Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome

Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal... Background: Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves. The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin- primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation (PPOS) protocol for infertile women with PCOS. Methods: A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d + CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics and the live birth rate. Result(s): The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P < 0.001) and harvested fewer oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P < 0.001). The study group showed a higher mid-follicular LH concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P < 0.05) but no endogenous LH surge. No between-group difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P > 0.05). The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P > 0.05). (Continued on next page) * Correspondence: yehongjuan7777@163.com; chenqj75@126.com; lihua-sun@163.com Centre of assisted reproduction, Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 2 of 8 (Continued from previous page) Conclusion(s): The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS. The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol for PCOS women. Keywords: Polycystic ovarian syndrome, Progestin-primed ovarian stimulation, Clomiphene citrate, In vitro fertilization, Freeze-only Background Methods Polycystic ovarian syndrome (PCOS) is an endocrine dis- Study setting and subjects order affecting 5–10% of reproductive-age women world- A retrospective cohort trial was conducted at the depart- wide [1]. Approximately 74% of women with PCOS seeks ment of assisted reproduction of the Ninth People’sHospital pregnancy assistance, including induced ovulation, in- of Shanghai Jiaotong University School of Medicine. This semination or in vitro fertilization (IVF) [2]. However, study was approval by the Ethics Committee (Institutional PCOS women undergoing IVF treatment typically pro- Review Board) of Shanghai Ninth People’sHospital. duce an increased number of oocytes, which are often The PCOS diagnosis criteria followed the Rotterdam of poor quality, leading to a lower fertilization rate and consensus. PCOS was diagnosed by the presence of a higher miscarriage rate [3]. They also face a higher menstrual disturbance combined with either hyperandro- risk of moderate/severe ovarian hyperstimulation syn- genism (hirsutism or hyperandrogenaemia) or polycystic drome (OHSS) [4, 5]. ovary on ultrasonography (defined as an ovary that con- Thanks to the progress of vitrification, oral progestin tained ≥12 antral follicles) and excluded other causes of has been successfully used to prevent premature LH surges hyperandrogenism (congenital adrenal hyperplasia, Cushing’s in women undergoing ovarian stimulation [6–8]. This syndrome, androgen-producing tumours) and ovulation progestin-primed ovarian stimulation (PPOS) yields a com- dysfunction (hyperprolactinaemia and thyroid dysfunc- parable pregnancy outcome, although it consumes a slightly tion). In addition, this study only included women no higher gonadotropin dosage than conventional short proto- more than 40 years of age and with baseline serum FSH cols [6]. PPOS is approved its efficacy and safety in the no more than 10 mIU/ml. Women with functional cysts population of low-ovarian-reserve, normal-ovarian-reserve on the ovaries or medical conditions that contraindicated and PCOS women [8–10], so PPOS in combination with a assisted reproductive technology and/or pregnancy were freeze-only policy shows good potential to compete with excluded. A total of 220 infertile women with PCOS from conventional protocols. The existing data from clinical trials April 2014 to November 2015 were included and classified often use the equal initiating doses of gonadotropin for into the study group (HMG + MPA + CC) and the control women with or without PCOS, but relevant data are lack- group (HMG + MPA). A flowchart of the study is shown ing about how to individualize the gonadotropin dose and in Fig. 1. regimen for PCOS women undergoing ovarian stimulation. Clomiphene citrate (CC) has been a first-line drug for Ovarian stimulation protocol ovulation induction for anovulatory infertility. Its advan- In the study group, a low dose of HMG (150 IU daily), tages include its oral route, low costs and easy access CC 50 mg and MPA 10 mg daily were started from cycle compared to gonadotropins [11, 12]. CC is also used in day 3 or after an episode of withdrawal bleeding. MPA GnRH antagonist protocols, and the combination of CC was used to prevent premature ovulation during the and GnRH antagonist is likely to reduce the risk of OHSS, ovarian stimulation. Follicle monitoring by transvaginal medication costs and gonadotropin duration compared to ultrasound and serum hormone measurements (FSH, those without CC, but it accompanies with an increased LH, E and progesterone) were performed 5 days later. risk of premature LH surges [13–15]. Limited data are HMG doses were then adjusted according to the ovarian available about the role of CC in PPOS for PCOS women response (range 150–300 IU daily). Oocyte maturation [16]. In this trial, we attempted to test the hypothesis that was triggered by triptorelin 0.1 mg (Decapeptyl, Ferring in women with PCOS, the milder stimulation of PPOS in Pharmaceuticals, Germany) and urinary human chori- combination with CC would provide an acceptable clinical onic gonadotropin (hCG 1000 IU, Lizhu Pharmaceutical outcome compared with standard PPOS protocol using Trading Co., China) when at least three follicles reached conventional initiating dose of gonadotropin. Our ultimate diameters of 18 mm or more. Cumulus oocyte com- aim was to optimize the PPOS protocol and make it more plexes were collected 36 h later. All follicles larger than patient-friendly. 10 mm in diameter were aspirated. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 3 of 8 Fig. 1 Study flowchart In the control group, HMG 225 IU and MPA 10 mg growth was monitored beginning on day 10. At times, a daily were initiated from cycle day 3 or after an episode low dose of HMG (75 IU/day) was used to stimulate fol- of withdrawal bleeding. Follicle monitor and hormone licle growth and endometrial lining. The timing of FET assay were performed 5 days later. HMG dose was then was performed 4 or 5 days later, after a spontaneous or adjusted according to the ovarian response, and MPA hCG-induced LH surge. Hormone replacement treat- dose was consistent up to the trigger day. The criteria of ment was recommended for patients with thin endomet- mature follicle and the trigger methods were the same as rium and patients in whom letrozole failed. Oral ethinyl above. oestradiol 75 mcg/day was administered from cycle day Fertilization was carried out in vitro after oocyte re- 3 onwards. Once the endometrial lining was > 8 mm trieval depending on the semen parameters and previ- thick, femoston (Solvay Pharmaceuticals B.V.) 8 mg/day ous fertilization situation. Embryos were examined for was started. The time of thawing and transfer was deter- the number or regularity of blastomeres and the degree mined on the third day after femoston administration of fragmentation. All top-quality cleavage-stage em- [17]. Each patient received no more than two embryos bryos (grade 1 and grade 2, 6-cell embryos and above) at one time. Once pregnancy was achieved, the luteal were frozen within three days after oocyte retrieval. support was continued until 10 weeks of gestation. The non-top-quality embryos were placed in further extended culture, and good-morphology blastocysts Hormone measurement were frozen. Cleavage-stage embryos and blastocysts Serum FSH, LH, E , and progesterone were measured were frozen by vitrification as described previously [17]. on menstrual cycle day 3, day 8–11 (after 5–7 days of stimulation), the trigger day and the day after trigger. Endometrium preparation and FET Hormone levels were determined with chemilumines- Endometrium preparation for FET was arranged on the cence (Abbott Biological B.V. Netherlands). The lower second cycle after oocyte retrieval. The first choice was limits of sensitivity were as follow: FSH 0.06 mIU/ml, using a letrozole-induced- ovulation cycle. Letrozole LH 0.09 mIU/ml, E 10 pg/ml and progesterone 0.1 ng/ml. 5 mg was administered for 5 days, and then, follicle The upper limit of E measurement was 5000 pg/ml. If 2 Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 4 of 8 serum E on thetrigger dayorthe day after was higher Table 1 The basic characteristics of PCOS women in this trial than the upper limit, it was recorded as 5000 pg/ml. Study group Control group (HMG + MPA + CC; (HMG + MPA; n = 110) n = 110) Outcome variables Age (y) 30.5 ± 3.7 30.6 ± 3.4 Theprimary measureanalysedwas the cumulativeongoing Duration of infertility (y), 3.5 ± 2.6 3.9 ± 2.3 pregnancy rate, which was defined as the proportion of patients with ongoing pregnancy after the gestation age of BMI (kg/m ) n (%) 12 weeks. The secondary measures included the stimula- 19~ 24.9 80(72.7%) 81(73.6%) tion duration, gonadotropin consumption, incidence of 25~ 29.9 25(22.7%) 24(21.8%) premature LH surge and OHSS, the number of oocytes re- > =30 5(4.5%) 5(4.5%) trieved, the number of viable embryos, the proportion of Previous IVF failures, n(%) mature oocytes and the live birth rate. The implantation 0 89(80.9%) 88(80.8%) rate was calculated as the number of gestational sacs visual- ized on transvaginal ultrasound divided by the number of 1–3 21(19.1%) 22(19.2%) transferred embryos. Clinical pregnancy was defined as the Indication for IVF n (%) presence of foetal cardiac activity confirmed by transvaginal PCOS only 27(24.5%) 30(27.3%) ultrasound. The cumulative live birth rate was defined as PCOS+ male factor 21(19.1%) 25(22.7%) the total number of live births divided by all participants. PCOS+ tubal factor 52(52.7%) 49(44.5%) PCOS+ other 4(3.6%) 6(5.5%) Statistical analysis The data were evaluated by Student’st-testfor continuous Menstrual cycle n (%) variables of normal distribution, the Mann-Whitney U-test Regular 3(2.1%) 3(2.7%) for continuous variables of non-normal distribution, the Oligomenorrhea 82(74.5%) 91(82.7%) x -test or Fisher’s exact for categorical variables, as appro- Amenorrhea 25(22.7%) 16(14.5%) priate. All tests were two-sided, and P <.05 was considered Antral follicle counts 17.9 ± 6.3 18.8 ± 7.1 statistically significant. All data were analysed using the Baseline hormones Statistical Package for the Social Sciences for Windows (SPSS, version 19). FSH (mIU/ml) 4.94 ± 1.10 5.0 ± 1.17 LH (mIU/ml) 5.03 ± 3.18 5.61 ± 3.36 Results E (pg/ml) 32.54 ± 10.34 30.32 ± 12.52 Patient characteristics P(ng/ml) 0.26 ± 0.19 0.27 ± 0.19 The basal demographical and hormonal characteristics T (ng/ml) 0.35 ± 0.13 0.40 ± 0.19 are shown in Table 1. A total of 220 patients completed No significant difference was found between the two groups (P > 0.05) this trial. There were no significant between-group dif- ferences in age, body mass index (BMI), previous IVF failures, infertility duration, menstrual cycle, indication in the study group was significantly lower than in the for IVF or basal hormonal profile. All women completed control group (4.8 ± 3.5 vs. 6.2 ± 3.7, P < 0.05). No one oocyte retrieval cycle, 208 patients had 1–15 viable between-group differences were found in the oocyte re- embryos harvested, and 12 cases were cancelled before trieval rate, but the maturation rate and the proportion transfer due to either non-fertilization or no transferra- of viable embryos per oocyte retrieved were better in the ble embryos. A total of 205 women completed 287 FET study group (respectively, 87.4% vs 80.3 and 39.5% vs cycles in the following two years. 34.0%, both P < 0.05). The cycle cancellation due to zero viable embryos was significantly higher in the study Ovarian stimulation, follicle development, and oocyte group (9.1% vs 1.8%, P < 0.05). One patient experienced performance moderate or severe OHSS in each group (P > 0.05). Clinical and cycle characteristics of ovarian stimulation in both groups are shown in Table 2. The study group Hormone profile during treatment (HMG + MPA + CC protocol) had a similar stimulation The serum concentrations of FSH, LH, E and P in the duration (9.2 ± 1.3 days vs 9.1 ± 1.2 days, P > 0.05) and two groups are presented in Fig. 2. FSH in the study consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± group was slightly lower than in the control group dur- 372.0 IU, P < 0.05). The numbers of oocytes retrieved, ing the mid-follicular phase (P < 0.05). LH gradually de- MII oocytes, and fertilized oocytes in the study group creased during ovarian stimulation in the control group; were significantly lower than those in the control group in contrast, LH in the study group showed a slight rise (P < 0.05). Consequently, the number of viable embryos initially, followed by a downward trend, and the mean Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 5 of 8 Table 2 The cycle characteristics of controlled ovarian stimulation in the two groups Study group Control group P value (HMG + MPA + CC; n = 110) (HMG + MPA; n = 110) hMG doses (IU) 1470.0 ± 360.1 1943.8 ± 372.0 < 0.001 hMG duration (days) 9.2 ± 1.3 9.1 ± 1.2 0.594 No. of > 10 mm follicles on trigger day 17.6 ± 8.4 21.2 ± 8.3 0.001 No. of > 14 mm follicles on trigger day 13.8 ± 8.4 17.2 ± 9.3 0.004 No. of oocytes retrieved(n) 12.2 ± 7.4 18.2 ± 9.7 < 0.001 No. of maturation oocytes (n) 10.7 ± 6.3 14.6 ± 8.2 < 0.001 No. of fertilization (n) 8.6 ± 5.6 12.6 ± 7.7 < 0.001 No. of viable embryos(n) 4.8 ± 3.5 6.2 ± 3.7 0.007 Oocyte retrieval rate (%) 58.8% (1343/2285) 60.1% (2006/3335) 0.302 Oocyte maturation rate (%) 87.4% (1174/1343) 80.3% (1610/2006) < 0.001 The proportion of viable embryo per oocyte retrieved (%) 39.5% (531/1343) 33.8% (678/2006) 0.001 Cancellation for no viable embryos (%) 9.1% (10/110) 1.8% (2/110) 0.018 Incidence of moderate/severe OHSS (%) 0.91% (1/110) 0.91% (1/110) 1.00 LH value on the trigger day was significantly higher than Pregnancy outcomes in FET cycles in the control group (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 The pregnancy outcomes from FET are shown in Table 3. mIU/ml, P < 0.05). No endogenous LH surge occurred in A total of 287 FET cycles were completed in the two either group (P > 0.05). The LH value on the post-trigger groups, including 66 women who finished at least two day showed a dramatic increase in the two groups, with transfers. The control group yielded more embryos, no between-group difference (P > 0.05). which were able to finish more FET cycles in the follow- E increased gradually, accompanied by with multiple ing two years. The mean transfer cycles per patient were growing follicles during the ovarian stimulation, and no 1.5 in the control group and 1.1 in the study group in difference was found between the two groups (P > 0.05). the following two years. A total of 560 embryos were The measured E values were underestimated in 114 thawed and the survival rate was 99.3% (556/560). The cases due to the upper limit of 5000 pg/ml, so the compari- remnant embryos were, respectively, 350 and 303 in the son of E between the two groups was compromised. control and study group, which were the suplus embryos Serum P showed a gradual increase during ovarian stimula- in pregnant cases except for three cases in study group tion and increased significantly after trigger in both groups. without their transfer. Fig. 2 The dynamic changes in hormones during ovarian stimulation in the two groups Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 6 of 8 Table 3 Pregnancy and live birth outcomes after FET Study group Control group Risk Ratio (95% CI) P value (HMG/MPA/CC) (HMG/MPA) Rates per embryo transfer Clinical pregnancy rate 73.9%(88/119) 62.5%(105/168) 1.70 (1.02, 2.85) 0.042 Implantation rate 52.2%(119/228) 42.7%(140/328) 1.47(1.04, 2.06) 0.027 Ectopic pregnancy rate 1.1%(1/88) 1.9%(2/105) 0.59(0.05, 6.64) 0.667 Miscarriage rate Early miscarriage 9.1%(8/88) 12.4%(13/105) 0.71(0.28,1.79) 0.465 Later miscarriage 6.8%(6/88) 5.7%(6/105) 1.21(0.38,3.89) 0.752 Ongoing pregnancy rate 66.4%(79/119) 53.6%(90/168) 1.71(1.05,2.78) 0.030 a a Live-birth rate 59.7%(71/119) 49.4%(83/168) 1.52(0.94,2.44) 0.086 Rates per participant Ongoing pregnancy rate 71.8%(79/110) 81.8%(90/110) 0.57(0.30,1.07) 0.079 a a Live birth rate 64.5%(71/110) 75.5%(83/110) 0.59(0.33,1.06) 0.077 Newborns Single birth (n) 50 60 Single birthweight (g) 3270.4 ± 644.9 3357.0 ± 437.1 0.422 Twin birth (n) 21 23 Twin birthweight (g) 2371.7 ± 460.7 2460.0 ± 423.5 0.497 3 pregnant women lost to follow up to live birth (2 in study group and 1 in control group) The synchronization methods of endometrium and standard PPOS protocol in PCOS women, and the inci- embryo were similar between the two groups. The on- dence of OHSS was low in both groups (0.91%). going pregnancy rate per transfer and the implantation In contrast to the standard protocol of HMG/MPA, rate were significantly higher in the study group (re- the combination protocol of HMG/CC/MPA showed the spectively, 66.4% vs 53.6%; 52.2% vs 42.7%, P < 0.05) but characteristics of milder stimulation, such as fewer oo- the live birth rate per transfer was comparable between cytes, fewer embryos, and a higher cancellation rate for two groups (59.7% vs 49.4%, P > 0.05). Sixty-four women non-transferrable embryos, but the harvested embryos experienced twin pregnancies, including 6 women with showed good developmental potential in terms of im- vanishing syndrome. One triplet pregnancy occurred in plantation rate. This protocol led to fewer oocytes at each group, and both resulted in live births after oper- the cost of low gonadotropin consumption. Serum FSH ation of multifetal reduction. The proportions of mul- in mid-follicular phase was slightly lower in the CC com- tiple pregnancies, miscarriage and ectopic pregnancy bination protocol. The extent of ovarian stimulation may were similar between groups (P > 0.05). The cumulative be regulated by using low dose of gonadotropin and CC, ongoing pregnancy and live birth rate per patient were which leaves much flexibility for controlled ovarian stimula- lower in the study group but did not reach the signifi- tion. Although the proportion of viable embryos per re- cant difference (respectively 71.8% vs 81.8%; 64.5% vs. trieved oocyte was better in the CC combination protocol 75.5%; P > 0.05). (39.5% vs 33.8%), the number of viable embryos was less All newborns were examined with no congenital mal- than the 1.5 embryos from the standard protocol. The total formation except that oesophageal atresia was found in number of transferrable embryos originating from the CC one baby of the control group and ventricular septal de- group was significantly lower, meaning the milder CC fect in one of the twin babies of the study group. combination stimulation yielded suboptimal pregnancy outcomes compared with the standard protocol. But Discussion these results from a CC combination regimen may pro- Milder stimulation, with its advantages of patient-friendliness, vide a new insight for develop a more patient-friendly is a good solution for producing an acceptable preg- protocol for PCOS women. nancy outcome and eliminating OHSS for high re- One of the strengths of this trial is that it verified the sponders. This retrospective cohort trial demonstrated feasibility of CC co-administration in the PPOS protocol that the milder PPOS with CC led to lower oocyte yields in PCOS women. Our results showed that the endogenous and suboptimal pregnancy outcomes compared to the LH was well-suppressed during ovarian stimulation, and Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 7 of 8 no spontaneous LH surge occurred in either group. CC oocyte yields and suboptimal pregnancy outcomes com- increased endogenous gonadotropin secretion by blocking pared to the standard PPOS protocol. The two regimens oestrogen’s negative feedback mechanism [11], as evi- both achieved a low incidence of OHSS. Milder PPOS denced byarelativelyhigherLHlevel during the stimula- with the CC combination regimen showed a higher tion with CC in this trial. More important, no spontaneous cancellation rate in exchange for low gonadotropin LH surge occurred even with the relatively higher LH, consumption, but the proportion of viable embryos per which indicated that P’s suppression of pituitary function oocyte and the implantation rate were higher. Our find- was still dominant. This phenomenon has also occurred in ings from this CC combination regimen provide a new normo-ovulatory women using a CC combination protocol insight for developing a more patient-friendly protocol of PPOS [18]. These data indicate that, although CC and for PCOS women. progesterone have separate action sites and pathways, the Abbreviations changed LH trend was the result of their collaborative AFC: Antral follicle count; CC: Clomiphene citrate; FET: Frozen embryo transfer; action, so the two drugs may act independently and have FSH: Follicle-stimulating hormone; ICSI: Intracytoplasmic sperm injection; IVF: In vitro fertilization; LH: Luteinizing hormone; MPA: Medroxyprogesterone acetate; the possibility to act collaboratively. OHSS: Ovarian hyperstimulation; P: Progestin; PCOS: Polycystic ovarian In PCOS women, multiple follicle growth in controlled syndrome; PPOS: Progestin-primed ovarian stimulation ovarian stimulation leads to a higher risk of OHSS due Acknowledgements to the higher sensibility and exaggerated response to We thank the entire staff of the Department of Assisted Reproduction, gonadotropins. The incidence of moderate or severe OHSS Shanghai Ninth People’s Hospital, for their support in this trial. in PCOS women is approximately 3.0 to 8.0% [5, 19]. Funding Therefore, it is important to decide the initiating gonado- This study was funded by the National Natural Science Foundation of China tropin dosage to avoid OHSS. The goal of the CC combin- (grant numbers: 81671520 and 81571397) and the Natural Science Foundation ation protocol using a low dose of initiating gonadotropin of Shanghai (grant numbers: 16411963800). is to maximize the advantages of CC administration. Availability of data and materials Although CC milder stimulation has the theoretical Data are not publicly shared; please contact the authors for data requests. advantages of a low risk of OHSS, less gonadotropin Authors’ contributions consumption, and avoiding the resource wastage of Dr. Sun, Dr. Ye and Dr. Chen were the chief investigators who completed the cryopreserving more embryos, but in this trial, only 0.91% entire study, including procedures, conception, design and completion. Dr. of patients had OHSS, with no difference between the two Tian, Dr. Lyu and Dr. He were responsible for the collection of data. Dr. Ye and Dr. Chen analysed the data and drafted the manuscript together. groups. This is due to multiple preventive treatments used Professor Kuang supervised the study. All authors participated in the ultimate in this trial: 150–225 IU HMG initiation, a co-trigger interpretation of the study data and manuscript revisions. All authors read using GnRHa and low-dose hCG and a freeze-only strat- and approved the final manuscript. egy. The current data indicate that CC made it possible to Ethics approval and consent to participate reduce the gonadotropin initiating dose in the PPOS This study was approved by the Ethics Committee of Shanghai Ninth protocol in PCOS women, which is helpful to establish a People’s Hospital (Institutional Review Board) (No: 2014–94). new, milder stimulation regimen with CC and yields an Consent for publication acceptable pregnancy outcome with the benefit of lower All patients have provided their consent for the data to be used for research gonadotropin dosage. and publications. It is worth noting that most PCOS women in China Competing interests have a relatively low BMI. The proportion of higher-BMI The authors declare that they have no competing interests. (> 25 kg/m ) women among PCOS patients is approxi- mately one third. Previous studies reported an association Publisher’sNote between obesity and an increased gonadotropin require- Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ment [20, 21], so we must be cautious about generalizing our conclusions, especially on the choice of the HMG Received: 23 March 2018 Accepted: 23 May 2018 initiating dose for obese PCOS women. This trial had a relative small sample size, with insufficient power to com- References pare the live birth rate and incidence of OHSS, so a 1. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The large-sample, prospective randomized controlled trial prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25:544–51. using milder PPOS with CC is needed to further confirm 2. Li R, Zhang Q, Yang D, Li S, Lu S, Wu X, Wei Z, Song X, Wang X, Fu S, Lin J, Zhu our conclusions. Y, Jiang Y, Feng HL, Qiao J. Prevalence of polycystic ovary syndrome in women in China: a large community-based study. Hum Reprod. 2013;28:2562–9. 3. Fulvia M, Rosa T, Francisca M, Coroleu B, Rodríguez I, Barri PN. Conclusions Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro This retrospective cohort trial showed that the milder fertilization patients with polycystic ovary syndrome: a meta-analysis. PPOS protocol with CC in PCOS women led to lower Gynecol Endocrinol. 2011;27:150–5. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 8 of 8 4. Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:13–21. 5. Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375:523–33. 6. Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril, 2015. 104:62–70. 7. Dong J, Wang Y, Chai WR, Hong QQ, Wang NL, Sun LH, Long H, Wang L, Tian H, Lyu QF, Lu XF, Chen QJ, Kuang YP. The pregnancy outcome of progesterone-primed ovarian stimulation using medroxyprogesterone acetate 4 mg versus 10mg daily in infertile women undergoing in vitro fertilization: a randomized controlled trial. B J Obstet Gynaecol. 2017;124: 1048–55. 8. Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017;23:211–20. 9. Chen Q, Wang Y, Sun L, Zhang S, Chai W, Hong Q, Long H, Wang L, Lyu Q, Kuang Y. Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders. Reprod Biol Endocrinol. 2017;15:71. 10. Zhu XX, Ye HJ, Fu YL. The Utrogestan and hMG protocol in patients with polycystic ovarian syndrome undergoing controlled ovarian hyperstimulation during IVF/ICSI treatments. Medicine. 2016;95:e4193. 11. Kerin JF, Liu JH, Phillipou G, Yen SS. Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. 1985;61:265–8. 12. Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril. 2009;92:858–9. 13. Tavaniotou A, Albano C, Smitz J, Devroey P. Effect of clomiphene citrate on follicular and luteal phase luteinizing hormone concentrations in in vitro fertilization cycles stimulated with gonadotropins and gonadotropin- releasing hormone antagonist. Fertil Steril. 2002;77:73. 14. Engel JB, Ludwig M, Felberbaum R, Albano C, Devroey P, Diedrich K. Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'? Hum Reprod. 2002;17:2022–6. 15. Figueiredo JB, Nastri CO, Vieira AD, Martins WP. Clomiphene combined with gonadotropins and GnRH antagonist versus conventional controlled ovarian hyperstimulation without clomiphene in women undergoing assisted reproductive techniques: systematic review and meta-analysis. Arch Gynecol Obstet. 2013;287:779–90. 16. Jiang S, Kuang Y. Clomiphene citrate is associated with favorable cycle characteristics but impaired outcomes of obese women with polycystic ovarian syndrome undergoing ovarian stimulation for in vitro fertilization. Medicine (Baltimore). 2017;96:e7540. 17. Kuang Y, Hong Q, Chen Q, Fu Y, Ai A, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing invitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014;101:105–11. 18. Liu Y, Chen Q, Yu S, Wang Y, He W, Chang HY-N, Wang B, Gao H, Long H, Wang L, Lyu Q, Ai A, Kuang Y. Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing IVF/ICSI: a prospective randomized controlled trial. Clinical Endocrinology. 2018;88:442–52. 19. Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;1:CD012103. 20. Fedorcsák P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, Omland AK, Abyholm T, Tanbo T. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19:2523–8. 21. Orvieto R, Meltcer SR, Rabinson J, Rabinson J, Anteby EY, Ashkenazi J. The influence of body mass index on in vitro fertilization outcome. Int J Gynecol Obstet. 2009;104:53–5. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Reproductive Biology and Endocrinology Springer Journals

Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome

Free
8 pages
Loading next page...
 
/lp/springer_journal/progestin-primed-milder-stimulation-with-clomiphene-citrate-yields-ekgpBCQnS9
Publisher
BioMed Central
Copyright
Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Reproductive Medicine; Endocrinology
eISSN
1477-7827
D.O.I.
10.1186/s12958-018-0373-7
Publisher site
See Article on Publisher Site

Abstract

Background: Oral progestin has recently been used to prevent premature LH surges in ovarian stimulation, and this progestin-primed ovarian stimulation (PPOS) is effective and safe in patients with different ovarian reserves. The current data are lacking regarding how to individualize the gonadotropin dose and regimen for women with polycystic ovarian syndrome (PCOS). A retrospective cohort trial was performed to evaluate the efficacy of progestin- primed milder stimulation with clomiphene citrate (CC) compared to the standard progestin-primed ovarian stimulation (PPOS) protocol for infertile women with PCOS. Methods: A total of 220 PCOS women were collected and classified into the study group (HMG 150 IU/d + CC 50 mg/d + MPA 10 mg/d) and control group (HMG 225 IU/d + MPA 10 mg/d). Ovulation was triggered by GnRH agonist 0.1 mg and hCG 1000 IU when dominant follicles matured. Viable embryos were cryopreserved for later transfer. The primary endpoint was the ongoing pregnancy rate. Secondary outcomes included the cycle characteristics and the live birth rate. Result(s): The study group consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± 372.0 IU, P < 0.001) and harvested fewer oocytes than the control group (12.2 ± 7.4 vs 18.2 ± 9.7, P < 0.001). The study group showed a higher mid-follicular LH concentration (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 mIU/ml, P < 0.05) but no endogenous LH surge. No between-group difference was found in the incidence of ovarian hyperstimulation syndrome (OHSS) (0.91% vs 0.91%, P > 0.05). The cumulative ongoing pregnancy rate and live birth rate per patient were lower but did not reach significance compared with the control group (71.8% vs 81.8 and 64.5% vs 75.5%, respectively, both P > 0.05). (Continued on next page) * Correspondence: yehongjuan7777@163.com; chenqj75@126.com; lihua-sun@163.com Centre of assisted reproduction, Shanghai East Hospital, Tongji University, Shanghai, People’s Republic of China Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 2 of 8 (Continued from previous page) Conclusion(s): The milder PPOS with CC in PCOS women led to lower oocyte yields and suboptimal pregnancy outcomes compared to the standard PPOS treatment. The two regimens both achieved a low incidence of OHSS. The results from the CC combination regimen provide a new insight for developing a more patient-friendly protocol for PCOS women. Keywords: Polycystic ovarian syndrome, Progestin-primed ovarian stimulation, Clomiphene citrate, In vitro fertilization, Freeze-only Background Methods Polycystic ovarian syndrome (PCOS) is an endocrine dis- Study setting and subjects order affecting 5–10% of reproductive-age women world- A retrospective cohort trial was conducted at the depart- wide [1]. Approximately 74% of women with PCOS seeks ment of assisted reproduction of the Ninth People’sHospital pregnancy assistance, including induced ovulation, in- of Shanghai Jiaotong University School of Medicine. This semination or in vitro fertilization (IVF) [2]. However, study was approval by the Ethics Committee (Institutional PCOS women undergoing IVF treatment typically pro- Review Board) of Shanghai Ninth People’sHospital. duce an increased number of oocytes, which are often The PCOS diagnosis criteria followed the Rotterdam of poor quality, leading to a lower fertilization rate and consensus. PCOS was diagnosed by the presence of a higher miscarriage rate [3]. They also face a higher menstrual disturbance combined with either hyperandro- risk of moderate/severe ovarian hyperstimulation syn- genism (hirsutism or hyperandrogenaemia) or polycystic drome (OHSS) [4, 5]. ovary on ultrasonography (defined as an ovary that con- Thanks to the progress of vitrification, oral progestin tained ≥12 antral follicles) and excluded other causes of has been successfully used to prevent premature LH surges hyperandrogenism (congenital adrenal hyperplasia, Cushing’s in women undergoing ovarian stimulation [6–8]. This syndrome, androgen-producing tumours) and ovulation progestin-primed ovarian stimulation (PPOS) yields a com- dysfunction (hyperprolactinaemia and thyroid dysfunc- parable pregnancy outcome, although it consumes a slightly tion). In addition, this study only included women no higher gonadotropin dosage than conventional short proto- more than 40 years of age and with baseline serum FSH cols [6]. PPOS is approved its efficacy and safety in the no more than 10 mIU/ml. Women with functional cysts population of low-ovarian-reserve, normal-ovarian-reserve on the ovaries or medical conditions that contraindicated and PCOS women [8–10], so PPOS in combination with a assisted reproductive technology and/or pregnancy were freeze-only policy shows good potential to compete with excluded. A total of 220 infertile women with PCOS from conventional protocols. The existing data from clinical trials April 2014 to November 2015 were included and classified often use the equal initiating doses of gonadotropin for into the study group (HMG + MPA + CC) and the control women with or without PCOS, but relevant data are lack- group (HMG + MPA). A flowchart of the study is shown ing about how to individualize the gonadotropin dose and in Fig. 1. regimen for PCOS women undergoing ovarian stimulation. Clomiphene citrate (CC) has been a first-line drug for Ovarian stimulation protocol ovulation induction for anovulatory infertility. Its advan- In the study group, a low dose of HMG (150 IU daily), tages include its oral route, low costs and easy access CC 50 mg and MPA 10 mg daily were started from cycle compared to gonadotropins [11, 12]. CC is also used in day 3 or after an episode of withdrawal bleeding. MPA GnRH antagonist protocols, and the combination of CC was used to prevent premature ovulation during the and GnRH antagonist is likely to reduce the risk of OHSS, ovarian stimulation. Follicle monitoring by transvaginal medication costs and gonadotropin duration compared to ultrasound and serum hormone measurements (FSH, those without CC, but it accompanies with an increased LH, E and progesterone) were performed 5 days later. risk of premature LH surges [13–15]. Limited data are HMG doses were then adjusted according to the ovarian available about the role of CC in PPOS for PCOS women response (range 150–300 IU daily). Oocyte maturation [16]. In this trial, we attempted to test the hypothesis that was triggered by triptorelin 0.1 mg (Decapeptyl, Ferring in women with PCOS, the milder stimulation of PPOS in Pharmaceuticals, Germany) and urinary human chori- combination with CC would provide an acceptable clinical onic gonadotropin (hCG 1000 IU, Lizhu Pharmaceutical outcome compared with standard PPOS protocol using Trading Co., China) when at least three follicles reached conventional initiating dose of gonadotropin. Our ultimate diameters of 18 mm or more. Cumulus oocyte com- aim was to optimize the PPOS protocol and make it more plexes were collected 36 h later. All follicles larger than patient-friendly. 10 mm in diameter were aspirated. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 3 of 8 Fig. 1 Study flowchart In the control group, HMG 225 IU and MPA 10 mg growth was monitored beginning on day 10. At times, a daily were initiated from cycle day 3 or after an episode low dose of HMG (75 IU/day) was used to stimulate fol- of withdrawal bleeding. Follicle monitor and hormone licle growth and endometrial lining. The timing of FET assay were performed 5 days later. HMG dose was then was performed 4 or 5 days later, after a spontaneous or adjusted according to the ovarian response, and MPA hCG-induced LH surge. Hormone replacement treat- dose was consistent up to the trigger day. The criteria of ment was recommended for patients with thin endomet- mature follicle and the trigger methods were the same as rium and patients in whom letrozole failed. Oral ethinyl above. oestradiol 75 mcg/day was administered from cycle day Fertilization was carried out in vitro after oocyte re- 3 onwards. Once the endometrial lining was > 8 mm trieval depending on the semen parameters and previ- thick, femoston (Solvay Pharmaceuticals B.V.) 8 mg/day ous fertilization situation. Embryos were examined for was started. The time of thawing and transfer was deter- the number or regularity of blastomeres and the degree mined on the third day after femoston administration of fragmentation. All top-quality cleavage-stage em- [17]. Each patient received no more than two embryos bryos (grade 1 and grade 2, 6-cell embryos and above) at one time. Once pregnancy was achieved, the luteal were frozen within three days after oocyte retrieval. support was continued until 10 weeks of gestation. The non-top-quality embryos were placed in further extended culture, and good-morphology blastocysts Hormone measurement were frozen. Cleavage-stage embryos and blastocysts Serum FSH, LH, E , and progesterone were measured were frozen by vitrification as described previously [17]. on menstrual cycle day 3, day 8–11 (after 5–7 days of stimulation), the trigger day and the day after trigger. Endometrium preparation and FET Hormone levels were determined with chemilumines- Endometrium preparation for FET was arranged on the cence (Abbott Biological B.V. Netherlands). The lower second cycle after oocyte retrieval. The first choice was limits of sensitivity were as follow: FSH 0.06 mIU/ml, using a letrozole-induced- ovulation cycle. Letrozole LH 0.09 mIU/ml, E 10 pg/ml and progesterone 0.1 ng/ml. 5 mg was administered for 5 days, and then, follicle The upper limit of E measurement was 5000 pg/ml. If 2 Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 4 of 8 serum E on thetrigger dayorthe day after was higher Table 1 The basic characteristics of PCOS women in this trial than the upper limit, it was recorded as 5000 pg/ml. Study group Control group (HMG + MPA + CC; (HMG + MPA; n = 110) n = 110) Outcome variables Age (y) 30.5 ± 3.7 30.6 ± 3.4 Theprimary measureanalysedwas the cumulativeongoing Duration of infertility (y), 3.5 ± 2.6 3.9 ± 2.3 pregnancy rate, which was defined as the proportion of patients with ongoing pregnancy after the gestation age of BMI (kg/m ) n (%) 12 weeks. The secondary measures included the stimula- 19~ 24.9 80(72.7%) 81(73.6%) tion duration, gonadotropin consumption, incidence of 25~ 29.9 25(22.7%) 24(21.8%) premature LH surge and OHSS, the number of oocytes re- > =30 5(4.5%) 5(4.5%) trieved, the number of viable embryos, the proportion of Previous IVF failures, n(%) mature oocytes and the live birth rate. The implantation 0 89(80.9%) 88(80.8%) rate was calculated as the number of gestational sacs visual- ized on transvaginal ultrasound divided by the number of 1–3 21(19.1%) 22(19.2%) transferred embryos. Clinical pregnancy was defined as the Indication for IVF n (%) presence of foetal cardiac activity confirmed by transvaginal PCOS only 27(24.5%) 30(27.3%) ultrasound. The cumulative live birth rate was defined as PCOS+ male factor 21(19.1%) 25(22.7%) the total number of live births divided by all participants. PCOS+ tubal factor 52(52.7%) 49(44.5%) PCOS+ other 4(3.6%) 6(5.5%) Statistical analysis The data were evaluated by Student’st-testfor continuous Menstrual cycle n (%) variables of normal distribution, the Mann-Whitney U-test Regular 3(2.1%) 3(2.7%) for continuous variables of non-normal distribution, the Oligomenorrhea 82(74.5%) 91(82.7%) x -test or Fisher’s exact for categorical variables, as appro- Amenorrhea 25(22.7%) 16(14.5%) priate. All tests were two-sided, and P <.05 was considered Antral follicle counts 17.9 ± 6.3 18.8 ± 7.1 statistically significant. All data were analysed using the Baseline hormones Statistical Package for the Social Sciences for Windows (SPSS, version 19). FSH (mIU/ml) 4.94 ± 1.10 5.0 ± 1.17 LH (mIU/ml) 5.03 ± 3.18 5.61 ± 3.36 Results E (pg/ml) 32.54 ± 10.34 30.32 ± 12.52 Patient characteristics P(ng/ml) 0.26 ± 0.19 0.27 ± 0.19 The basal demographical and hormonal characteristics T (ng/ml) 0.35 ± 0.13 0.40 ± 0.19 are shown in Table 1. A total of 220 patients completed No significant difference was found between the two groups (P > 0.05) this trial. There were no significant between-group dif- ferences in age, body mass index (BMI), previous IVF failures, infertility duration, menstrual cycle, indication in the study group was significantly lower than in the for IVF or basal hormonal profile. All women completed control group (4.8 ± 3.5 vs. 6.2 ± 3.7, P < 0.05). No one oocyte retrieval cycle, 208 patients had 1–15 viable between-group differences were found in the oocyte re- embryos harvested, and 12 cases were cancelled before trieval rate, but the maturation rate and the proportion transfer due to either non-fertilization or no transferra- of viable embryos per oocyte retrieved were better in the ble embryos. A total of 205 women completed 287 FET study group (respectively, 87.4% vs 80.3 and 39.5% vs cycles in the following two years. 34.0%, both P < 0.05). The cycle cancellation due to zero viable embryos was significantly higher in the study Ovarian stimulation, follicle development, and oocyte group (9.1% vs 1.8%, P < 0.05). One patient experienced performance moderate or severe OHSS in each group (P > 0.05). Clinical and cycle characteristics of ovarian stimulation in both groups are shown in Table 2. The study group Hormone profile during treatment (HMG + MPA + CC protocol) had a similar stimulation The serum concentrations of FSH, LH, E and P in the duration (9.2 ± 1.3 days vs 9.1 ± 1.2 days, P > 0.05) and two groups are presented in Fig. 2. FSH in the study consumed less HMG (1470.0 ± 360.1 IU vs 1943.8 ± group was slightly lower than in the control group dur- 372.0 IU, P < 0.05). The numbers of oocytes retrieved, ing the mid-follicular phase (P < 0.05). LH gradually de- MII oocytes, and fertilized oocytes in the study group creased during ovarian stimulation in the control group; were significantly lower than those in the control group in contrast, LH in the study group showed a slight rise (P < 0.05). Consequently, the number of viable embryos initially, followed by a downward trend, and the mean Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 5 of 8 Table 2 The cycle characteristics of controlled ovarian stimulation in the two groups Study group Control group P value (HMG + MPA + CC; n = 110) (HMG + MPA; n = 110) hMG doses (IU) 1470.0 ± 360.1 1943.8 ± 372.0 < 0.001 hMG duration (days) 9.2 ± 1.3 9.1 ± 1.2 0.594 No. of > 10 mm follicles on trigger day 17.6 ± 8.4 21.2 ± 8.3 0.001 No. of > 14 mm follicles on trigger day 13.8 ± 8.4 17.2 ± 9.3 0.004 No. of oocytes retrieved(n) 12.2 ± 7.4 18.2 ± 9.7 < 0.001 No. of maturation oocytes (n) 10.7 ± 6.3 14.6 ± 8.2 < 0.001 No. of fertilization (n) 8.6 ± 5.6 12.6 ± 7.7 < 0.001 No. of viable embryos(n) 4.8 ± 3.5 6.2 ± 3.7 0.007 Oocyte retrieval rate (%) 58.8% (1343/2285) 60.1% (2006/3335) 0.302 Oocyte maturation rate (%) 87.4% (1174/1343) 80.3% (1610/2006) < 0.001 The proportion of viable embryo per oocyte retrieved (%) 39.5% (531/1343) 33.8% (678/2006) 0.001 Cancellation for no viable embryos (%) 9.1% (10/110) 1.8% (2/110) 0.018 Incidence of moderate/severe OHSS (%) 0.91% (1/110) 0.91% (1/110) 1.00 LH value on the trigger day was significantly higher than Pregnancy outcomes in FET cycles in the control group (4.49 ± 2.49 mIU/ml vs 2.52 ± 2.09 The pregnancy outcomes from FET are shown in Table 3. mIU/ml, P < 0.05). No endogenous LH surge occurred in A total of 287 FET cycles were completed in the two either group (P > 0.05). The LH value on the post-trigger groups, including 66 women who finished at least two day showed a dramatic increase in the two groups, with transfers. The control group yielded more embryos, no between-group difference (P > 0.05). which were able to finish more FET cycles in the follow- E increased gradually, accompanied by with multiple ing two years. The mean transfer cycles per patient were growing follicles during the ovarian stimulation, and no 1.5 in the control group and 1.1 in the study group in difference was found between the two groups (P > 0.05). the following two years. A total of 560 embryos were The measured E values were underestimated in 114 thawed and the survival rate was 99.3% (556/560). The cases due to the upper limit of 5000 pg/ml, so the compari- remnant embryos were, respectively, 350 and 303 in the son of E between the two groups was compromised. control and study group, which were the suplus embryos Serum P showed a gradual increase during ovarian stimula- in pregnant cases except for three cases in study group tion and increased significantly after trigger in both groups. without their transfer. Fig. 2 The dynamic changes in hormones during ovarian stimulation in the two groups Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 6 of 8 Table 3 Pregnancy and live birth outcomes after FET Study group Control group Risk Ratio (95% CI) P value (HMG/MPA/CC) (HMG/MPA) Rates per embryo transfer Clinical pregnancy rate 73.9%(88/119) 62.5%(105/168) 1.70 (1.02, 2.85) 0.042 Implantation rate 52.2%(119/228) 42.7%(140/328) 1.47(1.04, 2.06) 0.027 Ectopic pregnancy rate 1.1%(1/88) 1.9%(2/105) 0.59(0.05, 6.64) 0.667 Miscarriage rate Early miscarriage 9.1%(8/88) 12.4%(13/105) 0.71(0.28,1.79) 0.465 Later miscarriage 6.8%(6/88) 5.7%(6/105) 1.21(0.38,3.89) 0.752 Ongoing pregnancy rate 66.4%(79/119) 53.6%(90/168) 1.71(1.05,2.78) 0.030 a a Live-birth rate 59.7%(71/119) 49.4%(83/168) 1.52(0.94,2.44) 0.086 Rates per participant Ongoing pregnancy rate 71.8%(79/110) 81.8%(90/110) 0.57(0.30,1.07) 0.079 a a Live birth rate 64.5%(71/110) 75.5%(83/110) 0.59(0.33,1.06) 0.077 Newborns Single birth (n) 50 60 Single birthweight (g) 3270.4 ± 644.9 3357.0 ± 437.1 0.422 Twin birth (n) 21 23 Twin birthweight (g) 2371.7 ± 460.7 2460.0 ± 423.5 0.497 3 pregnant women lost to follow up to live birth (2 in study group and 1 in control group) The synchronization methods of endometrium and standard PPOS protocol in PCOS women, and the inci- embryo were similar between the two groups. The on- dence of OHSS was low in both groups (0.91%). going pregnancy rate per transfer and the implantation In contrast to the standard protocol of HMG/MPA, rate were significantly higher in the study group (re- the combination protocol of HMG/CC/MPA showed the spectively, 66.4% vs 53.6%; 52.2% vs 42.7%, P < 0.05) but characteristics of milder stimulation, such as fewer oo- the live birth rate per transfer was comparable between cytes, fewer embryos, and a higher cancellation rate for two groups (59.7% vs 49.4%, P > 0.05). Sixty-four women non-transferrable embryos, but the harvested embryos experienced twin pregnancies, including 6 women with showed good developmental potential in terms of im- vanishing syndrome. One triplet pregnancy occurred in plantation rate. This protocol led to fewer oocytes at each group, and both resulted in live births after oper- the cost of low gonadotropin consumption. Serum FSH ation of multifetal reduction. The proportions of mul- in mid-follicular phase was slightly lower in the CC com- tiple pregnancies, miscarriage and ectopic pregnancy bination protocol. The extent of ovarian stimulation may were similar between groups (P > 0.05). The cumulative be regulated by using low dose of gonadotropin and CC, ongoing pregnancy and live birth rate per patient were which leaves much flexibility for controlled ovarian stimula- lower in the study group but did not reach the signifi- tion. Although the proportion of viable embryos per re- cant difference (respectively 71.8% vs 81.8%; 64.5% vs. trieved oocyte was better in the CC combination protocol 75.5%; P > 0.05). (39.5% vs 33.8%), the number of viable embryos was less All newborns were examined with no congenital mal- than the 1.5 embryos from the standard protocol. The total formation except that oesophageal atresia was found in number of transferrable embryos originating from the CC one baby of the control group and ventricular septal de- group was significantly lower, meaning the milder CC fect in one of the twin babies of the study group. combination stimulation yielded suboptimal pregnancy outcomes compared with the standard protocol. But Discussion these results from a CC combination regimen may pro- Milder stimulation, with its advantages of patient-friendliness, vide a new insight for develop a more patient-friendly is a good solution for producing an acceptable preg- protocol for PCOS women. nancy outcome and eliminating OHSS for high re- One of the strengths of this trial is that it verified the sponders. This retrospective cohort trial demonstrated feasibility of CC co-administration in the PPOS protocol that the milder PPOS with CC led to lower oocyte yields in PCOS women. Our results showed that the endogenous and suboptimal pregnancy outcomes compared to the LH was well-suppressed during ovarian stimulation, and Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 7 of 8 no spontaneous LH surge occurred in either group. CC oocyte yields and suboptimal pregnancy outcomes com- increased endogenous gonadotropin secretion by blocking pared to the standard PPOS protocol. The two regimens oestrogen’s negative feedback mechanism [11], as evi- both achieved a low incidence of OHSS. Milder PPOS denced byarelativelyhigherLHlevel during the stimula- with the CC combination regimen showed a higher tion with CC in this trial. More important, no spontaneous cancellation rate in exchange for low gonadotropin LH surge occurred even with the relatively higher LH, consumption, but the proportion of viable embryos per which indicated that P’s suppression of pituitary function oocyte and the implantation rate were higher. Our find- was still dominant. This phenomenon has also occurred in ings from this CC combination regimen provide a new normo-ovulatory women using a CC combination protocol insight for developing a more patient-friendly protocol of PPOS [18]. These data indicate that, although CC and for PCOS women. progesterone have separate action sites and pathways, the Abbreviations changed LH trend was the result of their collaborative AFC: Antral follicle count; CC: Clomiphene citrate; FET: Frozen embryo transfer; action, so the two drugs may act independently and have FSH: Follicle-stimulating hormone; ICSI: Intracytoplasmic sperm injection; IVF: In vitro fertilization; LH: Luteinizing hormone; MPA: Medroxyprogesterone acetate; the possibility to act collaboratively. OHSS: Ovarian hyperstimulation; P: Progestin; PCOS: Polycystic ovarian In PCOS women, multiple follicle growth in controlled syndrome; PPOS: Progestin-primed ovarian stimulation ovarian stimulation leads to a higher risk of OHSS due Acknowledgements to the higher sensibility and exaggerated response to We thank the entire staff of the Department of Assisted Reproduction, gonadotropins. The incidence of moderate or severe OHSS Shanghai Ninth People’s Hospital, for their support in this trial. in PCOS women is approximately 3.0 to 8.0% [5, 19]. Funding Therefore, it is important to decide the initiating gonado- This study was funded by the National Natural Science Foundation of China tropin dosage to avoid OHSS. The goal of the CC combin- (grant numbers: 81671520 and 81571397) and the Natural Science Foundation ation protocol using a low dose of initiating gonadotropin of Shanghai (grant numbers: 16411963800). is to maximize the advantages of CC administration. Availability of data and materials Although CC milder stimulation has the theoretical Data are not publicly shared; please contact the authors for data requests. advantages of a low risk of OHSS, less gonadotropin Authors’ contributions consumption, and avoiding the resource wastage of Dr. Sun, Dr. Ye and Dr. Chen were the chief investigators who completed the cryopreserving more embryos, but in this trial, only 0.91% entire study, including procedures, conception, design and completion. Dr. of patients had OHSS, with no difference between the two Tian, Dr. Lyu and Dr. He were responsible for the collection of data. Dr. Ye and Dr. Chen analysed the data and drafted the manuscript together. groups. This is due to multiple preventive treatments used Professor Kuang supervised the study. All authors participated in the ultimate in this trial: 150–225 IU HMG initiation, a co-trigger interpretation of the study data and manuscript revisions. All authors read using GnRHa and low-dose hCG and a freeze-only strat- and approved the final manuscript. egy. The current data indicate that CC made it possible to Ethics approval and consent to participate reduce the gonadotropin initiating dose in the PPOS This study was approved by the Ethics Committee of Shanghai Ninth protocol in PCOS women, which is helpful to establish a People’s Hospital (Institutional Review Board) (No: 2014–94). new, milder stimulation regimen with CC and yields an Consent for publication acceptable pregnancy outcome with the benefit of lower All patients have provided their consent for the data to be used for research gonadotropin dosage. and publications. It is worth noting that most PCOS women in China Competing interests have a relatively low BMI. The proportion of higher-BMI The authors declare that they have no competing interests. (> 25 kg/m ) women among PCOS patients is approxi- mately one third. Previous studies reported an association Publisher’sNote between obesity and an increased gonadotropin require- Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ment [20, 21], so we must be cautious about generalizing our conclusions, especially on the choice of the HMG Received: 23 March 2018 Accepted: 23 May 2018 initiating dose for obese PCOS women. This trial had a relative small sample size, with insufficient power to com- References pare the live birth rate and incidence of OHSS, so a 1. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The large-sample, prospective randomized controlled trial prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25:544–51. using milder PPOS with CC is needed to further confirm 2. Li R, Zhang Q, Yang D, Li S, Lu S, Wu X, Wei Z, Song X, Wang X, Fu S, Lin J, Zhu our conclusions. Y, Jiang Y, Feng HL, Qiao J. Prevalence of polycystic ovary syndrome in women in China: a large community-based study. Hum Reprod. 2013;28:2562–9. 3. Fulvia M, Rosa T, Francisca M, Coroleu B, Rodríguez I, Barri PN. Conclusions Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro This retrospective cohort trial showed that the milder fertilization patients with polycystic ovary syndrome: a meta-analysis. PPOS protocol with CC in PCOS women led to lower Gynecol Endocrinol. 2011;27:150–5. Ye et al. Reproductive Biology and Endocrinology (2018) 16:53 Page 8 of 8 4. Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:13–21. 5. Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375:523–33. 6. Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, Ai A, Shoham Z. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril, 2015. 104:62–70. 7. Dong J, Wang Y, Chai WR, Hong QQ, Wang NL, Sun LH, Long H, Wang L, Tian H, Lyu QF, Lu XF, Chen QJ, Kuang YP. The pregnancy outcome of progesterone-primed ovarian stimulation using medroxyprogesterone acetate 4 mg versus 10mg daily in infertile women undergoing in vitro fertilization: a randomized controlled trial. B J Obstet Gynaecol. 2017;124: 1048–55. 8. Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017;23:211–20. 9. Chen Q, Wang Y, Sun L, Zhang S, Chai W, Hong Q, Long H, Wang L, Lyu Q, Kuang Y. Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders. Reprod Biol Endocrinol. 2017;15:71. 10. Zhu XX, Ye HJ, Fu YL. The Utrogestan and hMG protocol in patients with polycystic ovarian syndrome undergoing controlled ovarian hyperstimulation during IVF/ICSI treatments. Medicine. 2016;95:e4193. 11. Kerin JF, Liu JH, Phillipou G, Yen SS. Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. 1985;61:265–8. 12. Casper RF. Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertil Steril. 2009;92:858–9. 13. Tavaniotou A, Albano C, Smitz J, Devroey P. Effect of clomiphene citrate on follicular and luteal phase luteinizing hormone concentrations in in vitro fertilization cycles stimulated with gonadotropins and gonadotropin- releasing hormone antagonist. Fertil Steril. 2002;77:73. 14. Engel JB, Ludwig M, Felberbaum R, Albano C, Devroey P, Diedrich K. Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'? Hum Reprod. 2002;17:2022–6. 15. Figueiredo JB, Nastri CO, Vieira AD, Martins WP. Clomiphene combined with gonadotropins and GnRH antagonist versus conventional controlled ovarian hyperstimulation without clomiphene in women undergoing assisted reproductive techniques: systematic review and meta-analysis. Arch Gynecol Obstet. 2013;287:779–90. 16. Jiang S, Kuang Y. Clomiphene citrate is associated with favorable cycle characteristics but impaired outcomes of obese women with polycystic ovarian syndrome undergoing ovarian stimulation for in vitro fertilization. Medicine (Baltimore). 2017;96:e7540. 17. Kuang Y, Hong Q, Chen Q, Fu Y, Ai A, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing invitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014;101:105–11. 18. Liu Y, Chen Q, Yu S, Wang Y, He W, Chang HY-N, Wang B, Gao H, Long H, Wang L, Lyu Q, Ai A, Kuang Y. Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing IVF/ICSI: a prospective randomized controlled trial. Clinical Endocrinology. 2018;88:442–52. 19. Mourad S, Brown J, Farquhar C. Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;1:CD012103. 20. Fedorcsák P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, Omland AK, Abyholm T, Tanbo T. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19:2523–8. 21. Orvieto R, Meltcer SR, Rabinson J, Rabinson J, Anteby EY, Ashkenazi J. The influence of body mass index on in vitro fertilization outcome. Int J Gynecol Obstet. 2009;104:53–5.

Journal

Reproductive Biology and EndocrinologySpringer Journals

Published: May 28, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off