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ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 97-102

Effect of progestin-primed ovarian stimulation protocol in infertile women with basal follicle-stimulating hormone levels ≥15 IU/L: A retrospective analysis


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

Date of Submission18-Aug-2019
Date of Decision16-Oct-2019
Date of Acceptance18-Feb-2020
Date of Web Publication03-Jun-2020

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: 10.4103/2096-2924.285780

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  Abstract 


Objective: To evaluate the efficacy of progestin-primed ovarian stimulation (PPOS) protocol in infertile women with high basal follicle-stimulating hormone (FSH) levels ≥15 IU/L.
Methods: Patients with high basal FSH levels ≥15 IU/L with autologous oocytes from September 2016 to March 2019 were reviewed. Either medroxyprogesterone acetate 4 mg/d or clomiphene citrate (CC) 50 mg/d was administered daily from day 3 to the trigger day. When serum FSH levels decreased to ≤15.0 IU/L, a low dose of human menopausal gonadotropin (hMG) 75/150 IU/d was administered to promote late follicular development.
Results: Two hundred and twenty women were retrospectively analyzed in this study. Among them, 139 patients were administered with PPOS protocol as the study group, and 81 patients were administered with CC protocol as the control group. The numbers of received oocytes and viable embryos were higher in the study group than those in the control group (1.5 ± 1.2 vs. 1.2 ± 0.8 and 0.8 ± 0.8 vs. 0.5 ± 0.6, respectively, P < 0.05). However, hMG duration and dosage were significantly higher in the study group than those in the control group (4.2 ± 2.7 d vs. 1.1 ± 2.3 d and 609.1 ± 424.5 IU vs. 140.7 ± 231.3 IU, respectively, P < 0.01). Incidence of luteinizing hormone surge and cycle cancellation rate were lower in the study group than those in the control group with statistical difference (2.88% vs. 16.05% and 36.50% vs. 50.63%, respectively, P < 0.05).
Conclusions: PPOS protocol can effectively downregulate the endogenous FSH levels. Compared with CC protocol, treatment with PPOS protocol in patients with high basal FSH levels ≥15 IU/L could receive more oocytes and more viable embryos.

Keywords: Diminished Ovarian Reserve; Follicle-Stimulating Hormone; In vitro Fertilization; Progestin-Primed Ovarian Stimulation Protocol


How to cite this article:
Fang L, Qi XJ, Zhu H. Effect of progestin-primed ovarian stimulation protocol in infertile women with basal follicle-stimulating hormone levels ≥15 IU/L: A retrospective analysis. Reprod Dev Med 2020;4:97-102

How to cite this URL:
Fang L, Qi XJ, Zhu H. Effect of progestin-primed ovarian stimulation protocol in infertile women with basal follicle-stimulating hormone levels ≥15 IU/L: A retrospective analysis. Reprod Dev Med [serial online] 2020 [cited 2020 Jul 8];4:97-102. Available from: http://www.repdevmed.org/text.asp?2020/4/2/97/285780




  Introduction Top


The management of diminished ovarian reserve (DOR) is difficult and controversial. Patients with DOR have high cycle cancellation, low pregnancy, and low live birth rates duringin vitro fertilization (IVF) treatment.[1],[2] According to the ESHRE guidelines, the main perspective of childbearing in women with high basal follicle-stimulating hormone (FSH) levels is egg donation or adoption.[3] However, many infertile couples reject to undergo donor egg IVF even if it has the best chance of success, and they want to try with their own oocytes.

At present, the management of extremely DOR presents a major challenge in reproductive medicine. A level of serum FSH higher than 13–15 IU/L is a negative prognostic factor for response to controlled ovarian hyperstimulation.[4],[5] Meanwhile, high basal FSH levels are associated with high cycle cancelation and decline in oocyte quality.[6],[7],[8],[9],[10] Mild stimulation protocol was one of the suggested ovarian stimulation strategies for them, because of its low cost and patient-centered approach (fewer injections, fewer visits, and less medication used).[11] Another treatment suggestion was pretreatment of high-dose estrogen supplementation or luteal gonadotropin release hormone (GnRH) antagonist, which could downregulate the endogenous FSH levels and induce granulosa cell FSH receptor expression.[3],[12] The increased number of FSH receptors enhances the response to exogenous gonadotropins.[13] However, some patients did not respond to pretreatment of estrogen, maintaining a persistently higher FSH levels.[14]

Progestin has been confirmed to effectively inhibit the premature luteinizing hormone (LH) surge when it is administered from the beginning of ovarian stimulation.[4],[15],[16] Patients treated with progesterone-primed ovarian stimulation (PPOS) protocol need more gonadotropin doses and have longer durationthan those with the conventional short protocol.[17] Inspired by the mentioned results, we hypothesized that medroxyprogesterone acetate (MPA) might downregulate the endogenous FSH levels during ovarian stimulation and improve the responsiveness of remnant ovarian follicles in women with elevated basal FSH levels.

This study aimed to retrospectively evaluate the efficacy of PPOS protocol in infertile women with high basal FSH levels ≥15 IU/L. The prime outcome measures for this study were number of retrieved oocytes and viable embryos. The secondary outcomes were the endocrinological profiles, incidence of premature LH surge, human menopausal gonadotropin (hMG) duration and dosage, and cycle cancellation rate.


  Methods Top


Study setting and patients

Patients who underwent IVF/intracytoplasmic sperm injection (ICSI) with autologous oocytes from September 2016 to March 2019 at our private fertility clinic were retrospectively reviewed. The inclusion criteria were: (1) aged 25–45 years; (2) a basal FSH level ≥ 15 IU/L; (3) the PPOS protocol treatment; and (4) without hormone treatments within 3 months before the study. Patients with high basal FSH levels in clomiphene citrate (CC) protocol were selected as the control group. The study was approved by the local institutional review boards. All data were extracted from the departmental medical records.

Ovarian stimulation protocols

MPA (4 mg/d; Shanghai Xinyi Pharmaceutical Co., China) or CC (50 mg/d; Codal-Synto Limited, France) was administered daily from cycle day 3 to the trigger day. After 5 days, transvaginal ultrasonography and serum hormone measurements were checked every other day. When serum FSH levels decreased to ≤15.0 IU/L during IVF treatment, a low dose of hMG (75–150 IU/d; Shanghai Lizhu Pharmaceutical Co., Shanghai, China) was administered to promote late follicular development. The final oocyte maturation was triggered with triptorelin (100 μg; Decapeptyl; Ferring GmbH, Kiel, Germany) or/and human chorionic gonadotropins (hCG) (2,000 IU; Lizhu Pharmaceutical Trading Co., China) when the dominant follicle reached a diameter of 16–18 mm. Transvaginal ultrasound-guided oocyte retrieval was performed 34–36 h after trigger. For cases with at least 1 mature follicle (oocyte diameter ≥15 mm) and the occurrence of a premature LH surge (LH >15 IU/L), triptorelin was administered immediately. Oocyte retrieval was arranged 24–30 h later, according to the spontaneous LH surge on the scheduled day.[18]

In vitro fertilization and embryo culture

Before oocyte retrieval, the presence of dominant follicles was confirmed with 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.

Outcome measures

The prime outcome measures for this study were number of retrieved oocytes and viable embryos. The secondary outcomes were the endocrinological profiles, incidence of premature LH surge, hMG duration and dosage, and cycle cancellation rate. Spontaneous LH surge is defined as a LH level ≥15 IU/L on the trigger day. Cycle cancellation rate was estimated on the number patients who completed oocyte retrieval without viable embryos.

Statistical analysis

Differences in continuous variables were presented as the mean ± standard deviation and tabulated by t-tests. If the data did not follow a normal distribution, the Mann–Whitney U-test was performed instead. Categorical variables were compared by Chi-square test. In all cases, P < 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (SPSS Inc., Chicago, IL, USA).


  Results Top


Patient characteristics

A total of 220 women were retrospectively analyzed in this study. Among them, 139 patients were administered with PPOS protocol as the study group, and 81 patients were administered with CC protocol as the control group. The baseline characteristics and hormonal profiles of the patients are presented in [Table 1]. In the study group, the average age was 38.0 ± 4.8 years, the basal FSH level was 21.9 ± 6.8 IU/L, the antral follicle count (AFC) was 2.0 ± 1.4, and anti-Müllerian hormone (AMH) was 0.42 ± 0.36 ng/mL, which suggested extremely DOR. No significant differences were observed between the two groups with respect to thebaseline characteristics.
Table 1: Baseline characteristics of the two groups

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In vitro fertilization performance

[Table 2] shows the cycle characteristics of the two protocols. The numbers of received oocytes and viable embryos were significantly higher in the study group than those in the control group (1.5 ± 1.2 vs. 1.2 ± 0.8, P = 0.012, and 0.8 ± 0.8 vs. 0.5 ± 0.6, P = 0.01). In addition, duration of stimulation and hMG dose were significantly higher in the study group than those in the control group (4.2 ± 2.7 days vs. 1.1 ± 2.3 days and 609.1 ± 424.5 IU vs. 140.7 ± 231.3 IU, respectively, P < 0.01). The incidence of LH surge was significantly lower in the study group than that in the control group (2.88% vs. 16.05%, P < 0.01). Accordingly, premature ovulation incidence was lower in the study group than that in the control group, but without statistical difference (P = 0.470). There were 50 cases in the study group and 40 cases in the control group being cancelled with no viable embryo. Cycle cancellation rate was lower in the study group than in the control group with statistical difference (36.50% vs. 50.63%, P = 0.03).
Table 2: Cycle characteristics of the two protocols (mean ± SD)

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Dynamic characteristics of the hormone concentrations

The serum FSH, LH, estradiol (E2), and progesterone (P) concentrations in the two groups are presented in [Figure 1]. The hormone levels were not normally distributed. The FSH levels of the two groups showed different trends [Figure 1]. In the study group, the FSH levels decreased gradually from the beginning of COS to the trigger day even after hMG administration. In the control group, the FSH levels maintained to 20 IU/L levels during the whole ovarian stimulation. Average FSH levels on the trigger day were decreased significantly in the study group than those in the study group with statistical difference (16.7 ± 13.1 IU/L vs. 21.1 ± 13.0 IU/L, P = 0.018).
Figure 1: Serum hormone profiles during ovarian stimulation with the two regimens. Blue lines represent the PPOS group; red ones represent the CC group. *P < 0.05 at the time point. CC: Clomiphene citrate; MC: Menstrual cycle; PPOS: Progesterone-primed ovarian stimulation.

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The LH levels in the two groups also showed different trends [Figure 1]. The LH values were a little higher on day 8 than on day 3 (9.6 ± 8.6 IU/L vs. 6.1 ± 3.1 IU/L, P < 0.01) and then gradually decreased in the study group. However, in the control group, it gradually increased during the ovarian stimulation. Average LH levels on trigger day were significantly lower in the study group than in the control group (6.0 ± 3.7 IU/L vs. 10.8 ± 7.7 IU/L, P < 0.01).

Serum E2 levels showed a gradual increase with the growth of follicles during ovarian stimulation in the two groups. However, serum E2 levels on the trigger day were significantly higher in the control group than that in the study group (563.1 ± 320.6 pg/mL vs. 398.4 ± 282.9 pg/mL; P < 0.01). Serum P values showed no difference in the two groups.


  Discussion Top


This study was the first trial to retrospectively evaluate the efficacy of PPOS protocol in infertile women with high basal FSH levels ≥15 IU/L. It has been demonstrated that women with high basal FSH levels could acquire more oocytes and more viable embryos with PPOS protocol than those with CC protocol. The rationale of PPOS protocol lies in the fact that MPA could downregulate the endogenous FSH levels through pituitary suppression, which could increase the number of FSH receptors and enhance the ovarian response to exogenous gonadotropins. Women with high basal FSH level could acquire more oocytes and more embryos with PPOS protocol. Therefore, PPOS protocol is one of the alternative strategies for women with elevated basal FSH levels.

It was generally accepted that the hypergonadotropic condition may reduce ovarian responsiveness.[19],[20] When a serum FSH level >40 IU/L, it is associated with sterility and ovulation induction in these patients is ineffective.[21] In this trial, we included participants with severely DOR, the average basal FSH level was 21.9 ± 6.8 IU/L (range 15.0–44.6 IU/L), the AFC was 2.0 ± 1.4, and AMH was 0.42 ± 0.36 ng/mL. The average retrieved oocytes and viable embryos were significantly higher in the PPOS group than those in the CC group (P < 0.05). A possible explanation might be the different mechanism between the two medicines. Oral progestin can lead to stronger pituitary suppression and inhibit gonadotrophin secretion during the early follicle phase.[19],[20] The reduction of circulating FSH levels induces FSH receptor expression in granulosa cell and enhances the ovarian response to exogenous gonadotropins. Consequently, more follicles grow up in patients with PPOS protocol. On the other hand, the higher number of retrieved oocytes and embryos were associated with the administration of hMG during the late follicular phase in the study group. On the contrary, CC is an estrogen agonist/antagonist that interacts with the hypothalamic estrogen receptors. It suppresses the negative feedback of circulating estrogen and triggers the pituitary to secrete endogenous FSH.[22],[23] Therefore, serum FSH levels maintained to 20 IU/L levels during the whole ovarian stimulation in the control group. However, it decreased from 21.9 ± 6.8 IU/L on the day 3 to 16.7 ± 13.1 IU/L on the trigger day in the study group.

Serum FSH levels in the PPOS group decreased gradually from the beginning of ovarian stimulation to the trigger day even after hMG administration. Previous studies demonstrated that follicular development continued with serum FSH level reduction during hormonal contraceptives treatment which contained progesterone in most combined oral contraceptives.[24] Cycles with the pretreatment of oral contraceptives (OC) or progesterone in the GnRH-antagonist protocol required high dosage of exogenous gonadotropins,[25],[26] and this might be due to the negative effect of steroids on the endogenous GnRH release. The possibility of P-mediated inhibition of dominant follicle development has been reported in animal models.[27] Therefore, hMG was administered during the late follicular phase to avoid the follicle regression in the study group. Accordingly, hMG duration and dosage were significantly higher in the study group than those in the control group.

The average LH levels in the PPOS group were significantly lower than that in the CC group, which was consisted with previous studies.[15],[17]Pslows the LH pulse frequency, augments the pulse amplitude, and reduces the serum LH levels.[14] In animal models, progestogen-induced suppression of LH surge is mediated by progesterone receptors in the hypothalamus, and the inhibition is reversible after progestogen discontinuation.[16],[28] In this trial, the average LH levels on the trigger day were 6.0 ± 3.7 IU/L, and the incidence of LH surge was 2.88% in the study group, which was consistent with previous report.[29] The decreased LH values and low incidences of spontaneous LH surges in the study group are signs of the hypothalamus suppression induced by MPA.

Although spontaneous LH surge has been frequently mentioned in the literature, the level of spontaneous LH surge remains disputing.[30] Most researches selected LH >10 IU/L as a cutoff point in the conventional ovarian stimulation protocol. It was reported that CC administration for 15 days (days 2–16 of the cycle) produced a continuous and progressive increase of basal LH levels with no LH surge and no ovulation in mild stimulation.[31] On the other hand, CC can alleviate pituitary suppression in the PPOS protocol by increasing serum LH levels.[5] Thus, we selected LH >15 IU/L as a cutoff level in this trial. However, premature ovulation occurred when serum LH >10 IU/L in the PPOS group.

Serum E2 levels were significantly lower in the study group than in the control group during the ovarian stimulation. It is well known that granulosa cells produce E2 stimulated by FSH and LH. The FSH and LH levels were significantly lower in the study group, because of P-priming pituitary inhibition. This possibility is consistent with the 'two-cell, two-gonadotropin' theory, whereinstimulation of theca cells by LH and of granulosa cells by FSH and LH is required for the production of ovarian steroids.[32],[33]

The lack of clinical pregnancy data for analysis remains a limitation of our study. As noted, the basal FSH levels in extremely DOR often fluctuate during different treatment cycles. Moreover, there are one or two viable embryos produced per IVF cycle in those patients. To improve their clinical outcome, two embryos were transferred every frozen-thawed embryo (FET) cycle. It is difficult to differentiate the origin of embryos. Finally, the retrospective nature of the study does not allow us to draw definitive conclusions concerning the practical applications of the exposed therapy in different types of DOR patients.

In conclusion, PPOS protocols can effectively downregulate the endogenous FSH levels and enhance the ovarian response to exogenous gonadotropins. Treatment with PPOS protocol in patients with high basal FSH levels ≥15 IU/L could receive more oocytes and more viable embryos, compared with CC protocol. Randomized trials with a larger cohort of patients are needed to confirm the results of our retrospective study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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