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ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 159-164

Clomiphene citrate or medroxyprogesterone acetate with human menopausal gonadotropin in poor responders during In vitro fertilization/intracytoplasmic sperm injection treatments combined with embryo cryopreservation?


Department of Assisted Reproduction, Shanghai Towako Hospital, Shanghai 200013, China

Date of Submission17-Oct-2018
Date of Web Publication27-Sep-2019

Correspondence Address:
Lu Fang
Department of Assisted Reproduction, Shanghai Towako Hospital, No. 477, Futexiyi Road, Shanghai 200013
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.268162

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  Abstract 


Objective: This study aimed to compare the efficacy of clomiphene citrate (CC) with human menopausal gonadotropin (hMG) and that of medroxyprogesterone acetate (MPA) with hMG in poor responders defined according to the Bologna criteria.
Methods: The data of patients with poor ovarian response (POR) according to the Bologna criteria from September 2016 to November 2017 were retrospectively reviewed. All participants received either CC + hMG or the progesterone-primed ovarian stimulation protocol (PPOS) protocol.
Results: A total of 340 patients and 563 in vitro fertilization cycles were analyzed in this study. The incidence of spontaneous luteinizing hormone (LH) surge and the mean LH level on trigger day were significantly lower in the PPOS group than in the CC + HMG group (0.04% vs. 3.49% and 4.26 ± 3.59 vs. 9.38 ± 6.92 mIU/mL, respectively, P < 0.05); however, the incidence of premature ovulation was similar between the two groups. The number of viable embryos harvested was not statistically different between the two groups (1.7 ± 1.1 vs. 1.5 ± 0.8, P = 0.06). The mean dose and duration of hMG were significantly higher in the PPOS group than in the CC + hMG group (908.7 ± 556.6 vs. 177.9 ± 214.5 IU and 6.0 ± 3.4 vs. 1.2 ± 1.5 days, respectively, P < 0.05). However, the number of oocytes retrieved, number of metaphase II oocytes, and fertilization rate were comparable between the two groups.
Conclusions: The CC with low-dose gonadotropin strategy was superior to the MPA with hMG protocol for POR.

Keywords: Clomiphene Citrate; In vitro Fertilization/Intracytoplasmic Sperm Injection; Medroxyprogesterone Acetate; Mild Ovarian Stimulation; Poor Responder


How to cite this article:
Fang L, Qi XJ, Zhu H. Clomiphene citrate or medroxyprogesterone acetate with human menopausal gonadotropin in poor responders during In vitro fertilization/intracytoplasmic sperm injection treatments combined with embryo cryopreservation?. Reprod Dev Med 2019;3:159-64

How to cite this URL:
Fang L, Qi XJ, Zhu H. Clomiphene citrate or medroxyprogesterone acetate with human menopausal gonadotropin in poor responders during In vitro fertilization/intracytoplasmic sperm injection treatments combined with embryo cryopreservation?. Reprod Dev Med [serial online] 2019 [cited 2019 Nov 18];3:159-64. Available from: http://www.repdevmed.org/text.asp?2019/3/3/159/268162




  Introduction Top


The management of patients with poor ovarian response (POR) remains controversial and has been a challenge to reproductive specialists for decades. A systematic review suggested 41 different definitions of POR,[1] causing confusions among clinicians, researchers, and patients. To standardize the definition of POR, Ferraretti et al.[2] proposed a new criteria, known as the “Bologna criteria,” based on three conditions: (i) advanced maternal age (≥40 years) or any other risk factors for POR, (ii) ≤3 oocytes with a conventional stimulation protocol, and (iii) an abnormal ovarian reserve test (i.e., antral follicle count <7 or anti-Müllerian hormone <1.1 ng/mL). Two of these three criteria are required for a POR diagnosis. Patients with POR have high cycle cancellation rates, low pregnancy rates, and low live birth rates during in vitro fertilization (IVF) treatment.[3],[4] Although various ovarian stimulation strategies have been adopted to increase clinical pregnancy rates, there is fair evidence, showing that clinical pregnancy rates after IVF are not substantially different among different ovarian stimulation protocols.[5]

The mild ovarian stimulation protocol was first introduced in 1999, and the distinct definition for this concept was proposed in 2007.[6],[7] The benefits of mild ovarian stimulation protocols include cost reductions, simple treatment, and patient friendliness. Clomiphene citrate (CC) is an estrogen agonist/antagonist that works by blocking estrogen receptors in the pituitary gland and reducing the normal decline in follicle-stimulating hormone (FSH) production.[8],[9] The introduction of CC into mild ovarian stimulation could sharply reduce cost, but results in a similar pregnancy rate to that of the conventional IVF protocol in poor responders.[10],[11],[12],[13]

The medroxyprogesterone acetate (MPA) with human menopausal gonadotropin (hMG) protocol is a novel ovarian stimulation strategy used in recent years, which is also called the progesterone-primed ovarian stimulation (PPOS) protocol. This protocol has been reported to prevent spontaneous luteinizing hormone (LH) surges and premature ovulation in the IVF program for poor responders.[14] It provides an alternative treatment for poor responders. However, studies about the difference between the two ovarian stimulation strategies (CC with hMG and MPA with hMG) are scarce.

In this study, we attempted to compare the efficiency between the CC with hMG and MPA with hMG protocols in poor responders according to the Bologna criteria. The primary aim of this study was to compare the numbers of retrieved oocytes, metaphase II (MII) oocytes, and viable embryos. The secondary objective was to compare the incidence of spontaneous LH surge, premature ovulation rate, and clinical pregnancy rate after frozen-thawed embryo transfer (FET).


  Methods Top


Study setting and patients

Patients who underwent IVF/intracytoplasmic sperm injection (ICSI) from September 2016 to November 2017 at the Department of Assisted Reproduction were retrospectively reviewed. Women were included in the study only if they fulfilled the definition of POR based on the Bologna criteria. The exclusion criteria were maternal age >45 years, increased body mass index (>30 kg/m 2), history of endocrine or metabolic disorders, and severe endometriosis. The study was approved by the local institutional review boards. All data were extracted from the departmental medical records.

Ovarian stimulation protocols

Patients who were classified as poor responders according to the Bologna criteria were routinely treated with either the CC with hMG or MPA with hMG protocol at our center. In the CC group, 50 mg/day CC was initiated on cycle day 3. On cycle day 8, 150 IU hMG (Shanghai Lizhu Pharmaceutical Co., Shanghai, China) every other day was administered to promote late follicular development until the trigger day. Transvaginal ultrasonography and serum hormone measurements were performed simultaneously. Hormone levels were measured using the enzyme immunoassay method (AIA-600II analyzer; TOSOH, Tokyo, Japan). Oocyte maturation was induced using triptorelin (0.1 mg; Decapeptyl; Ferring GmbH, Kiel, Germany) when at least 1 follicle had a mean diameter of 18 mm in the CC group. Oocyte retrieval was performed 34–36 h later. For cases with at least 1 mature follicle (oocyte diameter ≥15 mm) and the occurrence of a spontaneous LH surge (LH >20 mIU/mL), triptorelin was administered immediately. Oocyte retrieval was arranged 24–30 h later, according to the spontaneous LH surge on the scheduled day.[15]

In the MPA group, 10 mg MPA and 150 IU hMG were administered daily from cycle day 3. After 5 days, transvaginal ultrasonography and serum hormone measurements were performed every other day. When at least 1 follicle was 18 mm in diameter, the final stage of oocyte maturation was stimulated with triptorelin (0.1 mg) and human chorionic gonadotropin (2,000 IU). Oocyte retrieval was performed 34–36 h later.

In vitro fertilization and embryo culture

Before oocyte retrieval, the presence of dominant follicles was confirmed using transvaginal ultrasonography. If the dominant follicle disappeared, it was assumed that premature ovulation had occurred before the scheduled time. Oocyte retrieval was performed without sedation or local anesthesia with a 21-G single-lumen aspiration needle. All follicles >10 mm in diameter were retrieved. Retrieved oocytes were fertilized through IVF or ICSI, as clinically indicated. All top-quality embryos (including Grade I and Grade II 6–10 cell blastomeric embryos) were frozen by vitrification on the 3rd day after oocyte retrieval. Non-top-quality embryos were placed in extended culture to day 5 or day 6 until the blastocyst stage.

Endometrial preparation and frozen-thawed embryo transfer

For endometrial preparation, women with normal menstrual cycles followed the natural cycle, women with abnormal menstrual cycles were treated with letrozole, and women with thin endometrium during either their natural cycles or stimulated cycles were given hormone replacement therapy. FET was scheduled based on the timing of ovulation during the natural cycle and letrozole cycle and the timing of progesterone administration during hormone replacement therapy. When pregnancy was achieved, progesterone supplementation was continued until 10 weeks of gestation.

Outcome measures

The primary outcomes in this study were the numbers of retrieved oocytes, MII oocytes, and viable embryos. The secondary outcomes were the incidence of spontaneous LH surge, premature ovulation rates, and clinical pregnancy rates after FET. Spontaneous LH surge was defined as LH >20 mIU/mL during ovarian stimulation. Premature ovulation was defined as follicle rupture before the scheduled time.

Clinical pregnancy was defined as the presence of a gestational sac with or without fetal heart activity under ultrasound examination at 4–6 weeks after FET. The miscarriage rate was defined as the proportion of patients with spontaneous termination of pregnancy. Cycle cancellation was defined as completion of oocyte retrieval without viable embryos.

Statistical analysis

Data were presented as mean ± standard deviation and were analyzed using Student's t-test, Mann–Whitney U-test, and Chi-square test, as appropriate. The Mann–Whitney U-test was used for variables with a nonnormal distribution. P < 0.05 was considered to indicate statistical significance. All data were analyzed using the Statistical Package for the Social Sciences 19.0 software for Windows (SPSS Inc., Chicago, IL, USA).


  Results Top


Patient characteristics

A total of 340 patients and 563 IVF cycles were analyzed in this study. There were 166 patients receiving 315 cycles in the CC group and 174 patients receiving 248 cycles in the MPA group. The baseline patient characteristics are summarized in [Table 1]. No significant differences were observed between the two groups in baseline characteristics, indication for IVF, previous IVF failures, and basal hormonal profile.
Table 1: Baseline characteristics of the poor responders undergoing IVF/ICSI treatment

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In vitro fertilization performance

[Table 2] shows the cycle characteristics of the two regimens. Patients did not differ in the numbers of oocytes collected, MII oocytes, and viable embryos (P > 0.05). However, the dose of hMG was significantly lower in the CC group than in the MPA group (177.9 ± 214.5 vs. 908.7 ± 556.6 IU), with a mean difference of −730.8 IU. In addition, a significantly shorter duration of hMG treatment was used in the CC group, with a mean difference of 4.8 days. A total of 55 cases in the CC group and 53 cases in the MPA group were cancelled with no viable embryo. The rate of cycle cancellation with no embryos was slightly higher in the MPA group than in the CC group; however, the difference was not statistically significant (21.37% vs. 17.46%, P > 0.05).
Table 2: Stimulation and embryonic characteristics of the patients (mean ± SD)

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[Figure 1] shows that the mean LH level on trigger day was 9.38 ± 6.92 and 4.26 ± 3.59 mIU/mL in the CC group and the MPA group, respectively. The incidence of spontaneous LH surge (>20 mIU/mL) was 2.53% (8/315) in the CC group and 0.04% (1/248) in the MPA group (P < 0.05). Although the incidence of spontaneous LH surge and the mean LH level on trigger day were significantly lower in the MPA group than those in the CC group (4.26 ± 3.59 vs. 9.38 ± 6.92 mIU/mL and 0.04% vs. 3.49%, respectively, P < 0.05), the rate of premature ovulation was similar between the two groups. The FSH level on trigger day was higher in the CC group, but there was no statistically significant difference (16.31 ± 11.42 vs. 15.99 ± 5.52 mIU/mL, P = 0.84).
Figure 1: Serum hormone profiles during ovarian stimulation with the two regimens. Blue lines represent the CC group; red ones represent the MPA group. *P < 0.05 at the time point. CC: Clomiphene citrate; MC: Menstrual cycle; MPA: Medroxyprogesterone acetate.

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Pregnancy outcomes in frozen-thawed embryo transfer cycles

A total of 81 women completed 93 cryopreserved embryo transfer cycles in the CC group and 66 women completed 79 FET cycles in the MPA group until the end of study period. There were 110 embryos originated from IVF, 50 embryos from ICSI in the CC group, and 99 embryos from IVF, 39 embryos from ICSI in the PPOS group. There was no statistical difference in the two groups (P = 0.61) concerning to the proportion of embryos originated from IVF/ICSI. The CC group showed a slightly higher clinical pregnancy rate per transfer than the MPA group; however, the difference was not statistically significant (28.0% vs. 26.6%, P = 0.87). The implantation rates and miscarriage rates were similar between the two groups, indicating that the embryos shared similar development potential [Table 3]. There was no ectopic pregnancy in both the groups.
Table 3: Pregnancy outcomes of frozen-thawed embryos obtained using the two regimens

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  Discussion Top


In this study, we compared the efficacies of two ovarian stimulation protocols in poor responders based on the Bologna criteria. The results indicated that the use of CC or MPA with hMG resulted in similar quantities of oocytes retrieved, MII oocytes, and viable embryos. However, the CC with hMG protocol significantly reduced the dose and duration of gonadotropins. Furthermore, CC was as effective as MPA in preventing premature ovulation in poor responders, although MPA can effectively block premature LH surge through pituitary suppression.

CC has been widely used as the most traditional medicine for ovulation induction.[16] It is a nonsteroidal triphenylethylene derivative that exhibits both estrogenic agonist and antagonist properties.[17],[18],[19] About 85% of CC is eliminated from the blood after 6 days, although traces may remain in the circulation for months. At the cellular level, CC binds estradiol receptor (ER) for a long period of time, thus depleting ER concentration in blood circulation.[20] In ovulation induction, CC depletes ER at the level of the hypothalamus, suppressing the negative feedback by circulating estrogen.[9],[20] This triggers the hypothalamus to secrete gonadotropin-releasing hormone that will stimulate endogenous release of FSH and LH by the pituitary.[9] Hence, it requires a low dose of exogenous gonadotropins.[21],[22] In contrast, administration of MPA from the beginning of ovarian stimulation may lead to stronger pituitary suppression.[19],[23] It was reported that the extent of pituitary suppression is directly associated with the hMG dose. In this study, the dose and duration of hMG treatment in the CC group was 4-fold lower than those in the MPA group (P < 0.05). The result strongly suggested the advantage of CC in terms of reducing the gonadotropin doses.

Usually, CC is used for 5 days in ovulation induction. When it is administered for more than 5 days, LH release decreases. Thus, clinicians used CC as a suppressive agent for premature LH surge in many IVF protocols, especially in mild stimulation.[18],[19] Spontaneous LH surge is infrequently encountered in controlled IVF treatment. When it occurs, it always results in cycle cancellation, which is an extremely disappointing outcome for both patients and clinicians. Although spontaneous LH surge has been frequently mentioned in the literature, the level of spontaneous LH surge remains disputing.[24] Most researches selected LH >10 mIU/mL as a cutoff point. Messinis and Templeton reported that CC administration for 15 days (days 2 to 16 of the cycle) produced a continuous and progressive increase of basal LH levels with no LH surge and no ovulation in mild stimulation.[25] Thus, we selected LH >20 mIU/mL as a cutoff level. In this trial, the incidence of spontaneous LH surge was 2.53% and 0.04% in the CC and MPA groups, respectively, which suggested that both CC and MPA can effectively block premature LH surge in poor responders. Furthermore, administration of MPA from the beginning of ovarian stimulation may lead to stronger pituitary suppression.[19],[26] Therefore, the LH levels on trigger day were significantly lower in the MPA group than in the CC group (4.26 ± 3.59 vs. 9.38 ± 6.92 mIU/mL, P < 0.05), which was consistent with the findings of earlier studies.[14] Despite the low LH levels on trigger day in the MPA group, the premature ovulation rates were similar between the two groups. The mechanism of premature ovulation in poor responders is not known to date.

The serum FSH levels on trigger day were slightly higher in the CC group than in the MPA group, but without a statistical difference. One explanation for this result is the limited number of participants and the narrow range of FSH levels. In addition, while MPA decreases premature ovulation in POR through pituitary suppression, it also suppresses FSH production in the pituitary gland. In contrast, CC stimulates endogenous gonadotropins released by the pituitary. The different mechanisms of the two medicines result in different FSH levels on trigger day.

The numbers of oocytes retrieved, MII oocytes, and viable embryos in the CC group were similar to those in the MPA group. A large randomized controlled trial reported that the mild stimulation group had a significantly lower oocyte yield (2.7 vs. 4.8) and a significantly higher cycle cancellation rate (13.0% vs. 2.7%) than the traditional stimulation group.[10] Our trial showed a slightly smaller number of retrieved oocytes (1.8 ± 1.3) and slightly higher cycle cancellation rate (17.46%) in the CC group. This can be accounted for the difference in the selected patients. The patients selected in this trial had a smaller antral follicle count (3.1 ± 1.8) than those in the aforementioned randomized controlled trial, and antral follicle count is highly associated with the treatment outcome.

In this study, the two protocols used a freeze-all embryo strategy to prevent any potential adverse impact of ovarian stimulation on the endometrial receptivity.[27] CC binds to ER throughout the body, including the endometrium. It reduces growth of the endometrium compared to the natural cycle. Administration of MPA from the follicle phase also affects the growth of the endometrium. On the other hand, with improvements in cryopreservation techniques, the success rates of FET have consistently increased over the last decade.[28] Another advantage of the freeze-all embryo strategy is that recent data suggested that children born from frozen-thawed embryo cycles showed fewer perinatal morbidity and mortality compared to children born from fresh cycles.[29] The clinical pregnancy rate from FET cycles in the CC group was similar to that in the MPA group – it was slightly higher in the CC group with no statistical difference (P > 0.05). This result demonstrated that the two protocols had similar embryo developmental potential in poor responders. Further large-scale studies are needed to determine the live birth rate in the two groups.

This study has several limitations. Our study is a retrospective analysis, and selection bias might be present. Another limitation is the fact that some of the participants had not finished their FET cycle by the time of submission owing to reasons such as poor uterine environment or divorce. Third, the sample size was determined to have sufficient power to distinguish the difference in the number of retrieved oocytes and viable embryos; however, it was underpowered for comparisons of live birth. Thus, the results of this study should be interpreted with caution.

In conclusion, the CC with hMG protocol has distinct advantages including significantly reduced use of gonadotropins, low cost for patients, and acquiring similar numbers of oocytes and viable embryos compared with the MPA with hMG protocol in PORs. Thus, the CC with low-dose gonadotropin strategy is superior over the MPA with hMG protocol for the POR population. However, there is insufficient evidence to recommend a particular treatment for poor responders, and more randomized controlled trials with larger patient populations are needed to determine an appropriate approach for poor responders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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