancellation rate (%)
50
56.6
0.79
Clinical pregnancy rate/ cycle (%)
16.7
10
0.69
*p \ 0.05 Table 3 The endometrial thickness and Doppler ultrasound results of the groups Stair-step (n = 30) Endometrial thickness on hCG day (mm) The change in uterine artery PI The change in uterine artery RI
Control (n = 30)
p value
8.3 ± 2.1
9.3 ± 2.4
0.24
0.71 ± 0.61
0.58 ± 0.69
0.39
0.08 ± 0.09
0.11 ± 0.11
0.20
PI pulsatility index, RI resistivity index
pregnancy rates. The dose increment in the same treatment period did not reveal any additional side effects. In a retrospective study by Hurst et al. of 31 women with PCOS, 50 mg/day CC was given for 5 days and ultrasonographic evaluation was performed on days 11–14. In non-responsive patients, 100 mg/day CC was initiated for 5 days and ultrasonography was repeated 1 week later. If the patient was still non-responsive, 150 mg/day CC was administered for 5 days and ultrasonography was applied again 1 week after later. There was no control group in this study. Comparisons were made using the CC outcome results of published studies. The time to ovulation by the stair-step protocol was 32–53 days less compared to the traditional regimen. The dose-dependent ovulation rate was significantly higher in the stair-step protocol with 100 mg CC compared to the traditional protocol (64 vs. 22 %, respectively). The clinical pregnancy rates were similar between the stair-step and traditional protocol groups (13 vs. 15 %, respectively) [10]. It has been reported that 12–23 % of patients on infertility treatment have anxiety disorder and 12–54 % of them have depression [11–13]. Women with PCOS already have oligomenorrhea and the longer period of treatment related to CC resistance may contribute to their anxiety. Regarding ovulation induction using CC, it can be initiated at any time in anovulatory women with PCOS. There is no need to induce or wait for spontaneous menstruation for the initiation of CC treatment. The additional advantage of the stair-step protocol is that there is no need to wait for dose increment in nonresponsive patients. The major anti-estrogenic effect of CC treatment is on the endometrium and CC may interfere with the estrogen stimulated proliferation of endometrium. The anti-estrogenic effect of CC inhibits normal cyclical growth of the uterus and endometrium and endometrial thickness is altered in CC cycles [14–16]. The risk of negative effects on the endometrium may increase when the dose of CC is increased. Kurosawa et al. reported that CC acted as an antagonist at such a high concentration via ERa and ERb, hence the antagonistic activity of CC was stronger in ERb
Table 4 The distribution of side effects of the groups Stair-step (n = 30) None
Mild
Control (n = 30) Moderate
Severe
None
Mild
p value Moderate
Severe
Hot flushes, n (%)
21 (70)
9 (30)
0 (0)
0 (0)
26 (86.7)
3 (10)
0 (0)
1 (3.3)
0.55
Mood disturbances, n (%)
29 (96.7)
0 (0)
1 (3.3)
0 (0)
29 (96.7)
0 (0)
1 (3.3)
0 (0)
1.00
Pelvic pressure, n (%)
29 (96.7)
1 (3.3)
0 (0)
0 (0)
30 (100)
0 (0)
0 (0)
0 (0)
1.00
Nausea, n (%)
25 (83.3)
5 (16.7)
0 (0)
0 (0)
25 (83.3)
5 (16.7)
0 (0)
0 (0)
1.00
Pelvic pain, n (%) Breast tenderness, n (%)
26 (86.7) 21 (70)
4 (13.3) 6 (20)
0 (0) 3 (0)
0 (0) 0 (0)
27 (90) 22 (73.3)
3 (10) 8 (26.7)
0 (0) 0 (0)
0 (0) 0 (0)
1.00 0.19
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than ERa. CC related antagonistic activity on the endometrium was dose dependent and was affected by the presence of estrogen. One possible explanation for the low pregnancy rate compared to the high ovulation rate resulting from the use of CC is that CC inhibits progesterone action in the endometrium by an antagonistic effect via ERb [17]. However, Homburg [18] reported that suppression of endometrial proliferation using CC was unrelated to dose or duration of treatment but apparently idiosyncratic. Nakai et al. suggested that uterine artery blood flow increased from the follicular phase to ovulation in spontaneous cycles but this increase in blood flow in the uterine artery in the peri-ovulational period could not be detected in CC induced cycles. This may be a result of the depletion of endometrial receptors that are responsible for the endometrial changes due to CC treatment [19]. Endometrial receptivity is difficult to evaluate by noninvasive methods. Endometrial thickness measured by ultrasonography is an indirect marker of endometrial receptivity. It has been reported that endometrial thickness should be at least 5–6 mm for implantation [20, 21]. Shahin et al. [22] suggested that endometrial thickness in the range 5.5–8.25 mm and triple line pattern is highly predictive for pregnancy. Therefore, the potential side effects on the endometrium related to the cumulative doses of CC in the stair-step protocol were evaluated on ultrasound. No significant adverse effects were observed on the endometrial thickness in the stair-step protocol. Another important point is that the systemic side effects of CC use may increase in the stair-step protocol. Since CC causes a central misperception of low estrogen levels, natural vasomotor symptoms may be observed [23]. Mood disturbances are the most commonly observed side effect related to CC (64–78 %) [24, 25]. Transient hot flushes occur in 10 % of women [23, 24]. Visual disturbances are rare (1–2 %) and, breast tenderness, pelvic discomfort and nausea have been reported at on overall rate of 2–5 % inCC treated patients [26, 27]. In the results of the current study, there was a tendency for a higher rate of hot flushes, pelvic pressure, pelvic pain and breast tenderness in the stair-step protocol. However, these side effects did not reach statistical significance. The first limitation of this study was the evaluation of the cumulative CC doses up to 100 mg/day in the same cycle. Dosage of 150 mg/day was not given to the patients in the same cycle as the total dose of CC was limited to 750 mg/cycle in accordance with the US Food and Drug Administration (FDA) recommendations [28]. The second limitation was the small sample size of the study. Therefore, the presented study is accepted as a pilot study. A multicentre study is needed to provide required sample size for power. In conclusion, the stair-step protocol revealed a significantly shorter treatment period without
any detrimental effect on the ovulation and the pregnancy rates and without any increase in side effects in patients with polycystic ovary syndrome. The advantage of the shorter treatment period with similar side effects makes the stair-step protocol suitablefor use in routine clinical practice. Conflict of interest no funding support.
The authors declare no conflict of interests and
References 1. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group (2004) Revised 2003 consessus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19:41–47 2. Legro RS (2007) Pregnancy considerations in women with polycystic ovary syndrome. Clin Obstet Gynecol 50:295–304 3. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2008) Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 89:505–522 4. Gysler M, March CM, Mishell DR Jr, Bailey EJ (1982) A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 37:161–167 5. Gorlitsky GA, Kase NG, Speroff L (1978) Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 51:265–269 6. Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger WL (2004) Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Fertil Steril 81:1187–1193 7. Imani B, Eijkemans MJ, Faessen GH, Bouchard P, Giudice LC, Fauser BC (2002) Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency. Fertil Steril 77:83–90 8. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin (2002) Clinical management guidelines for obstetrician gynecologists number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists, Obstet Gynecol 99:347–358 9. Zaidi J, Jurkovic D, Campbell S, Pittrof R, McGregor A, Tan SL (1995) Description of circadian rhythm in uterine artery blood flow during the peri-ovulatory period. Hum Reprod 10:1642–1646 10. Hurst BS, Hickman JM, Matthews ML, Usadi RS, Marshburn PB (2009) Novel clomiphene ‘‘stair-step’’ protocol reduces time to ovulation citrate in women with polycystic ovarian syndrome. Am J Obstet Gynecol 200(5):510.e1–510.e4 11. Newton CR, Hearn MT, Yuzpe AA (1990) Psychological assessment and follow-up after in vitro fertilization: assessing the impact of failure. Fertil Steril 54(5):879–886 12. Chen TH, Chang SP, Tsai CF, Juang KD (2004) Prevalence of depressive and anxiety disorders in an assisted reproductive technique clinic. Hum Reprod 19(10):2313–2318 13. Volgsten H, Skoog Svanberg A, Ekselius L, Lundkvist O, Sundstro¨m Poromaa I (2008) Prevalence of psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment. Hum Reprod 23(9):2056–2063 14. Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME (1989) The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 73(2):187–190
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Arch Gynecol Obstet 15. Randall JM, Templeton A (1991) Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 56(2):208–212 16. Haritha S, Rajagopalan G (2003) Follicular growth, endometrial thickness, and serum estradiol levels in spontaneous and clomiphene citrate-induced cycles. Int J Gynaecol Obstet 81(3):287– 292 17. Kurosawa T, Hiroi H, Momoeda M, Inoue S, Taketani Y (2010) Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta. Endocr J 57(6):517–521 18. Homburg R (2005) Clomiphene citrate–end of an era? A minireview. Hum Reprod 20(8):2043–2051 19. Nakai A, Yokota A, Koshino T, Araki T (2002) Assessment of endometrial perfusion with Doppler ultrasound in spontaneous and stimulated menstrual cycles. J Nippon Med Sch 69(4):328– 332 20. Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM (1993) Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin. Fertil Steril 59:756–760 21. Piver P (2005) Uterine factors limiting ART coverage. J Gynecol Obstet Biol Reprod 34:30–33
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22. Shahin AY (2008) Endometrial sonographic characters predicting pregnancy following recurrent clomiphene induction in unexplained infertility. Reprod Biomed Online 17(6):795–802 23. Fritz MA, Speroff L (2011) Clinical gynecologic endocrinology and infertility, 8th edn. Lippincott Williams & Wilkins, Philadelphia 24. Blenner JL (1991) Clomiphene-induced mood swings. J Obstet Gynecol Neonatal Nurs 20:321–327 25. Choi SH, Shapiro H, Robinson GE, Irvine J, Neuman J, Rosen B et al (2005) Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin. J Psychosom Obstet Gynaecol 26:93–100 26. Purvin VA (1995) Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 113:482–484 27. The Practice Committee of the American Society for Reproductive Medicine (2013) Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 100(2):341–348 28. US Food and Drug Administration. Available at http://www. accessdata.fda.gov/
GYNECOLOGIC ENDOCRINOLOGY AND REPRODUCTIVE MEDICINE
Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial Canan Dura Deveci • Berfu Demir • Ozlem Sengul • Berna Dilbaz • Umit Goktolga
Received: 8 April 2014 / Accepted: 22 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To evaluate the efficacy of the stair-step protocol using clomiphene citrate (CC) and to assess the uterine and systemic side effects in patients with polycystic ovary syndrome (PCOS). Methods A total of 60 PCOS patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle were randomly allocated to the control (traditional protocol) and study (stair-step protocol) groups. In the stair-step protocol,patients were treated with CC 50 mg/day for 5 days and then in nonresponsive patients, the dosage was increased to 100 mg/day for 5 days in the same cycle. Patients who failed the 50 mg/day CC treatment in the previous cycle were stimulated with 100 mg/ day CC and were accepted as the control group. Ovulation and pregnancy rates, duration of treatment and uterine and systemic side effects were evaluated. Results Ovulation and pregnancy rates were similar between the stair-step and the control group (43.3 vs. 33.3 %, respectively) (16.7 vs. 10 %, respectively). The duration of treatment was significantly shorter in stair-step compared to traditional protocol (20.5 ± 2.0 vs. 48.6 ± 2.4 days, respectively). There were no significant This study was presented as an oral presentation at the American Society of Reproductive Medicine 67th Annual Meeting, 2011. C. D. Deveci Ankara Training and Research Hospital, Ankara, Turkey B. Demir (&) O. Sengul B. Dilbaz Etlik Zubeyde Hanım Women’s Health Teaching and Research Hospital, Ankara, Turkey e-mail: [email protected] U. Goktolga Bahceci Fulya IVF Center, Istanbul, Turkey
differences in the systemic side effects between the groups. Uterine side effects were evaluated with endometrial thickness and uterine artery Doppler ultrasound; no significant differences were observed in stair-step compared to traditional protocol. Conclusions The stair-step protocol was determined to have a significantly shorter treatment period without any detrimental effect on the ovulation and pregnancy rates. Keywords Clomiphene citrate Stair-step protocol Traditional protocol Polycystic ovary syndrome
Introduction According to the Rotterdam criteria, polycystic ovary syndrome (PCOS) is characterized by two of the following three criteria: oligo-anovulation, ultrasonographically defined polycystic ovaries and clinical or biochemical signs of hyperandrogenism with the exclusion of other androgen excess disorders [1]. Chronic anovulation is one of the most common causes of infertility in women with PCOS. Oocyte quality or endometrial and implantation abnormalities also may contribute to the pathogenesis of infertility in PCOS [2]. Infertile anovulatory women who want to conceive are candidates for ovulation induction. Clomiphene citrate (CC) is the first drug of choice in the management of infertility in PCOS [3]. Although CC treatment is usually initiated indays 2–5 of menstruation, it may be initiated at any time in patients with oligo-amenorrhea. However, clinicians usually prefer to begin CC treatment following spontaneous or progesterone-induced menstruation in these patients. Generally 50 mg CC for 5 days is used in the first cycle. In cases of anovulation, CC dose is increased by 50 mg in the
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subsequent cycle. With this protocol, it has been reported that 52 % of patients ovulate with a CC dose of 50 mg/day, 22 % with 100 mg/day and 12 % with 150 mg/day [4, 5]. A meta-analysis has suggested that only 46 % will respond to 50 mg/day, a further 21 % will respond to 100 mg and another 8 % will ovulate with 150 mg/day [6]. Approximately 20 % of the patients are refractory to CC regimen [7]. Although the maximum dose of CC is 250 mg/day, clinicians prefer not to use doses above 150 mg/day and these patients are regarded as CC resistant [8]. A new protocol is the stair-step protocol in which the increasing daily CC dose is administered without intervening menses between the dosages. The important point is that ultrasonographic monitoring is required during the stimulation. The potential advantage of stair-step protocol is the lack of a waiting period until the next menstruation. Potentially adverse effects of the cumulative doses in the same cycle on the endometrium and on systemic side effects may be disadvantages of stair-step protocol. The aim in this study was to evaluate the efficacy of the stairstep protocol in PCOS patients and to assess the uterine and systemic side effects of cumulative doses within a single cycle.
Materials and methods Sixty women diagnosed as PCOS according to the Rotterdam 2003 criteria were enrolled inthis prospective study. The exclusion criteria were confounding factors such as any other reasons for infertility such as tubal pathology, endocrinological disorders, previous gynecological operation, woman’s age C35 years’ old or male infertility. The demographic characteristics of the patients were obtained from the history and body mass indices (body weight (kg)/ body height (m))2 and day 3 serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactine and thyroid stimulating hormone (TSH) levels of the women were recorded. The study was carried in the infertility division of hospital between January 2010 and September 2010. The study was approved by the Ethics Board of the hospital. Informed consent was obtained from all the cases enrolled in the study. Computer-based randomization was applied using a block randomization scheme. Patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle were allocated to the control and study groups. In the stairstep protocol (n = 30), CC was administered at 50 mg daily for 5 days following the onset of a spontaneous or progestin-induced menses. Follicular response was monitored with transvaginal ultrasonography starting on day 8. When the mean diameter of the follicle size was below 11 mm on
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cycle day 14, the dosage was increased to 100 mg daily for 5 days. Then on cycle day 19, the evaluation by transvaginal ultrasonography was restarted. When the mean diameter of the leading follicle reached 17 mm, human chorionic gonadotrophin (hCG) was administered. Intrauterine insemination (IUI) was performed at 36 h after the hCG administration. When no follicular response was observed on cycle day 23, the cycle was cancelled. The daily dosage of CC was not increased to 150 mg daily because of the potentially adverse effects of the cumulative doses. In the control group (n = 30), CC was administered 100 mg daily for 5 days after the onset of a progestin-induced menstruation. Follicular response was monitored with transvaginal ultrasonography starting with day 8. When the mean diameter of leading follicle reached 17 mm, hCG was administered. IUI was performed at 36 h after the hCG administration. When no follicular response was observed on cycle day 20, the cycle was cancelled (Fig. 1). The duration of stimulation was calculated only in patients undergoing IUI and in the control group; this period was calculated from the beginning of the first treatment cycle. Serum progesterone and hCG were measured 7 and 14 days after the IUI, respectively. Ovulation was defined as a serum progesterone level greater than 10 ng/ml. Uterine side effects of the CC were evaluated with the measurements of the endometrial thickness and uterine artery Doppler ultrasonography. The measurement of Doppler ultrasound was performed between 8 and 12 am to exclude the effect of circadian rhythm on blood flow [9]. In the study protocol, the first uterine artery Doppler ultrasound was performed on the day of CC increment and on the first day of CC in the control group. The second examination was performed on the day of IUI both groups. The amounts of change on the pulsatility index and resistivity index were calculated in each group then compared. Systemic side effects were evaluated with a questionnaire. It was composed of six scales including hot flushes, mood disturbance, pelvic pressure, nausea, pelvic pain, and breast tenderness. Each parameter was evaluated as none, mild, moderate, and severe. The aim of this study was to evaluate the efficacy of the stair-step protocol using CC and to assess the uterine and systemic side effects in patients with PCOS. If the primary outcome was accepted as pregnancy rate, 10 % difference with 80 % power was required 401 sample size. A multicenter based study would be required for the collection of such large sample size. Therefore, the sample size of this prospective study failed the required power. The statistical analyses were performed using the Statistical Package for Social Sciences, version 18 (SPSS Inc., Chicago, IL, USA). Distribution of continuous variables was tested by using the Kolmogorow–Smirnov test.
Arch Gynecol Obstet Fig. 1 Consort diagram of the selection and treatment of the patients
Women who were diagnosed as PCOS according to the Rotterdam 2003 criteria who failed to respond to 50 mg/day for 5 days of CC treatment were enrolled to study (n=68) Patients who have any reasons for infertility except as oligo-anovulation like -tubal pathology, -endocrinological disorders, -previous gynecological operation, -women’s age ≥35 years’ old, -male infertility, were excluded the study (n=8). A total of 60 patients who failed to respond to 50 mg/day for 5 days of CC treatment within the cycle ( If follicle size was below 11 mm on cycle day 14) were randomly allocated to the control (traditional protocol) and study (stair-step protocol) groups.
Stair-step protocol (n=30) the dosage was increased to 100 mg daily for 5 days.
Traditional protocol (n=30) CC was administered 100 mg daily for 5 days after the onset of a progestin-induced menstruation.
On cycle day 19, the evaluation by transvaginal ultrasonography was restarted.
Ultrasonographic monitorization was started with day 8.
Mean diameter of the leading follicle was reached 17 mm, hCG was administered. Intrauterine insemination was performed at 36 hours after the hCG administration. No follicular response was observed on cycle day 23, the cycle was cancelled.
Student’s t test was used for variables with normal distribution. After testing the skewed distribution, comparisons between the groups were tested using the Mann–Whitney U test. The Chi-square test and Fisher’s exact test were used to analyze nominal variables. Continuous variables were expressed as mean ± standard deviation. A value of p \ 0.05 was accepted as statistically significant.
No follicular response was observed on cycle day 20, the cycle was cancelled.
Table 1 The demographic characteristics of the groups Stair-step gr. (n = 30)
Control gr. (n = 30)
p value
Age (years)
23.1 ± 3.7
24.9 ± 3.5
0.86
The duration of infertility (months)
22.4 ± 11.7
28.2 ± 19.7
0.17
BMI (kg/m2)
25.2 ± 3.6
27.1 ± 4.0
0.06
5.5 ± 1.2
5.7 ± 1.2
0.51
Day 3 FSH (IU/l)
Results The demographical characteristics of the groups were comparable (Table 1). The duration of ovulation hyperstimulation was significantly shorter in the stair-step group compared with the control group (p = 0.0001). There was a trend for a higher ovulation rate and clinical pregnancy rate in the stair-step protocol group compared to the traditional protocol group, although this difference did not reach statistical significance (Table 2).
Day 3 LH (IU/l)
10.7 ± 4.6
9.7 ± 4.6
0.38
Day 3 E2 (pg/ml) Day 3 TSH (mIU/ml)
47.3 ± 11.9 1.9 ± 1.0
43.7 ± 11.4 2.1 ± 0.9
0.23 0.58
Day 3 PRL (ng/ml)
12.8 ± 6.8
11.9 ± 6.8
0.61
There was no statistically significant difference between the stair-step and control groups in endometrial thickness (8.3 ± 2.1 vs. 9.3 ± 2.4 mm, respectively) on the day of hCG. The changes in uterine artery pulsatility index and resistivity index were similar between the groups (Table 3).
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The distribution of the systemic side effects according to the severity of the symptoms was similar between the groups. Although there were no statistically significant differences between the two groups in systemic adverse effects, rates of hot flushes, pelvic pressure, pelvic pain and breast tenderness were slightly higher in the stair-step group (Table 4).
Discussion The present study demonstrated that ovarian hyperstimulation using the stair-step protocol revealed shorter time period to reach to ovulation and/or decision resistance to CC without any detrimental effect on the ovulation and Table 2 The stimulation results of the groups Stair-step gr. (n = 30)
Control gr. (n = 30)
p value
Duration of treatment (days)
20.5 – 2.0
48.6 – 2.4
0.0001*
Ovulation rate/cycle (%)
43.3
33.3
0.64
Cycle cancellation rate (%)
50
56.6
0.79
Clinical pregnancy rate/ cycle (%)
16.7
10
0.69
*p \ 0.05 Table 3 The endometrial thickness and Doppler ultrasound results of the groups Stair-step (n = 30) Endometrial thickness on hCG day (mm) The change in uterine artery PI The change in uterine artery RI
Control (n = 30)
p value
8.3 ± 2.1
9.3 ± 2.4
0.24
0.71 ± 0.61
0.58 ± 0.69
0.39
0.08 ± 0.09
0.11 ± 0.11
0.20
PI pulsatility index, RI resistivity index
pregnancy rates. The dose increment in the same treatment period did not reveal any additional side effects. In a retrospective study by Hurst et al. of 31 women with PCOS, 50 mg/day CC was given for 5 days and ultrasonographic evaluation was performed on days 11–14. In non-responsive patients, 100 mg/day CC was initiated for 5 days and ultrasonography was repeated 1 week later. If the patient was still non-responsive, 150 mg/day CC was administered for 5 days and ultrasonography was applied again 1 week after later. There was no control group in this study. Comparisons were made using the CC outcome results of published studies. The time to ovulation by the stair-step protocol was 32–53 days less compared to the traditional regimen. The dose-dependent ovulation rate was significantly higher in the stair-step protocol with 100 mg CC compared to the traditional protocol (64 vs. 22 %, respectively). The clinical pregnancy rates were similar between the stair-step and traditional protocol groups (13 vs. 15 %, respectively) [10]. It has been reported that 12–23 % of patients on infertility treatment have anxiety disorder and 12–54 % of them have depression [11–13]. Women with PCOS already have oligomenorrhea and the longer period of treatment related to CC resistance may contribute to their anxiety. Regarding ovulation induction using CC, it can be initiated at any time in anovulatory women with PCOS. There is no need to induce or wait for spontaneous menstruation for the initiation of CC treatment. The additional advantage of the stair-step protocol is that there is no need to wait for dose increment in nonresponsive patients. The major anti-estrogenic effect of CC treatment is on the endometrium and CC may interfere with the estrogen stimulated proliferation of endometrium. The anti-estrogenic effect of CC inhibits normal cyclical growth of the uterus and endometrium and endometrial thickness is altered in CC cycles [14–16]. The risk of negative effects on the endometrium may increase when the dose of CC is increased. Kurosawa et al. reported that CC acted as an antagonist at such a high concentration via ERa and ERb, hence the antagonistic activity of CC was stronger in ERb
Table 4 The distribution of side effects of the groups Stair-step (n = 30) None
Mild
Control (n = 30) Moderate
Severe
None
Mild
p value Moderate
Severe
Hot flushes, n (%)
21 (70)
9 (30)
0 (0)
0 (0)
26 (86.7)
3 (10)
0 (0)
1 (3.3)
0.55
Mood disturbances, n (%)
29 (96.7)
0 (0)
1 (3.3)
0 (0)
29 (96.7)
0 (0)
1 (3.3)
0 (0)
1.00
Pelvic pressure, n (%)
29 (96.7)
1 (3.3)
0 (0)
0 (0)
30 (100)
0 (0)
0 (0)
0 (0)
1.00
Nausea, n (%)
25 (83.3)
5 (16.7)
0 (0)
0 (0)
25 (83.3)
5 (16.7)
0 (0)
0 (0)
1.00
Pelvic pain, n (%) Breast tenderness, n (%)
26 (86.7) 21 (70)
4 (13.3) 6 (20)
0 (0) 3 (0)
0 (0) 0 (0)
27 (90) 22 (73.3)
3 (10) 8 (26.7)
0 (0) 0 (0)
0 (0) 0 (0)
1.00 0.19
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than ERa. CC related antagonistic activity on the endometrium was dose dependent and was affected by the presence of estrogen. One possible explanation for the low pregnancy rate compared to the high ovulation rate resulting from the use of CC is that CC inhibits progesterone action in the endometrium by an antagonistic effect via ERb [17]. However, Homburg [18] reported that suppression of endometrial proliferation using CC was unrelated to dose or duration of treatment but apparently idiosyncratic. Nakai et al. suggested that uterine artery blood flow increased from the follicular phase to ovulation in spontaneous cycles but this increase in blood flow in the uterine artery in the peri-ovulational period could not be detected in CC induced cycles. This may be a result of the depletion of endometrial receptors that are responsible for the endometrial changes due to CC treatment [19]. Endometrial receptivity is difficult to evaluate by noninvasive methods. Endometrial thickness measured by ultrasonography is an indirect marker of endometrial receptivity. It has been reported that endometrial thickness should be at least 5–6 mm for implantation [20, 21]. Shahin et al. [22] suggested that endometrial thickness in the range 5.5–8.25 mm and triple line pattern is highly predictive for pregnancy. Therefore, the potential side effects on the endometrium related to the cumulative doses of CC in the stair-step protocol were evaluated on ultrasound. No significant adverse effects were observed on the endometrial thickness in the stair-step protocol. Another important point is that the systemic side effects of CC use may increase in the stair-step protocol. Since CC causes a central misperception of low estrogen levels, natural vasomotor symptoms may be observed [23]. Mood disturbances are the most commonly observed side effect related to CC (64–78 %) [24, 25]. Transient hot flushes occur in 10 % of women [23, 24]. Visual disturbances are rare (1–2 %) and, breast tenderness, pelvic discomfort and nausea have been reported at on overall rate of 2–5 % inCC treated patients [26, 27]. In the results of the current study, there was a tendency for a higher rate of hot flushes, pelvic pressure, pelvic pain and breast tenderness in the stair-step protocol. However, these side effects did not reach statistical significance. The first limitation of this study was the evaluation of the cumulative CC doses up to 100 mg/day in the same cycle. Dosage of 150 mg/day was not given to the patients in the same cycle as the total dose of CC was limited to 750 mg/cycle in accordance with the US Food and Drug Administration (FDA) recommendations [28]. The second limitation was the small sample size of the study. Therefore, the presented study is accepted as a pilot study. A multicentre study is needed to provide required sample size for power. In conclusion, the stair-step protocol revealed a significantly shorter treatment period without
any detrimental effect on the ovulation and the pregnancy rates and without any increase in side effects in patients with polycystic ovary syndrome. The advantage of the shorter treatment period with similar side effects makes the stair-step protocol suitablefor use in routine clinical practice. Conflict of interest no funding support.
The authors declare no conflict of interests and
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