Department of Gynaecology and Obstetrics, Endocrinological and Reproductive Unit, Copenhagen University Hospital, Herlev Hospital, Herlev, Denmark.
The Fertility Department, Copenhagen University Hospital, Copenhagen, Denmark.
Hum Reprod. 2022 Jun 30;37(7):1557-1571. doi: 10.1093/humrep/deac119.
What are the downstream endocrine and paracrine consequences of letrozole (LZ) cotreatment during ovarian stimulation and is follicle growth and recruitment affected?
Letrozole cotreatment induces marked changes in both the follicular and luteal phase endocrinology causing potentiation of follicle diameter and an improved corpus luteum function without affecting the secondarily recruited follicle cohort.
Letrozole is a third-generation aromatase inhibitor that is well-established as an effective ovulatory agent, while its possible benefits in standard in vitro fertilization protocols are less thoroughly investigated.
STUDY DESIGN, SIZE, DURATION: This study included a double-blinded, placebo-controlled, randomized study with LZ or placebo intervention during ovarian stimulation for IVF treatment, an observational preceding baseline natural cycle and a succeeding follow-up visit. Participants were enrolled between August 2016 and November 2018. Data from the randomized, stimulated cycle were part of a larger RCT, which was previously published.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a public fertility clinic at Herlev Hospital, Denmark, including 31 healthy, normo-responding women eligible for IVF treatment. They underwent a natural baseline cycle and were subsequently randomized to receive either LZ 5 mg (n = 16) or placebo (n = 15) daily during ovarian stimulation from cycle day (CD) 2-3 until induction of ovulation. Throughout both cycles, monitoring was performed every third day with transvaginal ultrasound for assessment of follicle count and diameter, and blood analyses for the determination of twelve endocrine and paracrine parameters. A follow-up assessment was performed at CD2-3 in the succeeding cycle. In the randomized part of the study, we determined differences in blood parameters, follicle recruitment, and follicle diameter. In the observational part of the study, we assessed follicle recruitment in between cycles and its correlation to endocrine parameters.
Letrozole cotreatment significantly suppressed oestradiol (E2) concentrations in the follicular phase (area under the curve (AUC) -58% (95% CI [-70%; -43%], P < 0.001)) and luteal phase (AUC -39% [-63%; -1%], P = 0.046). This had a marked effect on the endocrine and paracrine output with increased follicular phase luteinizing hormone (AUC +37% [3%; 82%], P = 0.033), androstenedione (AUC +36% [6%; 74%], P = 0.016), testosterone (AUC +37% [7%; 73%], P = 0.013) and 17-OH-progesterone (AUC +114% [10%; 318%], P = 0.027). Furthermore, follicle-stimulating hormone (FSH) was increased at stimulation day 5 in the LZ group (P < 0.05). In the luteal phase, increased corpus luteum output was reflected by elevated progesterone (AUC +44% [1%; 104%], P = 0.043), inhibin A (AUC +52% [11%; 108%], P = 0.011), androstenedione (AUC +31% [9%; 58%], P = 0.006) and testosterone (AUC +29% [6%; 57%], P = 0.012) in the LZ group. The altered balance between oestrogens and androgens was reflected in a markedly reduced SHBG concentration in the LZ group throughout the luteal phase (AUC -35% [-52%; -11%], P = 0.009). Endocrine and paracrine parameters were similar between groups at the follow-up visit. Letrozole cotreatment significantly increased the mean number of follicles >16 mm at oocyte retrieval (7.2 vs 5.2, difference: 2.0, 95% CI [0.1; 3.8], P = 0.036), while the mean total number of follicles at oocyte retrieval was the same (23.7 vs 23.5, difference: 0.2 [-5.8; 6.1], P = 0.958), and the mean FSH consumption during the stimulated cycle was similar (1500 vs 1520 IU, difference -20 IU [-175; 136], P = 0.794). Between cycles, the mean antral follicle count at CD2-3 was unchanged (natural cycle 19.0, stimulated cycle 20.9, follow-up cycle 19.7, P = 0.692) and there was no effect of LZ cotreatment on the recruitment of the next follicle cohort (test for interaction, P = 0.821).
LIMITATIONS, REASONS FOR CAUTION: This study included a relatively small, selected group of healthy women with an expected normal ovarian function and reserve, and the effects of LZ may therefore be different in other patient groups.
We confirm some previous findings concerning increased follicle growth and increased endogenous FSH and androgen production, which support the rationale for further studies on the use of LZ cotreatment, for example, as a form of endogenous androgen priming sensitizing the follicle to FSH. Letrozole appears to improve the luteal phase with better stimulation of corpus luteum and progesterone secretion.
STUDY FUNDING/COMPETING INTEREST(S): The authors declare no conflicts of interest relating to the present work.
NCT02939898.
在卵巢刺激过程中使用来曲唑（LZ）联合治疗会产生哪些下游内分泌和旁分泌后果，以及卵泡生长和募集是否会受到影响？
来曲唑联合治疗会导致卵泡和黄体期内分泌发生明显变化，从而导致卵泡直径增大和黄体功能改善，而不会影响次级募集的卵泡群。
来曲唑是一种第三代芳香化酶抑制剂，已被确立为有效的排卵药物，而其在标准体外受精方案中的潜在益处尚未得到充分研究。
研究设计、规模、持续时间：这项研究包括一项双盲、安慰剂对照、随机研究，其中在体外受精治疗的卵巢刺激期间给予 LZ 或安慰剂干预，随后进行一个前瞻性的基础自然周期和后续的随访访问。参与者于 2016 年 8 月至 2018 年 11 月期间入组。随机刺激周期的数据是先前发表的更大规模 RCT 的一部分。
参与者/材料、设置、方法：该研究在丹麦 Herlev 医院的一家公共生育诊所进行，包括 31 名符合条件的健康、正常反应的女性，适合进行体外受精治疗。她们接受了基础自然周期的检查，随后随机分为两组，分别在 CD2-3 时开始接受 LZ 5mg（n=16）或安慰剂（n=15）的每日治疗，直至诱导排卵。在两个周期中，每三天通过阴道超声进行监测，以评估卵泡计数和直径，通过血液分析确定 12 种内分泌和旁分泌参数。在随后的周期中，在 CD2-3 进行随访评估。在研究的随机部分，我们确定了血液参数、卵泡募集和卵泡直径的差异。在研究的观察部分，我们评估了周期之间的卵泡募集情况及其与内分泌参数的相关性。
来曲唑联合治疗显著抑制了卵泡期的雌二醇（E2）浓度（AUC-58%[-70%；-43%]，P<0.001）和黄体期（AUC-39%[-63%；-1%]，P=0.046）。这对内分泌和旁分泌输出有显著影响，增加了卵泡期促黄体生成素（AUC+37%[3%；82%]，P=0.033）、雄烯二酮（AUC+36%[6%；74%]，P=0.016）、睾酮（AUC+37%[7%；73%]，P=0.013）和 17-羟孕酮（AUC+114%[10%；318%]，P=0.027）。此外，在 LZ 组中，在刺激第 5 天 FSH 升高（P<0.05）。在黄体期，通过升高黄体输出的孕激素（AUC+44%[1%；104%]，P=0.043）、抑制素 A（AUC+52%[11%；108%]，P=0.011）、雄烯二酮（AUC+31%[9%；58%]，P=0.006）和睾酮（AUC+29%[6%；57%]，P=0.012）来反映。在 LZ 组中，雌激素和雄激素之间的平衡变化反映在黄体期 SHBG 浓度明显降低（AUC-35%[-52%；-11%]，P=0.009）。在随访时，两组之间的内分泌和旁分泌参数相似。来曲唑联合治疗显著增加了取卵时>16mm 的卵泡数量（7.2 比 5.2，差异：2.0，95%CI[0.1；3.8]，P=0.036），而取卵时的总卵泡数相同（23.7 比 23.5，差异：0.2[-5.8；6.1]，P=0.958），刺激周期中 FSH 的消耗也相似（1500 比 1520IU，差异-20IU[-175；136]，P=0.794）。在周期之间，CD2-3 时的平均窦卵泡数没有变化（自然周期 19.0，刺激周期 20.9，随访周期 19.7，P=0.692），来曲唑联合治疗对下一个卵泡群的募集没有影响（交互检验，P=0.821）。
局限性、谨慎的原因：本研究纳入了一组相对较小的、选择的健康女性，预期具有正常的卵巢功能和储备，因此 LZ 的作用可能在其他患者群体中有所不同。
我们证实了一些先前关于卵泡生长增加和内源性 FSH 和雄激素产生增加的发现，这支持了进一步研究来曲唑联合治疗的合理性，例如作为内源性雄激素诱导的形式，使卵泡对 FSH 敏感。来曲唑似乎改善了黄体期，更好地刺激黄体和孕激素分泌。
研究资金/利益冲突：作者声明没有与本工作相关的利益冲突。
NCT02939898。
