Levonorgestrel is an effective oral progesterone inhibitor [1]. Levonorgestrel can be used for contraception and can be combined with other drugs. Levonorgestrel has anti-cancer activity and can induce cell apoptosis, and is used in the research of osteoporosis and uterine leiomyoma [2].
In vitro, Levonorgestrel (5-25μg/mL; 72h) can inhibit cell proliferation and promote cell apoptosis in uterine smooth muscle tumor cells in a concentration-dependent manner. It can significantly reduce the expression of Bcl-2 and Survivin, increase the phosphorylation level of p38, and activate caspase 3 [2]. Levonorgestrel (50μM) has a time-dependent inhibitory effect on the proliferation of HESCs and HEGCs, and significantly increases cell apoptosis. Levonorgestrel causes a time-dependent increase in the total Cx43 content, but does not cause changes in Ser368 phosphorylated Cx43, while Ser255 phosphorylated Cx43 shows a nuclear translocation phenomenon [3].
In vivo, after random mating in mice, Levonorgestrel (8mg/kg) isintraperitoneally injected immediately, and the frequency of ciliary beating of the fallopian tubes (CBF) in mice decreases significantly. The average percentage of embryo-tube retention in the Levonorgestrel group is 18.27% [4]. Oral administration of Levonorgestrel (0.67mg/kg/day) and quinestrol for 7 days significantly reduces sperm count in SD rats and decreases androgen receptor and Wilms tumor nuclear protein 1 (WT1) staining. Quinestrolalone or in combination with Levonorgestrel induces low fertility in male rats, primarily by interfering with reproductive cell differentiation [5].
References:
[1] Tellería CM, Carrizo DG, Deis RP. Levonorgestrel inhibits luteinizing hormone-stimulated progesterone production in rat luteal cells. J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):161-6.
[2] Xu Qing, et al. Levonorgestrel inhibits proliferation and induces apoptosis in uterine leiomyoma cells. Contraception vol. 82,3 (2010): 301-8.
[3] Zhao X, Tang X, Ma T, et al. Levonorgestrel inhibits human endometrial cell proliferation through the upregulation of gap junctional intercellular communication via the nuclear translocation of Ser255 phosphorylated Cx43[J]. BioMed Research International, 2015, 2015(1): 758684.
[4] Li C, Zhang H Y, Liang Y, et al. Effects of Levonorgestrel and progesterone on Oviductal physiology in mammals[J]. Reproductive Biology and Endocrinology, 2018, 16(1): 59.
[5] Liu M, Wan X, Yin Y, et al. Subfertile effects of quinestrol and levonorgestrel in male rats[J]. Reproduction, Fertility and Development, 2012, 24(2): 297-308.
Levonorgestrel是一种口服有效的孕酮抑制剂 [1]。Levonorgestrel能够用于避孕且能与其他药物进行联用。Levonorgestrel具有抗癌活性，能够诱导细胞凋亡，能够用于骨质疏松、子宫平滑肌瘤的研究 [2]。
在体外，Levonorgestrel (5-25μg/mL; 72h) 在子宫平滑肌瘤细胞中能以浓度依赖方式抑制细胞增殖和促进细胞凋亡，能够显著降低Bcl-2和Survivin的表达，升高p38磷酸化水平以及激活caspase 3 [2]。Levonorgestrel（50μM）对HESCs和HEGCs的增殖有时间依赖性的抑制作用，并显著增加细胞凋亡。Levonorgestrel以时间依赖的方式导致总Cx43的含量相对增加，但并未引起Ser368磷酸化Cx43的变化，而Ser255磷酸化Cx43出现了核内转移的现象 [3]。
在体内，在小鼠进行随机交配后立即腹腔注射Levonorgestrel（8mg/kg），小鼠体内输卵管纤毛搏动频率（CBF）显著降低。Levonorgestrel组小鼠的平均胚胎-输卵管保留百分比为18.27% [4]。Levonorgestrel（0.67mg/kg/day）和quinestrol通过口服给药7天，显著减少了SD大鼠的精子数量，并且雄激素受体和Wilms肿瘤核蛋白1染色减少。quinestrol单独或与Levonorgestrel组合诱导雄性大鼠生育力低下，主要是通过干扰生殖细胞分化 [5]。