IVF protocol efficacy in women with expected suboptimal response depending on ovary stimulation mode

Abstract

Investigation objective

IVF protocol efficacy estimation in women with expected suboptimal response depending on ovary stimulation mode.

Materials and technique

A randomized controlled study embracing results of 51 IVF cycle in women with ovary suboptimal response. The suboptimal response prognostic analysis was performed basing on ≤9 oocyte cumulus complexes obtained in previous IVF programs, the presence of no less than 5–9 antral follicles in both oocytes and amount of anti-Mullerian Hormone ≥0,8 ng/mL. In Group I (n = 25), the stimulation was performed by recombinant corifollitropin alfa combined with highly purified urinary gonadotropin, while in Group II (n = 26) it was made by means of recombinant follitropin/lutropin alfa within the protocol of applying gonadotropin-releasing hormone antagonists.

Results

The total gonadotropin dose in Group II patients was authentically lower compared to Group I (p˂,01). No statistical difference between the two studied groups was detected concerning the number of obtained oocytes, 2pn zygote, good-quality transferred embryos and clinical pregnancy rate (p>.05). Embryo cryopreservation was performed only for group-II patients.

Conclusion

Corifollitropin alfa administration combined with highly purified menotropin in IVF cycles for suboptimal responders is quite effective, however, this strategy has no preference over other stimulation modes. The strategy of using recombinant follitropin/lutropin alfa can be promotive to IVF outcomes for suboptimal responders by means of embryo banking. ClinicalTrials.gov Identifier: NCT03177538

Keywords:

• Corifollitropin alfa
• suboptimal ovarian response
• IVF
• infertility

The oocyte response to gonadotropin hormone stimulation is crucially significant for ART programs efficacy in general. Its weakening is associated with received oocyte number decrease and thus with good quality embryos declining number and finally with live birth rate decrease. One of most convincing confirmations to this fact may be found in the analysis of Great Britain ART national register results for 20 years performed on 59,000 cycles data. The analysis expressly showed a considerable live birth rate growth in cases of ovarian stimulation compared to cycles without stimulation [1]. Thus, ovary stimulation aimed at obtaining optimal oocyte number appears to be one of most important objectives for assisted reproductive technology programs. The priority in this field should be given to oocyte stimulation protocol individualization to improve IVF program efficacy and reduce complication risks [2,3].

The specificity of long-acting follicle stimulating hormone (FSH)—corifollitropin alfa pharmacokinetics is seen in FSH high concentration on the first day of stimulation capable of recruiting more follicles in case of ovary suboptimal response. The highly purified menotropins are specific for FSH acid isoform predominance, which is also significant for follicle genesis and in menstrual cycle first phase [4].

The study objective was a comparative estimation of IVF protocol efficacy in women with expected suboptimal response depending on ovary stimulation mode.

Materials and methods

The randomized controlled clinical study involved results of 51 IVF cycles of women with suboptimal response to gonadotropin stimulation, who underwent their treatment at the Department of Assisted Reproductive Technologies in FSBI D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg.

The inclusion criteria were: infertility of various origin: age of 35–41; body weight index from 17,5 to 30 kg/m²; patients with risk of developing ovary suboptimal response to gonadotropin stimulation; FSH concentration in blood serum ≤15 IU/L; personal consent to participate in the study.

The prognostic analysis of ovary suboptimal response to gonadotropin stimulation was performed observing the following two conditions:

• ≤9 oocyte cumulus complexes (without oocyte maturity estimation) obtained in previous IVF cycles with FSH recombinant dose of no less than 150 IU.

• presence of less than 5–9 antral follicles in both ovaries with diameter < 10 mm at the randomization moment.

• Anti-Mullerian Hormone concentration in blood serum 0,8–3,5 ng/mL.

The exclusion criteria were: extragenital or gynecological disease as contraindication to infertility treatment by assisted reproductive technologies; quantitative or/and structural karyotype changes; recurrent pregnancy loss; severe spermatogenic disorders (azoospermia, cryptozoospermia).

The randomization was performed by ‘envelope’ technique (2:2 blocks) into one of two groups. The basic clinical group (Group I) included 25 women who underwent superovulation stimulating by recombinant corifollitropin alfa 150 mcg (Elonva – N.V. Organon) combined with highly purified menotropins150/150 IU (Meriofert – IBSA) within a protocol comprising administration of gonadotropin releasing hormone (GnRH) antagonists. The comparison group (Group II) included 26 women receiving ovary stimulation of similar layout by recombinant follitropin/lutropin alfa 300/150 IU (Pergoveris – Merck Serono). In course of superovulation stimulation ultrasound monitoring of folliculogenesis and endometrium growth was performed. On the 5^th day of stimulation gonadotropin dose correction was made along with a decision whether to apply GnRH antagonists (Orgalutran – N.V. Organon, Cetrotid – Merck Serono) to prevent a luteinizing hormone (LH) preterm peak when one or several leading follicles had achieved 12 mm size. The indication for administering a final oocyte maturity trigger was achieving 17 mm size by at least two follicles. As a final oocyte maturity trigger, recombinant chorionic gonadotropine alfa was applied (Ovitrelle – Merck Serono, Figure 1).

Figure 1. Ovarian stimulation protocol layouts.

Thirty-six hour after ovulation trigger administration preovulatory follicle transvaginal puncture was performed for oocyte aspiration and further in vitro fertilization. The procedure was performed under intravenous anesthesia through the posterior vaginal vault using a transvaginal ultrasound transducer with a puncture adapter and special needles. The follicle contents aspiration was performed by an aspiration pump (COOK ASPIRATION UNIT). To support the stimulation cycle lutein phase micronized progesterone was administered in 600 mg per day starting from the day of transvaginal follicle puncture.

Protocol layout for ovarian stimulation by recombinant follitropin/lutropin alfa

Protocol layout for ovarian stimulation by corifollitropin alfa combined with menotropins

Results

Age and body weight indexes of studied patients did not significantly differ. The main clinical and medical history characteristics of patients in both groups were comparable and detected intergroup differences were not significant.

The analysis of initial hormone status indications showed no authentic difference for FSH and AMH basic concentrations as well as for antral follicle count (AFC) (Figure 2).

Figure 2. Ovarian reserve indexes a – AMH and AFС median values of compared groups; b – AMH and AFС individual values of compared groups. On IVF program embryology stage estimation, the study ignored the cases of negative ovary response to gonadotropin stimulation (1/25 in group I) and those of oocyte cumulus complex absence at the moment of follicle puncture (1/25 in group I and 2/26 in group II). Therefore, only 48 treatment cycles were analyzed. The statistical analysis of IVF program embryological stage index efficacy no difference was observed concerning obtained oocyte and double-nucleus zygote number (Table 1).

The total gonadotropin dose in group-II patients was authentically lower than in group I. Apart from that one group-I patient had no ovulating stimulation response. The duration of stimulation was comparable for both study groups (Table 1).

Table 1. Comparison of ovary stimulation and IVF program embryological stage.

Parameter	GroupI, n = 25			GroupII, n = 26			Mann–Whitney U-test	p-value
	Me	LQ	UQ	Me	LQ	UQ
Gonadotropin total dose (FSH), IU	3562	3062	4375	2400	2100	2700	63	.001
Duration of stimulation, days	8	7	9	8	7	9	287	.637
Follicle number on the day of stimulation trigger administration	7	4	8	6	5	10	279,5	.698
Number of obtained oocytes	5	2	8	6	3	8	264,5	.492
Number of double-nucleus zygotes	4	2	7	5	3	7	254,5	.487
Endometrium thickness on embryo transfer day, mm	9	8	10	10	9	10	275	.482

LQ: low quartile; Me: median: UQ: upper quartile.

Note: cases of negative response to gonadotropin stimulation (1/25 in group I) and those of no oocyte retrieval at the moment of TVP (1/25 in group I and 2/26 in group II) were excluded.

No statistically significant difference between the studied groups could be established concerning the number of follicles registered at the moment of ovulation trigger administration within IVF program as well as the number of oocytes obtained by transvaginal puncture (Table 1).

On IVF program embryology stage estimation, the study ignored the cases of negative ovary response to gonadotropin stimulation (1/25 in group I) and those of oocyte cumulus complex absence at the moment of follicle puncture (1/25 in group I and 2/26 in group II). Therefore, only 48 treatment cycles were analyzed. The statistical analysis of IVF program embryological stage index efficacy no difference was observed concerning obtained oocyte and double-nucleus zygote number (Table 1).

Forty-two patients of 51 treatment cycles achieved the embryo transfer stage (20/25 in group I and 22/26 in group II). The embryo transfer was performed on days 4 and 5 of development in vitro. Embryo maximum number did not exceed 2. No authentic difference could be observed concerning morphologically good embryo number on the day of transfer (Y-χ2 = 1,754, p > .05). Embryo freezing was performed only in group-II patients where LH recombinant forms application made it possible (9/22). The probability of morphologically good embryo occurrence did not also authentically differ (OR (95% CI) =2,75 (0,8–9,447) p > .05). No statistically significant difference was detected in course of endometrium thickness evaluation on embryo transfer day (Table 1).

The IVF cycle cancel frequency on the program different stages was 17,65%. (9/51). The cancel probability in the examined patients did not significantly differ (OR (95%CI) =0,475 (0,113–1,841) p >.05).

The pregnancy occurrence frequency in studied groups was 30% in group I and 31,81% in group, respectively. Thus, no authentic difference was detected. The pregnancy occurrence probability in the examined patients also did not authentically differ ((OR (95%CI) =1,754 (0,368–8,374) p > .05).

Discussion

According to the study data, the total gonadotropin dose was authentically lower in case of ovary stimulation by recombinant follitropin/lutropin alfa which belong to low glycosylated gonadotropins. This observation may be connected to the ability of this very isoform to combine with FSH receptor in a proportion near 1:1 [5]. Thus, the predomination of high glycosylated FSH forms in menotropins is associated with a decrease of their specific activity. Apart from that molecular mechanisms of human chorionic gonadotropin (HCG) impact compared to those of LH are different [6–8]. The HCG mainly affects the steroidogenesis by stimulating the adenylate cyclase signaling system while LH shows an expressed proliferative and anti-apoptotic effect by activating arestin signaling pathways and a cascade of mitogen-activated protein kinases [9,10]. Along with that we should stress that menotropins have some advantage thanks to ability of preventing ovary FSH dependent cascade hyperactivity, promoting follicle normal development and stimulating good oocyte selection processes [4]. Our study results show no observed statistical difference in obtained oocyte number, bipronuclear zygotes and morphologically good embryos on transfer day dependent on ovary stimulation mode in women with suboptimal response.

According to the majority of studies including analytical reviews based on clinical study meta-analysis natural forms HCG and recombinant LH have similar biological activity [11,12]. The COMPORT randomized study embracing 150 patients under the age of 40 with expected ‘weak’ response detected statistical difference in respect of progressing pregnancy frequency between a group of corifollitropin alfa combined with recombinant FSH (8,5%) and that of combined with menotropins (28%) [14]. No authentic difference within the present study framework was detected concerning pregnancy occurring frequency and cycle canceling depending on LH activity nature. However, only LH recombinant form application allowed to perform additional embryo freezing. The obtained data correspond the retrospective analysis of 4828 IVF cycles in women with ovary suboptimal response which is testimony to oocyte quality improvement in case of administering LH containing drugs of different origin [13].

Conclusion

Overcoming the infertility in the presence of suboptimal response predictors remains an unsolved problem. We have no proper understanding of how to modify the ovary stimulation protocol no reasonable approaches to adjuvant therapy for such kind of patients aimed at improving the IVF programs efficacy. Corifolitropin alfa combined with menotropins administration in women with predicted suboptimal response is quite effective according to clinical pregnancy occurrence index for embryo transfers but has no advantage against other stimulation modes. The strategy of administering recombinant follitropin/lutropin alfa described in the present study may drive the improvement of ovary suboptimal response treatment by creating embryo banking with the perspective of preimplantation genetic testing of aneuploidy. Considering the small sampling of patients and lack of various stimulation protocol influence on pregnancy occurring frequency in women with ovary suboptimal response we find it reasonable to continue multicenter randomized controlled clinical studies in the context of increasing recruited follicle number, oocyte competence and embryo quality improvement.

Disclosure statement

Authors report no conflict of interest.