The Fertility Department, Section 4071, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Faculty of Health and Medicine, University of Copenhagen, Rigshospitalet, Copenhagen N, Denmark.
Laboratory of Reproductive Biology, Section 5712, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, Faculty of Health and Medicine, University of Copenhagen, Rigshospitalet, Copenhagen N, Denmark.
Hum Reprod. 2023 Apr 3;38(4):716-725. doi: 10.1093/humrep/dead012.
Does 8 weeks of continuous low-dose hCG administration increase the proportion of antral follicles that reach the preovulatory state during ovarian stimulation (OS) in women with low ovarian reserve?
The proportion of antral follicles (2-10 mm) that reached the preovulatory state did not increase.
The administration of androgens prior to OS might upregulate FSH receptor (FSHR) expression on granulosa cells, making follicles more responsive to exogenous FSH stimulation during OS. LH and hCG stimulate the local follicular androgen synthesis in theca cells and may be used as an endogenous androgen priming method. Exogenous priming by testosterone and dehydroepiandrosterone (DHEA) have been shown to increase the number of retrieved oocytes and live birth rate but the studies are small, and their use is associated with side effects.
STUDY DESIGN, SIZE, DURATION: A prospective, paired, non-blinded single-center study including 20 women serving as their own controls conducted between January 2021 and July 2021 at The University Hospital Copenhagen Rigshospitalet, Denmark.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants underwent two identical consecutive IVF/ICSI treatments, a Control cycle and a Study cycle, separated by ∼8 weeks (two menstrual cycles) of daily injections of 260 IU recombinant hCG (rhCG). A freeze-all strategy was applied in the Control cycle. Both IVF/ICSI cycles were performed in a fixed GnRH antagonist protocol using a daily dose of 300 IU recombinant FSH (rFSH) and GnRH antagonist 0.25 mg from stimulation days 5-6.
Follicular output rate, defined as the number of follicles >16 mm on hCG trigger day divided by the antral follicle count (2-10 mm) at baseline, did not increase after 8 weeks of hCG priming (P = 0.8). The mean number of oocytes retrieved was significantly higher after the hCG priming being 4.7 (2.8) vs 3.2 (1.7) in the Study and Control cycle, respectively (P = 0.01). The duration of stimulation was longer in the Study versus the Control cycle (P = 0.05), despite the use of identical hCG trigger criterion and similar diameters of the three biggest follicles on hCG trigger day in the two cycles (P = 0.9).
LIMITATIONS, REASONS FOR CAUTION: The sample size was small, and the number of oocytes retrieved was not the primary endpoint. Larger studies are needed to confirm this finding.
Long-term, low-dose rhCG administration may increase the number of oocytes retrieved during IVF/ICSI in women with low ovarian reserve, but more research is needed before firm conclusions can be drawn.
STUDY FUNDING/COMPETING INTEREST(S): This study was funded by an unrestricted grant from Gedeon Richter. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S and receipt of equipment by the institution from Gedeon Richter Nordics AB is reported. The remaining authors have no conflicts of interest to declare.
ClinicalTrials.gov Identifier: NCT04643925.
在卵巢刺激（OS）期间，连续 8 周低剂量 hCG 给药是否会增加卵巢储备低的女性中达到排卵前状态的窦卵泡比例？
达到排卵前状态的窦卵泡（2-10mm）比例没有增加。
在 OS 之前给予雄激素可能会上调颗粒细胞上的 FSH 受体（FSHR）表达，使卵泡在 OS 期间对外源性 FSH 刺激更敏感。LH 和 hCG 刺激卵泡膜细胞中的局部卵泡雄激素合成，并可用作内源性雄激素启动方法。已证明外源性睾酮和脱氢表雄酮（DHEA）启动可增加可回收卵母细胞的数量和活产率，但这些研究规模较小，并且其使用与副作用相关。
研究设计、大小和持续时间：一项前瞻性、配对、非盲单中心研究，包括 20 名作为自身对照的女性，于 2021 年 1 月至 7 月在丹麦哥本哈根大学医院 Rigshospitalet 进行。
参与者/材料、设置、方法：参与者接受了两次相同的连续 IVF/ICSI 治疗，分别是对照周期和研究周期，间隔约 8 周（两个月经周期），每天注射 260IU 重组 hCG（rhCG）。在对照周期中应用了冷冻全部策略。两种 IVF/ICSI 周期均采用固定 GnRH 拮抗剂方案进行，使用 300IU 重组 FSH（rFSH）和 GnRH 拮抗剂 0.25mg，从刺激第 5-6 天开始。
卵泡输出率定义为 hCG 触发日>16mm 的卵泡数除以基线时的窦卵泡计数（2-10mm），在 hCG 启动后 8 周没有增加（P=0.8）。在 hCG 启动后，可回收卵母细胞的数量明显更高，研究周期为 4.7（2.8），对照周期为 3.2（1.7）（P=0.01）。与对照周期相比，研究周期的刺激时间更长（P=0.05），尽管在两个周期中使用了相同的 hCG 触发标准和 hCG 触发日三个最大卵泡的相似直径（P=0.9）。
局限性、谨慎的原因：样本量较小，可回收卵母细胞的数量不是主要终点。需要更大的研究来证实这一发现。
长期低剂量 rhCG 给药可能会增加卵巢储备低的女性在 IVF/ICSI 期间可回收的卵母细胞数量，但在得出明确结论之前，还需要进行更多的研究。
研究资助/利益冲突：这项研究得到了盖德恩·里希特公司的一项无限制赠款的资助。A.P.报告了来自 PregLem SA、Novo Nordisk A/S、Ferring Pharmaceuticals A/S、Gedeon Richter Nordics AB、Cryos International 和 Merck A/S 的个人咨询费，以及来自 Gedeon Richter Nordics AB、Ferring Pharmaceuticals A/S、Merck A/S 和 Theramex 和 Organon & Co 的演讲酬金。该机构还获得了 Gedeon Richter Nordics AB、Ferring Pharmaceuticals A/S 和 Merck A/S 的赠款，该机构还收到了 Gedeon Richter Nordics AB 的设备。其余作者没有利益冲突需要申报。
ClinicalTrials.gov 标识符：NCT04643925。
