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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 156-162

A modified ultra-long downregulation protocol improves pregnancy outcomes in high body mass index patients undergoing In vitro fertilization/intracytoplasmic sperm injection treatment

1 Institute of Reproductive and Stem Cell Engineering, Basic Medicine College, Central South University, Changsha 410000, China
2 Institute of Reproductive and Stem Cell Engineering, Basic Medicine College, Central South University; Reproductive Center, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410000, China
3 Institute of Reproductive and Stem Cell Engineering, Basic Medicine College, Central South University; Reproductive Center, Reproductive and Genetic Hospital of CITIC-XIANGYA; Key Laboratory of Reproductive and Stem Cell Engineering, Ministry of Health, Changsha 410000, China
4 Reproductive Center, Reproductive and Genetic Hospital of CITIC-XIANGYA; Key Laboratory of Reproductive and Stem Cell Engineering, Ministry of Health, Changsha 410000, China

Date of Submission05-Dec-2019
Date of Decision03-Jan-2020
Date of Acceptance03-Mar-2020
Date of Web Publication04-Sep-2020

Correspondence Address:
Fei Gong
Department of Reproductive Center, Reproductive and Genetic Hospital of CITIC-XIANGYA, No. 84, Xiangya Road, Kaifu District, Changsha 410000
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.294315

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Objective: Overweight and obesity are increasingly epidemic and negatively related to reproductive outcome. The aim of this study was to investigate the advantages of a modified ultra-long downregulation protocol on pregnancy outcomes of patients with high body mass index (BMI) undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), compared to the long protocol (LP).
Methods: We retrospectively analyzed the clinical data of 3,920 infertile patients at the Reproductive and Genetic Hospital of Citic-Xiangya from January 2012 to December 2017 by propensity score matching (PSM). Patients were divided into two groups: modified ultra-LP (MULP) (n = 1,960) and LP (n = 1,960).
Results: In the MULP group, live birth rate (52.65% vs. 46.79%,P < 0.001, odds ratio [OR]: 1.784, 95% confidence interval [CI]: 1.563–2.036), clinical pregnancy rate (62.50% vs. 57.91%, P = 0.003, OR: 1.211, 95% CI: 1.066–1.377), and implantation rate (53.24% vs. 49.65%, P = 0.004, OR: 1.155, 95% CI: 1.048–1.272) were statistically significantly higher than those of the LP group. Moreover, the cycle cancellation rates (12.70% vs. 15.15%, P = 0.027, OR: 0.815, 95% CI: 0.68–0.977), abortion rates (12% vs. 14.8%, P = 0.046, OR: 0.785, 95% CI: 0.619–0.996), and ectopic pregnancy rates (1.06% vs. 2.11%, P = 0.04, OR: 0.497, 95% CI: 0.252–0.98) were lower than those in the LP group.
Conclusion: The modified ultra-long downregulation protocol improved the pregnancy outcomes in patients with high BMI undergoing IVF/ICSI treatment, providing a potential option for physicians when deciding an optimized ovary stimulation protocol for high BMI patients.

Keywords: Endometrial Receptivity; High Body Mass Index; In vitro Fertilization/Intracytoplasmic Sperm Injection; Modified Ultra-Long Protocol; Pregnancy Outcome

How to cite this article:
Chen HJ, Li Y, Li XF, Lin G, Lu GX, Gong F. A modified ultra-long downregulation protocol improves pregnancy outcomes in high body mass index patients undergoing In vitro fertilization/intracytoplasmic sperm injection treatment. Reprod Dev Med 2020;4:156-62

How to cite this URL:
Chen HJ, Li Y, Li XF, Lin G, Lu GX, Gong F. A modified ultra-long downregulation protocol improves pregnancy outcomes in high body mass index patients undergoing In vitro fertilization/intracytoplasmic sperm injection treatment. Reprod Dev Med [serial online] 2020 [cited 2021 Nov 30];4:156-62. Available from: https://www.repdevmed.org/text.asp?2020/4/3/156/294315

  Introduction Top

Body mass index (BMI) is a measurement parameter used to categorize people who are overweight and/or obese according to the World Health Organization.[1] People with a BMI of 25–29 kg/m2 are classified as overweight and those with a BMI above 30 as obese. Increasing evidence shows that the number of overweight and obese people is on a steep rise and as a result, the world is facing numerous health problems and related disorders.[2],[3]

Women of childbearing age with high BMI may have shorter luteal phases, longer follicular phases,[4] and lower levels of follicle-stimulating hormone (FSH) and progesterone,[5] due in part to obesity's effects on the hypothalamus–pituitary–gonadal axis.[5] Moreover, lower peak estradiol concentrations were also noted in obese women, which is associated with impaired oocyte quality and cycle outcomes.[6] Accordingly, hyperandrogenemia, hypersecretion of luteinizing hormone (LH), insulin resistance and hyperinsulinemia, and hyperlipidemia often co-exist in women with high BMI.[7] Moreover, increased androgen activity can also be found in such patients.[8]

Previous studies revealed that overweight or obese women had significantly lower clinical pregnancy rate, live birth rate, and higher miscarriage rate following assisted reproductive technology (ART) treatment.[9],[10] Consequently, some researchers proposed that maternal weight loss in the preconception period may improve reproductive functions and ART outcomes.[11],[12] Bellver et al. reported that the chances of pregnancy usingin vitro fertilization (IVF) decreased by 0.84 units with an increase in BMI by one unit, and that reduction of BMI by one unit increased the odds of pregnancy by 1.19.[13] Conversely, a recent large randomized clinical trial (RCT) published in the New England Journal of Medicine investigated whether weight loss increased the chances of conception, yielding a negative outcome. In obese infertile women, modest weight loss preceding infertility treatment did not result in higher rates of healthy singleton birth,[14] which is in accordance with the findings of Einarsson et al.[15]

The current study aims to investigate whether modified ultra-long downregulation protocol can improve pregnancy outcomes in high BMI patients undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment.

  Methods Top

Our study was approved by the Ethics Committee of the Reproductive and Genetic Hospital of Citic-Xiangya (LL-SC-2018). Patients were not asked to participate in this study and did not write an informed consent as it is a retrospective analysis based on the existing data.

The study included patients with the following criteria: (1) age <35 years old, (2) BMI ≥ 25 kg/m2 before downregulation, (3) those with first IVF/ICSI cycle, (4) those with fresh cycle embryo transfer, (5) those with infertility due to tubal factors or male factors, and (6) those with regular menstruation. Exclusion criteria were those with (1) endometritis, (2) endometriosis, (3) uterine malformations (mediastinum ≥0.6 cm, single-horned uterus, and double uterus), (4) untreated hydrosalpinx, (5) intrauterine adhesions, (6) scarred uterus, (7) uterine fibroids compressing inner endometrium, and (8) polycystic ovary syndrome (PCOS).

In the current retrospective study, a total of 5,103 infertile patients' information from January 2012 to December 2017 was extracted from the electronic medical database in the Reproductive and Genetic Hospital of Citic-Xiangya. By considering live birth as the primary outcome, we matched patients' age, BMI, infertility duration, basal estradiol (E2), progesterone (P), FSH, and LH level by propensity score matching (PSM) with 1:1 ratio because of the incomparability in patients' baseline characteristics. Afterward, 3,920 patients were selected in the analysis. The patients were divided into two groups: modified ultra-long protocol (MULP) group (n = 1,960) and long protocol (LP) group (n = 1,960)[Figure 1].
Figure 1: Flow chart.

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For MULP, on days 20–23 of the patient's first menstrual cycle, 1.5–1.875 mg gonadotropin-releasing hormone agonist (GnRH-a) (Diphereline, Ipsen Pharma Biotech, France) was intramuscularly injected, and it was repeated on days 20–23 of the following menstrual cycle. After 13–20 days, when enough pituitary-ovarian suppression was achieved (standard:[1] serum concentration of E2 <50 pg/mL,[2] serum concentration of P < 1.0 ng/mL,[3] serum concentration of LH ≤ 5 mIU/mL,[4] endometrium thickness ≤ 5 mm and follicular diameter ≤ 10 mm by ultrasound, and[5] no corpus luteum cyst was observed in both ovaries), human menopausal gonadotropin (hMG, 75 U–375 U/d, Menopur; Ferring Pharmaceuticals, Kiel, Germany) was injected for 4–5 days, and the dosage was adjusted according to the ovarian response.

For LP, GnRH-a 1.5–1.875 mg was administrated on days 20–23 of the menstrual cycle. After 13–20 days, following enough pituitary-ovarian suppression, 150–300 IU recombinant human FSH (rhFSH, Gonal-F; Merck Serono SA, Geneva, Switzerland) was injected, and the dosage was adjusted every 3–4 days according to the ovarian response.

For both groups, recombinant human chorionic gonadotropin (hCG) (Ovidrel, Merck Serono Biopharma; LIVZON, China) 5,000–10,000 IU was administered after confirming adequate follicle stimulation by ultrasound and hormone concentrations to trigger: 2–3 follicles ≥ 18 mm in diameter; follicles ≥ 18 mm accounting for 60%–70%; follicles ≥ 14 mm in diameter; and follicles ≥ 20 mm made up 40%–50% of follicles ≥ 14 mm in diameter; serum E2 level was increased enough (200–300 pg/mL multiplied by follicles ≥ 14 mm in diameter).

Patients were scheduled for oocyte retrieval 35–36 h following hCG administration. Indications and techniques for oocyte retrieval, oocyte and embryo culture, insemination, ICSI, and embryo transfer (ET) were based on the routine of the center (ISO 9001 Certification).

The count of live birth events was used to define live birth, while clinical pregnancy was defined as existence of gestational sac(s) with fetal heart activity by ultrasound at week 4 after ET. Implantation rate was defined as the total number of embryos transferred divided by the number of sacs. Thereafter, miscarriage was defined as intrauterine pregnancy loss after confirmation of gestational sacs.[16]

Statistical analyses were performed using Statistical Package for Social Sciences for Windows, version 25.0 (SPSS Inc., Chicago, IL, USA). Homogeneity of variance and normality of data were estimated using the Levene and Kolmogorov–Smirnov tests, respectively. Values were expressed as mean ± standard deviation. Comparison of quantitative variables between groups was performed using the t-test or the Mann–Whitney U-test according to their normality. Qualitative variables were compared by the Chi-square test. Binary and multivariant logistic regression analysis of confounding factors were carried out. Statistically significant data were indicated with P < 0.05.

  Results Top

The demographic and clinical characteristics of the total number of patients are illustrated in [Table 1]. All the baseline characteristics did not differ significantly except antral follicle count (AFC). Patients in the MULP group had statistically significantly higher AFC (21.95 ± 9.49 vs. 21.26 ± 8.43, P = 0.015). As depicted in [Table 2], the MULP group was characterized by longer controlled ovarian hyperstimulation (COH) day, more consumption of gonadotropin (Gn) (2,979.94 ± 1,037.16 vs. 2,238.51 ± 1,003.23, P < 0.001), and thicker endometrium, but no obvious differences in endometrium morphology (III-1, III-2, III-3, III-unclear) between the two groups. Serum concentration of E2 and LH on hCG administration day were significantly lower in the MULP group. Additionally, the number of oocyte retrieved (11.34 ± 5.29 vs. 12.48 ± 5.79, P < 0.001), the cleavage rate (97.19% vs. 97.71%, P = 0.002), and the number of embryos transferred (1.94 ± 0.25 vs. 1.96 ± 0.21, P = 0.013) were also lower in the MULP group, There was no difference in the serum P level on hCG day, the fertilization rate, the rate of IVF and ICSI, different stages of embryo transferred, and good-quality embryo transferred rate.
Table 1: Demographic and clinical characteristics of the total population (n = 3,920)

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Table 2: COH characteristics after modified ultra-long and long protocol

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The pregnancy outcomes are demonstrated in [Table 3]. The MULP group achieved higher live birth rates (52.65% vs. 46.79%, P < 0.001, odds ratio [OR]: 1.784, 95% confidence interval [CI]: 1.563–2.036), clinical pregnancy rates (62.50% vs. 57.91%, P = 0.003, OR: 1.211, 95% CI: 1.066–1.377), and implantation rates (53.24% vs. 49.65%, P = 0.004, OR: 1.155, 95% CI: 1.048–1.272). Furthermore, they achieved lower cycle cancellation rates, lower ectopic pregnancy rates, and miscarriage rates. The reasons for cycle cancellation are detailed in [Table 4]. However, ovarian hyperstimulation syndrome (OHSS) rates were a litter higher in the MULP group (4.54% vs. 2.96%, P = 0.009, OR: 1.56, 95% CI: 1.114–2.185). There was no difference in mild and severe OHSS between the two groups; only higher moderate OHSS (31 vs. 12, P = 0.004, OR: 2.609, 95% CI: 1.336–5.095) was achieved in the MULP group. There was no significant difference in singleton or multiply pregnancy.
Table 3: Pregnancy outcomes after modified ultra-long and long protocol

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Table 4: Reasons for cycle cancellation

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In order to adjust for confounding factors, we took live birth rate as primary outcome and made a binary logistic regression analysis of these confounding factors. Then, significant factors were picked up into multivariant logistic regression analysis. The results showed that MULP was a positive factor to live birth rate. However, age and infertility duration were negative factors [Table 5] and [Table 6].
Table 5: Binary logistic regression analysis of confounding factors

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Table 6: Multivariant logistic regression analysis of significant confounding factors

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  Discussion Top

In our MULP group, the live birth rates, clinical pregnancy rates, and implantation rates were significantly improved, which were consistent with those of previous studies.[17],[18] The ectopic pregnancy rates, miscarriage rates, and cycle cancellation rates were significantly lower since those have been found to be higher in obese patients undergoing COH and IVF.[19]

It is clear that women with higher BMIs usually have insulin resistance and hyperinsulinemia, which decreases the production of sex hormone-binding globulin, resulting in a larger quantity of circulating free androgens, due to which their aromatization increases the circulating free estrogens.[20] Moreover, the resultant hypersecretion of LH also contributes to the higher levels of estrogen, which alters endocrine milieu and impairs folliculogenesis. On the other hand, estrogen suppresses the release of FSH from the pituitary gland, thus hampering follicular recruitment and ovulation.[5] The entire gonadal axis system could be synchronized after the injection of long-acting GnRH-a 3.75 mg once a month/1–2 times, which could effectively prevent premature LH surges and thus improve fertilization and pregnancy rates.[21] To inhibit oversuppression of the pituitary after long-term use of the full dose of long-acting GnRH-a, we adopted an MULP, in which the dose of long-acting GnRH-a was reduced from 3.75 mg to 1.875 mg and injected twice. The MULP protocol was reported to achieve a better pregnancy outcome in patients with endometriosis, PCOS, and insufficient downregulation.[22] The double desensitization could suppress gonadotropins to a lower level, especially LH level, which could result in lower serum androgen, thus inhibiting premature endogenous LH surge and promoting oocyte survival.[17] However, sometimes, the initial serum LH was suppressed to an extremely low level, which, in turn, affected the synthesis of E2. Consequently, the use of hMG, which contains 75 IU FSH and 75 IU LH to initiate, was necessary. The serum E2 level and LH level on hCG administration day in the MULP group were lower than that in the LP group, and the number of oocyte retrieval was less, all of which were statistically significant, but comparable in terms of clinical significance. This indicates that using hMG to initiate can be a successful solution. More importantly, patients in the MULP group received less embryos transferred but achieved significantly higher implantation rate, which probably suggests that the MULP could improve the oocyte quality instead of its quantity, which is in accordance with a previous study.[23] A study showed that the increased BMI was associated with the poor oocyte quality because of the poor morphology of the cumulus–oocyte complex.[5] The increased BMI was also linked with the increased androgen level, contributing to follicular degeneration and decreased oocyte maturation.[24] Our MULP was characterized by two times' injections of GnRH-a, through which the androgen can be significantly reduced.[25] What's more, androgen production can be directly inhibited by the decreased LH level.[26] The decrease of androgen level could reduce the adverse effects on the follicle development and avoid the excessive recruitment of follicles, thus improving oocyte quality and pregnancy outcomes.[17]

Leptin levels increase with increasing BMI, contributing to the dysregulation of gonadotropin-releasing hormone (GnRH), alteration in ovarian steroidogenesis, and inhibition of folliculogenesis.[27] Alterations to these hormonal levels can lead to decreased oocyte quality and impaired endometrial receptivity.[19] However, the MULP method was claimed to improve endometrial receptivity by preventing the forward transformation of the window of implantation because of the lower serum concentration ofPand the ratio of P/E2 on the hCG trigger day.[18] Unfortunately, we did not observe this result in our current study. It was proposed that the high level of LH could mediate estrogen's and Preceptors' expression and appearance prematurely on the endometrium, and the forward endometrial transformation to secretory phase had adverse effect on embryo implantation.[28] We assumed that the decreased LH level could inhibit the forward shift of the implantation window and improve endometrial receptivity in our study by the mechanism above. Additionally, thicker endometrium was achieved in the MULP group, which is in accordance with our previous study. Our previous study also demonstrated that patients in the MULP group had better endometrial blood flow and morphology, all of which are vital for successful embryo implantation.[18]

We previously collected endometrial sample from patients with MULP and LP 6 days after oocyte retrieval and did some basic research. Our results showed that more fully developed pinopodes (the morphology marker of endometrial receptivity) were detected under telescope in patients with MULP than patients with LP. More interestingly, the expression of some other endometrial receptivity functional markers such as LPAR3, COX2, and HOXA10 was also higher in MULP group in either messenger RNA level or protein level, contributing to a more receptive endometrium.[29]

Studies have suggested that obesity-induced infertility and hyperandrogenism can be corrected by deleting the insulin receptor in the theca cell based on a mouse model.[7] Meanwhile, other studies reported that certain genes are responsible for obesity and found their overlap with human infertility and reproduction.[30] Thus, we propose a theory that our MULP method may improve the endometrial receptivity by affecting the insulin signaling pathway and the genes' expression. Accordingly, it was demonstrated that GnRH-a could mediate IκB signal pathway in a time- and dose-dependent manner, thus affecting the insulin signal pathway and improving endometrial receptivity.[31] Whether the related gene expression could be affected by GnRHa and the regulation mechanism requires further investigation.

However, except for the strengths mentioned above, limitations also existed in the current study which cannot be ignored; most of which are related to the retrospective nature of the study. First, an important evaluation index such as anti-Müllerian hormone (AMH) was not carried out, which could have indicated the number of oocyte retrieval. Then, serum testosterone level, oral glucose tolerance test, and insulin resistance test were not routine examination items, so the patients' baseline characteristics were not as complete as possible. On the other hand, even though we matched the patients' baseline by PSM, selection bias cannot be completely excluded. Therefore, in order to verify our results, a well-designed RCT is required in future investigations.

In conclusion, These results suggest that the MULP may improve pregnancy outcomes for patients with high BMI that are undergoing IVF/ICSI treatment, providing a potential option for physicians when deciding an optimized ovary stimulation protocol for high BMI patients.


Thanks to my colleagues for their help in data retrieval and analysis and the revision of the paper.

Financial support and sponsorship

The study had financial support from the National Natural Science Foundation of China (grant No. 81501328).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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