JBRA Assisted Reproduction 2022;26(4):599-605 doi: 10.5935/1518-0557.20210112 Original Article The step-up protocol increases clinical pregnancy rates compared with the step-down in patients with unexplained infertility. A randomized controlled trial Ana Robles1, Sonia Gayete-Lafuente1, Maria Prat1, Mireia Gonzalez-Comadran1, Miguel Ángel Checa1 1 Reproductive Endocrinology Unit. Department of Obstetrics and Gynecology. Hospital del Mar de Barcelona. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain ABSTRACT The precise mechanisms of mono/oligofollicular devel- Objective: Unexplained infertility is a relevant opment goal for IUI are still unknown, making it difficult indication for controlled ovarian stimulation associated to to design safe pharmacological strategies. In this con- intrauterine insemination. The “step-up” and “step-down” text, two different controlled ovarian stimulation proto- gonadotropin-based protocols were designed to reduce cols, known as “step-up” and “step-down”, were designed multiple pregnancy and ovarian hyperstimulation syndrome to avoid multifollicular growth. Both protocols are based in polycystic ovary syndrome patients, but there is no on adapted sequential gonadotropin dosage changing to related evidence in normoovulatory women undergoing induce a more physiological ovulation, either by increas- intrauterine insemination. Our aim was to compare the ing doses in the step-up protocol or by decreasing them efficacy and safety of both protocols with intrauterine in the step-down. These regimens have been widely but insemination in unexplained infertility patients. heterogeneously evaluated in polycystic ovary syndrome Methods: Randomized clinical trial including 145 (PCOS) patients, with major risk of multifollicular growth women with unexplained infertility randomly following the because of their elevated ovarian reserve and particularly step-up (n=73) or step-down (n=72) protocol. In the step- extreme sensitivity to exogenous gonadotropins (Sagle et up group, patients started on day 3 of a spontaneous cycle al., 1991; Homburg et al., 1995; Kamrava et al., 1982; administrating recombinant FSH 75IU sc/day, increasing Seibel et al., 1984; Polson et al., 1987; Buvat et al., 1989; it to 150IU if no response after 7 days. In the step-down, Shoham et al., 1991; Dale et al., 1993; van Santbrink et patients started administrating 150IU sc/day, constantly al., 1995; White et al., 1996). Although both protocols decreasing it to 75IU after 5 days. Recombinant hCG was have shown to be successful in reducing the number of administered when a follicle reached ≥18mm diameter. growing follicles versus other strategies, the authors found Results: Clinical pregnancy rate was higher in the step- conflicting results when comparing their efficacy on time to up group than in the step-down (20.5% vs. 8.3%; p=0.037). follicular recruitment, hormone concentrations, and result- Significant differences between step-up and step-down ing pregnancy rates (Mizunuma et al., 1991; van Santbrink protocols were found regarding days of rFSH administration & Fauser, 1997; Andoh et al., 1998; Balasch et al., 2001; (8.83±4.01% vs. 7.42±2.18%; p=0.001) and cancellation rate Christin-Maitre & Hugues, 2003). Moreover, their potential due to hyper response (8.21% vs. 25%; p=0.05). No differences benefits have not been evaluated in non-PCOS patients, were detected in miscarriage rates, multiple pregnancy rates/ who represent the leading cause of IUI performance. cycle and hyper stimulation syndrome incidence. As decreasing multifollicular growth may reduce the Conclusions: The step-up protocol is longer-lasting risk of multiple pregnancy and OHSS in all patients, test- but more effective obtaining pregnancies than the step- ing the step-up and step-down protocols in non-PCOS may down in patients with unexplained infertility undergoing contribute to diminish the adverse events related to IUI. intrauterine insemination. This effect could be explained In this study, our aim was to compare these protocols in by lower cancellation rates due to ovarian hyper response patients with unexplained infertility undergoing IUI. than the step-down protocol, with no differences in ovarian hyper stimulation syndrome incidence. MATERIALS AND METHODS Study design Keywords: ovarian stimulation, step-up protocol, step- This study is a prospective randomized parallel con- down protocol, intrauterine insemination, unexplained trolled clinical trial with 1:1 allocation performed at Hos- infertility pital del Mar, Barcelona, and designed to compare the efficacy and safety of two different gonadotropin-based ovarian stimulation protocols in unexplained infertile couples undergoing IUI. It was approved by the local INTRODUCTION Clinical Research Ethics Committee, and all patients Unexplained infertility is defined as the lack of a cause signed informed consent to take part in. No changes to for conceiving failure after standard infertility testing, methods were conducted after the trial commencement. and affects 30-50% of couples unable to conceive (Ray ClinicalTrials.gov Identifier: NCT01376999. et al., 2012). It includes idiopathic cases, usually treated by ovarian stimulation with gonadotropins associated with Participants intrauterine insemination (IUI) in order to increase preg- Eligible individuals were women aged 18-40 years old nancy likelihood by rising the number of eggs available for who had been diagnosed of unexplained infertility and fertilization up to 2-3 (Steures et al., 2006). Nevertheless, planning IUI, selected for enrolment between June 2011 these strategies increase the multifollicular development and February 2013 after an extended medical history re- risk, leading to higher incidence of multiple pregnancy and cord and baseline evaluation. In the first visit, patients ovarian hyper stimulation syndrome (OHSS) (Sagle et al., were explained the purpose, requisites and procedures of 1991; Homburg et al., 1995; Sociedad Española de Ferti- the study, and no invasive tests were indicated before ob- lidad, 2017). taining informed consents. Received July 16, 2021 599 Accepted February 20, 2022 Original Article 600 Unexplained infertility was defined as constant attempt ≥1 follicle reached ≥18 mm diameter, so a single dose of to become pregnant for 1 year before the initial fertility rhCG (Ovitrelle pen®) 250 µg sc was given. Cycles were evaluation, with no clear cause of conceiving failure after cancelled if ≥4 follicles of ≥14mm were observed. IUI was routine infertility study procedures in our unit. In all pa- performed 36 hours after rhCG administration, previous tients, tubal permeability was demonstrated by hystero- semen capacitating. In both groups luteal phase was sup- salpingography. Ovarian function was evaluated using a ported with progesterone (Utrogestan®) 200mg/24 hours basal serum determination of FSH, LH, estradiol (E2) and after IUI. prolactin; only patients with basal FSH <10mUI/ml and Figure 1 summarizes the study protocols. normal prolactin levels and were included. Moreover, ovar- ian reserve was evaluated with an antimullerian hormone Outcomes (AMH) determination, as well as seric inhibin B levels and The primary outcomes were clinical pregnancy rates; ultrasonographic antral follicles count (AFC). Women with defined according to the ART terminology (Zegers-Hoch- oligoamenorrhea or meeting the criteria for PCOS diagnose schild et al., 2009). Also multiple pregnancy rates, OHSS based on Rotterdam Criteria 2004 were excluded (Rotter- rates and miscarriage rates were registered. dam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Secondary outcomes were: duration of the completed Group, 2004). Uterine integrity was evaluated by vaginal ovarian stimulation for each protocol (days), total amount ultrasound. Cases of benign uterine pathologies and dys- of rFSH used (IU), number of growing follicles, diameter functional bleeding were excluded, as well as history of of growing follicles (mm), serum E2 levels achieved at day >3 previous cycles of IUI. Male factor was studied with at of rhCG (pg/ml), and hyper response rate leading to IUI least one seminogram evaluated according to WHO criteria cancellation in each group of patients. 2010; only patients with partners presenting >5 millions of motile sperm were included. Other exclusion criteria were Sample size <20/>30 body mass index (BMI), any chronic systemic Predefining an alfa and beta risk of 0.05 and 0.20, disease, and any positive serology to HIV, HVC/HVB or respectively, in a bilateral contrast, we calculated a sam- syphilis. ple size of 75 patients in each group to find statistically Interventions significant differences >20% in pregnancy rates between Step-up protocol group: Women received rFSH (Gonal groups. A total 10% follow-up loss was accepted. pen®) 75IU sc daily, starting on day 3 of a spontaneous cycle. Vaginal ultrasound was performed on day 7 of treat- Randomization ment, and the rFSH dose was increased to 150 IU if no Randomization was generated by computerization on response was observed. a web-based program, then automatically exported to an Step-down protocol group: Women started with rFSH excel program. (Gonal pen®) 150IU sc daily from day 3 of a spontaneous cycle. Vaginal ultrasound was performed on day 5 of treat- Statistical analysis of results ment, and the rFSH dose was decreased to 75 IU in all An unpaired Student´s t-test of variance was per- cases. formed when appropriate. For primary outcomes, we ap- In both protocols, from the respective first control vis- plied an intention-to-treat approach to get clinically rele- it, vaginal ultrasound was performed every 48 hours until vant findings for medical practice. Data were analyzed by Figure 1. Step-up and Step-down ovarian stimulation protocols. JBRA Assist. Reprod. | v.26 | no4 | Oct-Nov-Dec/ 2022 Step-up/step-down protocols in IVF. RCT - Robles, A. 601 SPSS software (18.0 version, Chicago, USA) assuming a The number of intermediate grown follicles (14-17mm statistically significant level of 5% (p<0.05). diameter at the time of hCG) did significantly differ be- tween the step-up and the step-down protocols (1.48±2.26 Cost analysis vs. 2.32±2.40; p=0.019). Moreover the cases of ovarian The financial costs of both stimulation protocols and hyper response were significantly higher with the step- the costs per pregnancy obtained in each group of patients down protocol than with the step-up (18 vs. 6), leading were calculated as follows: to a major cancellation rate (25% vs. 8.21%; p=0.005). -Cost of a stimulation protocol = (Cost of gonadotropins When comparing the patients undergoing IUI only, without x mean of the total sFSH used units) + €50 Ovitrelle as considering the cancelled cycles, we found no statistical trigger medication + €300 cost of seminal preparation and differences regarding clinical pregnancy rates between in-office insemination including cannula, speculum, etc. the step-up and the step-down group (22.4% vs. 11.1%; -Cost per pregnancy obtained = (Cost of the protocol / p=0.103). patient x nº of stimulated patients) / pregnancies achieved. No cases of severe OHSS were documented, although 1 patient suffered a mild case in the step-up group and 3 RESULTS patients in the step-down (1.23% vs. 4.16%; p=0.363). Those four cases had a favorable evolution and did not A total of 158 eligible patients with unexplained infertil- require medical intervention. All outcomes are presented ity were recruited. 79 were randomly allocated in the step- in Table 2. up group and 79 in the step-down. Finally, 73 cycles in the The step-up protocol financial cost was €682.31 per step-up group and 72 in the step-down were initiated and patient [(€0.38/ IU Gonal-F x 874.5 IU) + €50 Ovitrelle + analyzed. Flow chart is shown in Figure 2. €300 insemination]; while the step-down protocol cost was Basal characteristics of patients were comparable be- €675.47 per patient [(€0.38/ IU Gonal-F x 856.5 IU) + €50 tween groups, as reported in Table 1. Ovitrelle + €30]. We observed a significantly higher clinical pregnancy rate The financial cost per pregnancy obtained in the step- in the step-up group than in the step-down (20.5% vs. 8.3%; up group was €3.320.58 [(€682.31 x 73 patients) / 15 p=0.037). Twin pregnancies showed a non-significant ten- pregnancies achieved]; while the cost per pregnancy ob- dency to be higher in the step-down group than in step-up tained in the step-down was €8,105.64 [(€675.47 x 72 (16.7% vs. 6.7%; p=0.5). The miscarriage rate was similar patients) / 6 pregnancies achieved]. between both regimens (13.3% vs. 16.7%; p=1.0). Figure 2. Participant flow chart. JBRA Assist. Reprod. | v.26 | no4 | Oct-Nov-Dec/ 2022 Original Article 602 safer and resulted in more monofollicular cycles, others Table 1. Basal characteristics of 145 patients with unex- totally differ in their findings supporting the step-down plained infertility. Women were randomized for step-up or step-down protocol. strategy. There is also controversy about the treatment duration, rFSH needed and E2 levels achieved. The only Step-down Step-up authors also analyzing the related pregnancy rates, found (n=72) (n=73) no differences between the two protocols (Christin-Maitre (Mean ± SD*) (Mean ± SD) & Hugues, 2003). However, the important heterogene- ity in the design of these studies, including different kind Age (years) 34.69±3.87 34.73±3.81 and doses of administered gonadotropins, could induce to FSH (mIU/ml) 6.79±1.57 7.00±1.75 contradictory conclusions. Moreover, PCOS patients are at particular higher risk of multifollicular development, so of LH (mIU/ml) 6.20±2.21 6.63±2.15 multiple pregnancy and OHSS, than normoovulatory pa- Estradiol (pg/ml) 48.72±23.65 53.77±36.18 tients as the included in our study (Sagle et al., 1991; AMH (mcg/L) 3.32±3.20 2.54±2.59 Homburg et al., 1995). Although many patient-specific factors as age, AFC, Inhibin B (pg/ml) 87.78±101.16 68.61±49.58 high AMH levels, BMI and previous response to ovulation Right antral follicles 5.68±1.99 6.42±2.65 induction can influence the number of growing follicles per cycle (Checa et al., 2010; Jeon et al., 2013; Thijssen et al., Left antral follicles 6.32±3.09 6.48±3.21 2017; Speyer et al., 2013); these baseline characteristics *SD=standard deviation. were comparable between study groups in our trial. The pregnancy rates we obtained in the step-up group were superior than the reported for IUI in our media ac- Both compared protocols represent similar prices cording to the last Spanish national register (Sociedad Es- per patient, but the cost per pregnancy in the Step- pañola de Fertilidad, 2017), around 15.6% in women aged up group is 2.44 times lower. Therefore, we found that <40 years old and 9.9% in those >40. Contrarily, pregnan- the Step-up protocol is not only associated to a higher cy rates in the step-down group were lower than expected. clinical pregnancy rate in the study population (20.5% The higher cancellation rate in the step-down group might vs. 8.3%; p-value=0.037), but also remarkably cost-ef- have influenced the pregnancy rate difference reported, ficient. Given that the Step-down protocol relates with favoring the step-up protocol. This difference is not found a significantly lower clinical pregnancy rate, higher can- when comparing the cycles finally undergoing IUI only, cellation rate and much higher financial cost per preg- which sustains our rationale and represents a relevant nancy, we reinforce our recommendation of using the finding for clinical practice. Differences were neither found step-up protocol in patients with unexplained infertility in AMH levels and basal AFC between the patients with undergoing IUI. cancelled cycles due to hyper response and those who un- derwent IUI. In ovulatory women, starting the treatment DISCUSSION with higher rFSH doses initially recruits a major number of follicles explaining the greater multifollicular response This study found that the step-up protocol is more ef- in the step-down group, which does not seem to decrease fective achieving clinical pregnancy by IUI than the step- by diminishing rFSH later in the cycle (Tan et al., 2005). down in unexplained infertile couples, presenting a lower Similarly, increasing rFSH dose during the step-up protocol cancellation rate due to ovarian hyper response, and with- course does not seem to rectify an initial monofollicular out differences in the assessed adverse events. growth, thus not leading to hyper response (van Hooff et To date, there were no studies comparing the efficacy al., 1993; Hock et al., 1998; Khalaf et al., 2002). and safety of the step-up and the step-down protocols in The higher multifollicular developments in the step- this group of patients, but both regimens have been widely down group causing a 25% of cancellations are consistent studied in PCOS patients, mainly regarding follicular growth with some reports from studies on PCOS patients (Andoh outcomes (Mizunuma et al., 1991; van Santbrink & Faus- et al., 1998), differing from others (van Santbrink & Faus- er, 1997; Andoh et al., 1998; Balasch et al., 2001; Chris- er, 1997; Andoh et al., 1998; Balasch et al., 2001). Van tin-Maitre & Hugues, 2003; Hugues et al., 1996). While Santbrink & Fauser (1997) observed a higher monofollic- some authors reported that the step-up protocol seems ular development in PCOS clomiphene-resistant patients Table 2. Clinical results among de two study groups. Step-up (n=73) Step-down (n=72) p-value N (positives/total, %) N (positives/total, %) Clinical pregnancy 15 (20.5) 6 (8.3) 0.037 Twin pregnancy 1 (6.7) 1 (16.7) 0.5 Miscarriages 2 (13.3) 1 (16.7) 1.0 Treatment duration (days) 8.83±4.01 7.42±2.18 0.001 Total amount of rFSH (IU) 874.5±300.75 856.5±327 0.34 Intermediate follicles (14-17mm) 1.48±2.26 2.32±2.40 0.019 Estradiol at day of rhCG (pg/ml) 640.83±501.4 845.31±564.565 0.034 Hyper response. cancelled 7 (8.21) 18 (25) 0.005 OHSS 1 (1.37) 3 (4.17) 0.363 *N=total number. JBRA Assist. Reprod. | v.26 | no4 | Oct-Nov-Dec/ 2022 Step-up/step-down protocols in IVF. RCT - Robles, A. 603 following the step-down protocol compared with the ones examination. MP, MGC and MAC critically revised earlier following the step-up (88% vs. 56%; p=0.04). This could drafts of the article for important intellectual content; and be attributed to their basal anovulatory condition, better all authors gave final approval of the version to be sub- responding to higher initial doses followed by a more phys- mitted. iological decrease of rFSH than to a stepping up approach possibly leading them to a higher number of cancellations CONFLICT OF INTEREST (Koundouros, 2008). However, our study included normo- None ovulatory women only, with better chances of initial mono- follicular response to rFSH lower doses than some PCOS Corresponding author: (Sagle et al., 1991; Homburg et al., 1995). Also, our step- Miguel Ángel Checa up regimen resulted in a longer-lasting induction with com- Department of Obstetrics and Gynecology parable rFSH units required versus the step-down, similar- Hospital del Mar, ly to what other authors reported (van Santbrink & Fauser, Consorci Parc de Salut Mar 1997; Christin-Maitre & Hugues, 2003). Barcelona, Spain. We found no difference in multiple pregnancy rates be- E-mail: macheca@parcdesalutmar.cat tween groups, although the sample size of this study was not specifically calculated to detect so. In contrast, a trial involving 1682 ovarian stimulated IUI cycles reported a REFERENCES multiple pregnancy rate of 10.5%, associating the rate of Andoh K, Mizunuma H, Liu X, Kamijo T, Yamada K, Ibu- multiplets to the number of follicles >14mm diameter ob- ki Y. 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