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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 2  |  Page : 69-76

Impact of progesterone on inhibins during controlled ovarian stimulation


Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

Date of Web Publication17-Oct-2017

Correspondence Address:
Yan-Ping Kuang
Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.216866

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  Abstract 


Background: To explore the impact of progesterone on inhibins during controlled ovarian stimulation in women with normal ovarian reserve and to compare cycle characteristics and pregnancy outcomes in subsequently frozen-thawed embryo transfer (FET) cycles.
Methods: A total of 93 patients were randomly divided into two groups, study group (human menopausal gonadotropin [hMG] + medroxyprogesterone acetate [MPA]) and control group (short protocol). Serum hormones were detected on day 3 before ovarian and day 10-12, the trigger day, and the day after trigger (approximately 10 h after trigger). Viable embryos were cryopreserved for later transfer in both protocols.
Results: In the study group, inhibins signifcantly increased during ovarian stimulation, and the average inhibins level on the trigger day was signifcantly higher than the basal levels. Inhibin A level increased significantly to 2046.7 ± 1280.5 ng/L after trigger 10 h. Serum inhibin B level slightly decreased at the time of trigger 10 h later compared with the trigger time but did not reach a significant difference. The number of oocytes retrieved in study group was similar to that in control (10.5 ± 4.5 vs. 9.0 ± 5.2, P > 0.05). No statistically significant differences were found in the clinical pregnancy rate (47.4% vs. 52.2%, P > 0.05), implantation rate (36.5% vs. 36%), and live birth rate (43.4% vs. 39.1%, P > 0.05) between the two groups.
Conclusions: The high level of progesterone did not affect the secretion in granulosa cells during the controlled ovarian stimulation. Therefore, sufficient oocytes/embryos can be obtained by hMG and MPA co-treatment in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatments, with optimal pregnancy outcomes in FET cycles.

Keywords: Controlled Ovarian Stimulation; Inhibins; Progesterone


How to cite this article:
Ye J, Chen QJ, He W, Zhang J, Ye HJ, Fu YL, Lyu QF, Kuang YP. Impact of progesterone on inhibins during controlled ovarian stimulation. Reprod Dev Med 2017;1:69-76

How to cite this URL:
Ye J, Chen QJ, He W, Zhang J, Ye HJ, Fu YL, Lyu QF, Kuang YP. Impact of progesterone on inhibins during controlled ovarian stimulation. Reprod Dev Med [serial online] 2017 [cited 2020 Aug 10];1:69-76. Available from: http://www.repdevmed.org/text.asp?2017/1/2/69/216866




  Introduction Top


In prior decades, whenin vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) relied on fresh embryo transfer, progesterone (P) could not be considered for use during controlled ovarian stimulation (COS) because it was known to have a negative impact on endometrial receptivity. Therefore, few studies reported that P could be used in ovarian stimulation. Steroidal hormones are powerful modulators for pituitary gonadotropin (Gn) secretion and hypothalamus gonadotropin-releasing hormone (GnRH) secretion. Previous studies reported that oral contraceptive pills and synthetic progestin sharply decreased both serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) level, with recovery of normal basal levels after a 5-day washout period.[1]

The achievements of cryopreserved embryo of superior quality and precise thawing have been made possible by advanced vitrification techniques. It is proved that the frozen embryo transfer (FET) strategy could improve the pregnancy and delivery outcomes.[2],[3],[4],[5] Under the strategy of FET in our previous studies, we found that ovarian stimulation under the milieu of high-level P was progestin-primed ovarian stimulation (PPOS), and it was feasible to obtain competent oocytes/embryos in women undergoing IVF/ICSI treatments, with optimal pregnancy outcomes in FET cycles.[6],[7],[8],[9],[10],[11] Besides, a premature LH surge or moderate/severe ovarian hyperstimulation syndrome (OHSS) occurred in an exceedingly low proportion of cases in PPOS. The birth defect rate of the luteal phase ovarian stimulation (LPS) was not higher than that of the short protocol and mild ovarian stimulation.[12]

Inhibins are glycoproteins of the transforming growth factor-β superfamily that are mostly produced by granulosa cells in women. Inhibins have been recognized to play an important role in regulating FSH secretion.[13],[14] Some studies highlight another important role of inhibins in the reproductive axis: the paracrine regulation of gametogenesis in the gonads.[15],[16] They also reported that serum inhibin levels were a surrogate for follicle health and viability.[15] Inhibin B may be a suitable marker of ovarian reserve and ovarian response to exogenous Gn stimulation, whereas inhibin A may indicate follicle maturity.[17],[18],[19],[20],[21]

Most of the previous studies on inhibins focused on the traditional ovarian stimulation that is on the milieu of low P level,[22],[23],[24],[25],[26] and fewer studies measured inhibin on high P level. This study was designed to evaluate the influence of progesterone on inhibins during COS and to compare the cycle characteristics and pregnancy outcomes in subsequently FET cycles between PPOS and the short protocol.


  Methods Top


Study setting and patients

This is randomized, parallel-controlled trial. Women underwent IVF/ICSI for treatment of infertility at the Department of Reproductive Medicine of the 9th People's Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China), from September 2014 to April 2015. The study protocol was approved by the Ethics Committee (Institutional Review Board) of Shanghai 9th People's Hospital. The trial was conducted according to the Declaration of Helsinki for medical research. All participants provided informed consent after counseling for infertility treatments and routine IVF procedures.

Patients who planned to undergo IVF/ICSI were eligible to participate in the study. The following inclusion criteria were used: patients younger than 38 years with regular menstrual cycle (24–35 days) over the previous 3 months, an antral follicle count of 5–15 at the early menstrual cycle phase, and a baseline serum FSH concentration of no more than 10 IU/L. The exclusion criteria were as follows: patients with endometriosis Grade 3 or higher or with the diagnosis of polycystic ovarian syndrome or hyperprolactinemia, who presented a functional ovarian cyst with E2>100 ng/L, received hormonal treatment in the previous 3 months, or showed any contraindication to ovarian stimulation treatment.

Treatment protocol

After transvaginal ultrasound and detection of serum FSH at the early menstrual phase, patients were randomly divided into study group (human menopausal gonadotropin [hMG] + medroxyprogesterone acetate [MPA]) and control group (short protocol). hMG (150-225 IU/d) (Livzon Pharmaceutical Co., China) and MPA (10 mg/d) (Zhejiang Xianju Pharmaceutical Co., China) were administered in study group from menstrual cycle 3/4 days. Follicular monitoring was started from day 10 to 12 and continued at 2–4-day intervals using transvaginal ultrasound to record the number of developing follicles. Serum FSH, LH, estradiol (E2), P, inhibin A, and inhibin B concentrations were measured on the day of the ultrasound examination. The doses of hMG and MPA were adjusted according to the follicle development and hormone levels. When three dominant follicles reached 18 mm in diameter, or one dominant follicle reached 20 mm, the final stage of oocyte maturation was triggered using 0.1 mg of triptorelin (Decapeptyl, Ferring Pharmaceuticals, Germany) or co-triggered by subcutaneous injection of 0.1 mg of triptorelin and 1,000 IU of hCG (Livzon Pharmaceutical Co., China).

The short protocol was used in control group, where 1.36 mg of leuprorelin (Livzon Pharmaceutical Co., China) was administered on menstrual cycle day 2/3, and hMG (150-225 IU/d) was administered daily 1 day after leuprorelin administration. After 7-day hMG administration, ultrasound examination and serum hormone level test were performed, and the dose of hMG was adjusted according to the follicle development and hormone levels. When three dominant follicles reached 18 mm in diameter, or one dominant follicle reached 20 mm, the final stage of oocyte maturation was induced by an intramuscular injection of hCG. If a patient had more than three dominant follicles, 3,000 IU of hCG was administered, whereas in patients with no more than three dominant follicles, 5,000 IU hCG was used for the final stage of oocyte maturation.

All follicles with diameters >10 mm were retrieved. Transvaginal ultrasound-guided oocyte retrieval was performed 36 h to 37 h after the triggering. Depending on semen parameters, the retrieved oocytes were fertilizedin vitro using conventional IVF or ICSI. Embryos were examined for the number and regularity of blastomeres and the degree of embryonic fragmentation on the 3rd day, according to the criteria described by Cummins et al.[27] The freeze-all strategy was implemented for all IVF-/ICSI cycles. Good-quality embryos (including Grade 1 and Grade 2 ≥8-cell embryos) were frozen by vitrification on the 3rd day after oocyte retrieval. Embryos that were not of top quality, including some good-quality embryos required by patients, were placed in extended culture until they reached blastocyst stage. During this stage, only good-morphology blastocysts were frozen on day 5 or day 6.

Hormonal measurement

The levels of FSH, LH, E2, P, inhibin A, and inhibin B in serum were detected on day 3 before initiation of stimulation, day 10–12 (after 7–8 days of stimulation), the trigger day, and the day after trigger (approximate10 h after the injection of GnRH-a and/or hCG). Blood samples were obtained by venipuncture and processed within 2 h after withdrawal. Serum FSH, LH, E2, and P levels were measured with chemiluminescence (Abbott Biologicals B.V., The Netherlands). The upper limit of E2 was 5,000 ng/L. The E2 was also recorded as 5000 ng/L if E2 level was higher than the upper limit. Serum dimeric inhibin A and inhibin B levels were assessed using double-antibody sandwich ELISA (Ansh Labs, Webster, TX, USA). The lower limits of sensitivity were as follows: FSH = 0.06 IU/L, LH = 0.09 IU/L, E2 = 10 ng/L, P = 0.1 μg/L, inhibin A = 10 ng/L, and inhibin B = 10 ng/L.

Endometrium preparation and cryopreserved embryo transfer

In FET cycle, embryo and endometrium were synchronized using the same method in two groups. According to the patients' condition, natural cycle, stimulation cycle, and hormone replacement cycle were selected. For patients with a thin endometrium during either natural cycle or stimulation cycle, hormone replacement treatment was recommended for endometrial preparation. When the endometrial lining thicker than 8 mm, dydrogesterone (Abbott Healthcare Products B.V., The Netherlands) (or E2 plus dydrogesterone) and vaginal progesterone soft capsules (200 mg bid) (Laboratoires Besins International, France) were administered for corpus luteum support. Clinical pregnancy was defined as the presence of a gestational sac with fetal heart activity under ultrasound examination 28 days after embryo transfer. After pregnancy had been achieved, the P supplement was continued until 10 weeks of gestation.

Statistical analysis

In this study, normal distribution quantitative data are presented as mean ± standard deviation (SD), and nonnormal distribution data are presented as the median (interquartile range), determined using SPSS software 17.0 version (SPSS Inc., Chicago, IL, USA). Comparisons of two groups were performed by the independent-sample t-test and paired-sample t-test. Enumeration data were shown as a ratio, and the statistical process was conducted using the Chi-square test. The Mann–Whitney U-test was employed for variables of nonnormal distribution. Differences between groups were considered to be statistically significant if P < 0.05.


  Results Top


Patient characteristics

Ninety-three women included in this study were assigned to study group (hMG + MPA) and control group (short protocol). A profile summary of the study is shown in [Figure 1]. There was no difference in the indication proportions between the two groups. Patients' basic characteristics such as age, body mass index, baseline level of FSH, LH, E2, P, inhibin A, inhibin B, duration of infertility, and antral follicles count were comparable between the two groups [Table 1]. The results showed that there were no differences on the above indexes (P > 0.05).
Figure 1: Profile summary of the pilot study. n represents the number of patients.

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Table 1: Basic characteristic of women in the trial undergoing IVF/ICSI treatment

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Ovarian stimulation parameters and laboratory outcomes

The clinical and cycle characteristics of COH treatment in both groups are listed in [Table 2]. Duration of stimulation was similar in the two groups. HMG dose in study group was significantly higher than that in control group (P< 0.05). The number of follicles with diameters larger than 10 mm or 14 mm was similar in the two groups. The number of oocytes retrieved in study group was slightly higher but did not reach a significant difference in comparison with control group (10.5 ± 4.5 vs. 9.0 ± 5.2; P > 0.05). The rate of oocyte retrieval was similar in the two groups (79.4 ± 15.9% vs. 79.1 ± 24.7%; P > 0.05). No significant differences were found in oocyte maturation rate and cleavage rate between the two groups (P > 0.05). Importantly, we found that the fertilization rate was significantly higher in study group than control group (85.5 ± 26.5% vs. 65.5 ± 20.1%, P < 0.05). However, the fertilization rate in control group was lower than our previous observation,[10] which might have been related to the failed of IVF using conventional IVF. The number of good-quality embryos on day 3 (3.9 ± 3.2 vs. 2.2 ± 1.9 P < 0.05) and cryopreserved embryos (4.0 ± 2.7 vs. 2.6 ± 2.2, P < 0.05) were significantly higher in study group than those in control group. The cycle cancellation rate due to the lack of viable embryos was not significantly different between the two groups (11.7% vs. 15.2%, P > 0.05). No patients experienced moderate or severe OHSS during the study.
Table 2: Ovarian stimulation parameters and laboratory outcomes of the two groups

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Hormone profile during treatment

The circulating concentrations of FSH, LH E2, P, inhibin A, and inhibin B in study group are presented in [Figure 2]. The trends of FSH, LH, E2, and P levels during the ovarian stimulation were similar to our previous experiment.[10] In study group, LH level gradually decreased during the ovarian stimulation, and the average LH level on the trigger day was significantly lower than the baseline level (1.4 ± 0.9 IU/L vs. 3.4 ± 1.6 IU/L, P < 0.001) and then increased significantly to 42.3 ± 26.9 IU/L after triggering 10 h (P< 0.001). The levels of LH in study group were significantly lower compared with the control group during ovarian stimulation. P levels stay low during the ovarian stimulation and the trigger day (0.7 ± 0.3 ng/mL), after which it increased significantly to 4.6 ± 2.0 ng/mL (P< 0.05). In study group, inhibin A level was significantly higher than the baseline level (1416.4 ± 924.7 ng/L vs. 29.7 ± 23.40 ng/L, P < 0.001) during ovarian stimulation, and then increased significantly to 2046.7 ± 1280.5 ng/L after trigger 10 h. The levels of inhibin A after ovarian stimulation in the study group were significantly higher than the control group. Serum inhibin B level also rapidly increased on the trigger day compared with the baseline (1188.5 ± 819.1 ng/L vs. 82.5 ± 49.4 ng/L, P < 0.001), and then slightly decreased but did not reach a significant difference after trigger 10 h (1188.5 ± 819.1 vs. 1074.2 ± 745.7 ng/L, P > 0.05). Moreover, the average inhibin B levels after ovarian stimulation in the study group were also significantly higher compared with the control group.
Figure 2: Serum hormone profiles present during ovarian stimulation in study group and control group. The asterisks (*) stand for the significant changes between the two groups (P < 0.05). The arrows (↓) pointed to represent the significant changes at different time points in study group (P < 0.05).

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Clinical outcomes of FET cycles

FET pregnancy outcomes of the two groups are presented in [Table 3]. A total of 66 women from both groups completed a total of 99 FET cycles, including 22 women who finished two FET cycles and 4 women who finished more than three FET cycles. A total of 177 embryos were thawed, and the rate of viable frozen-thawed embryos was 100% (177/177). The clinical pregnancy rate per transfer was 47.4% (36/76) in study group, in contrast to 52.2% (12/23) in control group (P > 0.05). In study group, 2.8% (1/36) patients had early miscarriages before reaching the gestational age of 12 weeks, whereas the proportion was 16.7% (2/12) in control group. The implantation rate of embryos derived from control group was higher than that in control group (36.5% vs. 35.0%) but did not reach a statistical significance (P > 0.05). No difference was found in the cumulative pregnancy rate per woman between the two groups (68.0% vs. 68.8%, P > 0.05).
Table 3: Pregnancy outcomes of frozen-thawed embryos originating from the two groups

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Of all the pregnancies, 33 women in study group (including 20 single and 13 twin pregnancies) and 9 women in control group (including 8 single and 1 twin pregnancies) have delivered. The live-birth rate was slightly higher in study group than that in control group but did not reach a statistical significance (43.4% vs. 39.1%, P > 0.05). No congenital malformations were found in any of the live-birth babies in the two groups.


  Discussion Top


The results of our studies proved that oral P is an effective treatment for the prevention of premature LH surge in women undergoing COH for IVF/ICSI. Furthermore, the pregnancy outcomes from the FET cycles indicated that the embryos obtained from the hCG + MPA regimen had similar developmental potential with the short protocol, which was consistent with our previous observations.[10] The milieu of high progesterone during ovarian stimulation did not influence the secretion function of the surrounding granulosa cells to support the development of follicles and did not affect the development of the oocytes and embryos.

As known, the traditional ovarian stimulation was on the milieu of low-level P. Several studies have shown that high serum P levels during the ovarian stimulation could adversely affect the oocyte quality and thus had negative effects on the fertilization rate, embryo quality, and pregnancy rate.[28],[29] However, in other investigations, the elevated P levels during ovarian stimulation likely impaired endometrial receptivity rather than oocyte quality and thus exerted a negative effect on the pregnancy rate.[30],[31],[32] Using FET, we found that ovarian stimulation under the milieu of high-level P is feasible to obtain competent oocytes and embryos in women undergoing IVF/ICSI treatments, with optimal pregnancy outcomes in FET cycles.[5],[6],[7],[8],[9],[10]

It is well known that inhibins are glycoproteins of the transforming growth factor-β superfamily that are mostly produced by granulosa cells in women. Within the reproductive axis, inhibins have been studied extensively as endocrine-negative regulators of FSH release from the anterior pituitary. Are there any other biological activities of inhibin in human?

The knockout of the inhibin α-subunit in mice lead to the development of gonadal stromal tumors as early as 4 weeks of age that progressively worsened and were accompanied by cachexia, eventually resulting in death.[15],[33] In female mice, the overexpression of the α-subunit resulted in a dramatic reduction in litter size that is associated with reduction of ovulating oocyte number.[15],[34] The overexpression of α-subunit lead to fluid in ovarian cyst, and the decrease of antral follicles numbers and corpora lutea.[15],[35] In male mice, overexpression of the α-subunit resulted in sperm count decreased,[34] testes smaller, and seminiferous tubule volume reduced.[35] These findings highlighted another important role of inhibins in the reproductive axis: the paracrine regulation of gametogenesis in the gonads.[15],[16]

The granulosa cells release inhibins. As follicles developed into the antral stage, the number of granulosa cells increased. The pattern of inhibins A and B secretion during folliculogenesis is nonsynchronous; small antral follicles produce mainly inhibin B, whereas the dominant follicles and corpus luteum secrete inhibin A.[15],[36],[37] In human and primate, the levels of circulating inhibin A and B oscillate throughout the menstrual cycle: inhibin A remains at low levels during the follicular phase, then rises rapidly through ovulation, and peaks at the midluteal phase, whereas the maximum inhibin B levels occur during the early-follicular and early-luteal phases.[38],[39],[40] In females, the granulosa cells of the ovary produce inhibin, and inhibin production by each follicle increases as the granulosa cell population expands during normal follicle growth and maturation.[40] Based on the above results, it may be inferred that inhibin levels could provide a good surrogate measure of follicle health and viability.[15]

In this trial, the level of inhibin A and inhibin B significantly increased during ovarian stimulation, and in study group, the average inhibin A and inhibin B levels on the trigger day were significantly higher than the baseline levels (P< 0.001). Inhibin A increased significantly after triggered 10 h while serum inhibin B value slightly decreased but did not reach a significant difference compared with the value on the trigger day (P > 0.05). We also observed that the number of oocytes retrieved in study group was slightly higher than that in control group (P > 0.05). The rate of oocyte retrieval was similar in the two groups (P > 0.05), and no significant differences were found in oocyte maturation rate and cleavage rate between the two groups. However, the fertilization rate was significantly higher in the study group than in the short protocol. In addition, the numbers of good-quality embryos on day 3 and cryopreserved embryos were also significantly higher in study group. It was noteworthy that optimal pregnancy outcomes were obtained from subsequent FET rather than with the short protocol. In this study, we also found that inhibins level during ovarian stimulations in study group were higher than control group. Some studies found that inhibin had an important role in regulating gametogenesis in the gonads and providing a good surrogate measure of follicle health and viability.[15],[16] We presume that the milieu of high P during ovarian stimulation did not influence the secretion function of the surrounding granulosa cells of the developing follicles and did not affect the development of the oocytes and embryos. Nevertheless, the mechanisms need to be further studied using multicenter studies in a large scale of populations.

The current evidence about the safety of MPA used in COH is scarce. In previous studies, there was no direct evidence demonstrating the role of MPA in the potential oocyte development. An investigation in female patients using another progestin, levonorgestrel, during conception indicated that there was no association between the use of progestin and the risk of major congenital malformations.[41] In our center, the follow-up of 587 live-born infants from LPS showed that the high P levels in COH did not increase the risk of congenital malformations compared with the short protocol and mild ovarian stimulation.[12] In this study, we found that MPA co-treatment resulted in comparable counts of oocytes, fertilized eggs, cleavage embryos, and optimal pregnancy outcomes from subsequent FET compared with the short protocol. The long-term safety for children conceived with ovarian stimulation using MPA co-treatment should be further confirmed by follow-up visits.

In conclusion, we found that ovarian stimulation on the milieu of high-level P did not affect the function of inhibin secretion of the granulosa cells. Moreover, MPA co-treatment resulted in comparable counts of oocytes, fertilized eggs, and cleavage embryos, and optimal pregnancy. As it is a new protocol for ovarian stimulation, the endocrine characteristics remain to be further explored. The long-term safety of children conceived with MPA co-treatment should further be followed up.

Financial support and sponsorship

This study was funded by the National Nature Science Foundation of China (grant numbers: 31071275, 81270749, and 31101070) and the Natural Science Foundation of Shanghai (grant number: 11411950105).

Conflicts of interest

There are no conflicts of interest.



 
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