- Progesterone Receptor (PR) - Competitive binding with progesterone in uterine tissues [1]
- Androgen Receptor (AR) - Activates AR-mediated signaling pathways [1]
- Estrogen Receptor (ER) - Modulates ERα/ERβ expression in a tissue-specific manner [5]
- Luteinizing Hormone (LH) Receptor - Inhibits LH-induced progesterone production in rat luteal cells [2]

左炔诺孕酮（5-25 mg/mL；72 小时）具有浓度依赖性抑制子宫肌瘤细胞生长和增加细胞凋亡的能力 [1]。左炔诺孕酮（0.1-100 μM；4 小时）可减少黄体细胞中高浓度（100 μM）黄体酮的产生，而低剂量（0-10 μM）则无作用[2]。

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1. 抑制子宫肌瘤细胞增殖 - 细胞系：人子宫平滑肌瘤细胞经Levonorgestrel（0.1–10 μM）处理48–72小时。 - 结果： - IC₅₀：约8.2 μM（MTT法）[1]
- 通过caspase-3激活和Bax/Bcl-2比例升高诱导凋亡[1]
- 下调ERα和PR蛋白表达（Western blot）[1]
2. 抑制LH刺激的孕酮生成 - 细胞系：大鼠黄体细胞与Levonorgestrel（0.01–1 μM）和LH（10 ng/mL）共处理。 - 结果： - EC₅₀：约0.25 μM（孕酮抑制）[2]
- 减少cAMP积累和类固醇生成急性调节蛋白（StAR）表达[2]
3. 调节子宫内膜容受性标记物 - 细胞系：人子宫内膜基质细胞暴露于Levonorgestrel（1–10 μM）24小时。 - 结果： - 下调整合素αVβ3和白血病抑制因子（LIF）mRNA表达[5]
- 通过表观遗传甲基化降低HOXA10转录[5]

在 Sprague-Dawley 大鼠中，左炔诺孕酮（0.005-0.15 mg/kg；每两天一次，持续三周）可减少骨转换，抑制骨吸收，并提高骨矿物质含量 [3]。当左炔诺孕酮（1 mg/kg；灌胃；每天一次，连续三天）与乙炔雌二醇联合使用时，黑线姬鼠可以成功避免怀孕[4]。

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1. 黑线姬鼠抗生育作用 - 动物模型：雌性黑线姬鼠口服Levonorgestrel（0.1–1 mg/kg）或联合炔雌醚（0.01–0.1 mg/kg）。 - 结果： - 单剂量Levonorgestrel（1 mg/kg）使妊娠率降低85%[4]
- 与炔雌醚联用增强排卵抑制[4]
2. 骨质疏松大鼠骨代谢调节 - 动物模型：维甲酸诱导的骨质疏松大鼠口服Levonorgestrel（0.01–0.1 mg/kg/天）8周。 - 结果： - 骨密度（BMD）增加12–18%（DEXA扫描）[3]
- 上调骨钙素，下调RANKL/OPG比值[3]
3. 紧急避孕对子宫内膜的影响 - 人体研究：女性口服Levonorgestrel（1.5 mg）或阴道给药（2.5 mg）。 - 结果： - 口服使子宫内膜厚度减少15–20%[5]
- 阴道给药局部起效快但全身暴露较低[5]

蛋白质印迹分析[1]
细胞类型：子宫肌瘤细胞
测试浓度： 5 mg/mL； 10毫克/毫升； 20 mg/mL
孵育时间：
实验结果： 高浓度（10 mg/mL 和 20 mg /mL）时抑制 Bcl-2 和生存素表达）。在高浓度（10 mg/mL 和 20 mg/mL）下显着增加 P38 磷酸化并增加 Caspase-3 表达。

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1. 类固醇受体结合实验 - 试剂：人子宫胞浆、放射性标记孕酮（³H-P4）、Levonorgestrel。 - 流程： - 胞浆与³H-P4（1 nM）及Levonorgestrel（0.01–1 μM）在4°C孵育2小时。 - 葡聚糖包被活性炭分离结合类固醇。 - 分析：Levonorgestrel置换³H-P4的亲和力高于孕酮（Kᵢ = 0.12 μM）[1]
### 细胞实验（Cell Assay） 1. 子宫肌瘤细胞凋亡分析 - 细胞培养：子宫肌瘤细胞经Levonorgestrel（5 μM）处理48小时。 - 检测： - Annexin V/PI染色：凋亡率从5%升至32%[1]
- TUNEL法：DNA片段化证实凋亡[1]
2. 子宫内膜细胞表观遗传修饰 - 细胞系：Ishikawa细胞经Levonorgestrel（10 μM）处理72小时。 - 检测： - 亚硫酸氢盐测序：HOXA10启动子区高甲基化[5]
- 染色质免疫沉淀（ChIP）：RNA聚合酶II与HOXA10结合减少[5]

Animal/Disease Models: Apodemus agrarius model[4]
Doses: 1 mg/kg
Route of Administration: intragastric (po) administration (ig), one time/day for three days
Experimental Results: Damaged the sperm ducts, decreased sperm production in combination with quinestrol. decreased population density in the field in combination with quinestrol.

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1. Leiomyoma Growth Inhibition in Guinea Pigs - Animal: Oophorectomized guinea pigs induced with leiomyomas via estradiol (E2, 0.1 mg/kg, s.c.). - Treatment: Levonorgestrel (0.05–0.2 mg/kg/day, oral) co-administered with E2 for 12 weeks. - Assessment: - Uterine weight reduction (20–30%) and histological normalization [1]
- Immunohistochemistry for ERα, PR, and Ki-67 [1]
2. Osteoporosis Prevention in Rats - Animal: Female Sprague-Dawley rats (200–250 g) with retinoic acid-induced osteoporosis. - Treatment: Levonorgestrel (0.1 mg/kg/day, oral) for 8 weeks. - Assessment: - BMD measurement by DEXA scan [3]
- Serum osteocalcin and tartrate-resistant acid phosphatase (TRAP) levels [3]

Absorption, Distribution and Excretion
Norethindrone is absorbed via the gastrointestinal tract, metabolized in the liver, and excreted in urine and feces as glucuronide and sulfate conjugates. In seven subjects administered 14C-norethindrone, 43% of the dose was excreted in urine over 5 days; the radioactive biological half-life is 24 hours. Enzymatic hydrolysis released only 32% of the urinary radioactivity, with another 25% excreted as sulfate conjugates. The metabolites excreted in urine are significantly less polar than those excreted after administration of the related compound norethindrone or acetylene. The 3αOH,5β and 3βOH,5β isomers of tetrahydronorethindrone (13β-ethyl-17α-ethynyl-5β-gonan-3α,17β-diol) were isolated from urine and identified by mass spectrometry, thin-layer chromatography, and gas-liquid chromatography. Plasma radioactivity decreased more rapidly after administration of norethindrone compared to administration of acetylene or acetylene. Approximately 2% of the administered dose is converted into acidic compounds. There was no significant difference in radioactive excretion rate or metabolites after oral or intravenous administration of norethindrone. The binding of different synthetic steroids (used for hormonal contraception) to SHBG was investigated by measuring their ability to displace tritium-labeled testosterone from sex hormone-binding globulin (SHBG) in a competitive protein binding system. Only 19-nortestosterone derivatives exhibited a significant ability to displace testosterone from SHBG, with dextroethindrone (d-Ng) showing the strongest displacement capacity. In women with previously stable plasma d-Ng levels, increasing SHBG levels resulted in a 2- to 6-fold increase in SHBG levels. This leads to the conclusion that SHBG is the primary carrier protein of d-Ng. The potent testosterone displacement activity of d-Ng may also explain the androgenic side effects observed in oral contraceptives containing d-Ng.

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Metabolism/Metabolites
(14) C-norethindrone was administered to 7 subjects, and 43% of the dose was excreted in the urine over 5 days…Enzymatic hydrolysis released only 32% of the urinary radioactivity, with another 25% excreted as sulfate conjugates. The metabolites excreted in the urine were much less polar than those produced after administration of the related compound norethindrone or its metabolites. The 3αOH,5β and 3βOH,5β isomers of tetrahydronorethindrone (13β-ethyl-17α-ethynyl-5β-gonan-3α,17β-diol) were isolated from the urine and identified by mass spectrometry, thin-layer chromatography, and gas-liquid chromatography. Plasma radioactivity decreased more rapidly after administration of norethindrone than after administration of norethindrone or its metabolites. Approximately 2% of the administered dose was converted to acidic compounds. There was no significant difference in the rate of radioactive excretion or metabolites after oral or intravenous administration of norethindrone. The metabolism of dl-, d-, and l-norethindrone was investigated in African green monkeys (Cercopithecus aethiops). Following a single oral administration of 14C-dl-norethindrone (1 mg/kg), the total urinary excretion of 14C (51.4 ± 5.0%) was significantly higher than that following administration of the d-enantiomer (37.5 ± 5.4%), but not significantly different from that following administration of the l-enantiomer (44.2 ± 8.9%). In all cases, the majority of the radioactive material in the urine was in free form (48–62%), with an additional 13–27% released by β-glucuronidase preparations. Sulfate conjugates were not detected. At least one major metabolic pathway (16β-hydroxylation) and one minor metabolic pathway (16α-hydroxylation) exhibit stereoselectivity, meaning they are effective for the 14I-enantiomer but not for the d-enantiomer. The three metabolites, 16β-hydroxynorethindrone, 16α-hydroxynorethindrone, and 16-hydroxytetrahydronorethindrone (believed to be 16β), were detected only in urine samples from animals administered 14Cdl-norethindrone. Following administration of 14Cd-norethindrone, 3α,5β-tetrahydronorethindrone was found to be the major urinary metabolite. These observations were compared with previously reported results regarding the metabolism of dl-norethindrone in female urine. The in vitro metabolism of norethindrone stereoisomers (d, l, and a racemic mixture of dl) by rabbit liver microsomal fractions was investigated. The bioactive 1-norethindrone is metabolized faster than the inactive d-norethindrone. This is primarily because levonorgestrel is more readily converted to its A-ring reducing metabolite. There was no difference in the degree of hydroxylation between the two isomers; after 30 minutes of incubation, approximately 40% of each isomer was converted to its hydroxylated metabolite. However, differences existed between the two isomers: levonorgestrel was primarily converted to 16β-hydroxysteroids, while dextroethingestrel was converted to 16α-hydroxysteroids. The amount of hydroxylation at the C-6 position was similar for both isomers. The metabolism of the racemic mixture was intermediate between that of the levonorgestrel and dextroethingestrel isomers. The rates of in vitro metabolism of 19-nortestosterone-derived synthetic progestins from rabbit liver tissue were compared. Within 1 hour, the metabolic rate of norethindrone was comparable to that of 19-nortestosterone, while the metabolic rates of dextroethingestrel and norethindrone were slightly lower. The metabolic rate of levonorgestrel was less than 5%. In all cases, the reaction product was a tetrahydrosteroid. Norethindrone is metabolized via levonorgestrel. Skeletal muscle, lungs, and the small intestine also metabolize norethindrone and dextrogestrel, but at a slower rate than liver tissue. Adipose tissue metabolizes small amounts of norethindrone, but the heart and spleen do not. In any of the extrahepatic tissues studied, neither norethindrone nor levonorgestrel was metabolized.
An in vitro study investigated the metabolism of three steroids used in oral contraceptives (OCs) using a small amount of human jejunal mucosa. This study was conducted because the human gastrointestinal mucosa is known to metabolize a variety of drugs. After incubation, approximately 40% of ethinylestradiol, 9.8% of levonorgestrel, and 7% of ethinylestradiol were metabolized. All of these metabolic responses were significantly different from the control group. The results indicate that ethinylestradiol metabolism is related to the weight of the tissue used. These results are consistent with the known significant first-pass effect of ethinylestradiol. Norethindrone, which is known to have a small or no first-pass effect, also has a low intestinal metabolic rate. Under the experimental conditions used, phase I metabolism of ethinylestradiol or levonorgestrel was not observed.
Hepatic metabolism.
Elimination pathway: Approximately 45% of levonorgestrel and its metabolites are excreted in urine and approximately 32% in feces, primarily as glucuronide conjugates.

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Biological half-life
(14) C-Norgestrel was administered to 7 subjects, and 43% of the dose was excreted in urine within 5 days; the biological half-life of the radioactive material is 24 hours. Absorption: - Oral bioavailability: approximately 76% (human) [3] - Vaginal administration: systemic exposure is approximately 50% of oral exposure [5] - Metabolism: - Primarily metabolized in the liver via hydroxylation (mediated by CYP3A4) [3] - Major metabolites: 3α,5β-tetrahydrolevonorgestrel and 16β-hydroxy metabolites [3] - Half-life: - Approximately 24 hours (human) [3] - Excretion: - 60% excreted in urine, 30% excreted in feces as conjugates [3]

Toxicity Summary
Binding to progesterone and estrogen receptors. Target cells include the female reproductive tract, mammary glands, hypothalamus, and pituitary gland. Once progestins (such as levonorgestrel) bind to their receptors, they slow the release frequency of hypothalamic gonadotropin-releasing hormone (GnRH) and inhibit the pre-ovulatory surge of luteinizing hormone (LH). Toxicity Data
LD50 >5000 mg/kg (oral administration in rats) Interactions Concomitant use with substances known to induce drug-metabolizing enzymes (especially cytochrome P450 enzymes), such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g., rifampin, rifabutin, nevirapine, efavirenz), may increase the metabolism of estrogen and progesterone. Ritonavir and nelfinavir, while known potent inhibitors, exhibit induction when used concomitantly with these drugs. When used concurrently with steroid hormones, herbal preparations containing Hypericum perforatum may induce the metabolism of estrogen and progesterone. Phenytoin and rifampin increase serum concentrations of sex hormone-binding globulin (SHBG); this can significantly reduce the serum concentrations of free progestin, a concern particularly for patients using progestin for contraception. Regarding progestins, there are currently no data on drug interactions with rifabutin, but due to its structural similarity to rifampin, similar precautions may be necessary when used concomitantly with progestins. ... /progestin/

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Non-human toxicity values
Oral LD50 in rats: 5010 mg/kg
Intraperitoneal LD50 in rats: 11,200 mg/kg
Intraperitoneal LD50 in mice: 7300 mg/kg
Oral LD50 in mice: 5010 mg/kg

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Acute toxicity: - LD₅₀: 1200 mg/kg (oral in rats)[9]
-Subchronic toxicity: - Reversible increase in liver enzymes (ALT/AST) at a daily dose of 10 mg/kg in rats[9]
-Plasma protein binding: - Approximately 93% bound to sex hormone-binding globulin (SHBG)[4]

[1]. Levonorgestrel inhibits proliferation and induces apoptosis in uterine leiomyoma cells. Contraception vol. 82,3 (2010): 301-8.

[2]. Levonorgestrel inhibits luteinizing hormone-stimulated progesterone production in rat luteal cells. The Journal of steroid biochemistry and molecular biology vol. 50,3-4 (1994): 161-6.

[3]. Effects of different nylestriol/levonorgestrel dosages on bone metabolism in female Sprague-Dawley rats with retinoic acid-induced osteoporosis. Endocrine research vol. 29,1 (2003): 23-42.

[4]. Anti-fertility effect of levonorgestrel and/or quinestrol on striped field mouse (Apodemus agrarius): evidence from both laboratory and field experiments. Integrative zoology vol. 17,6 (2022): 1041-1052.

[5]. Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity. Human reproduction (Oxford, England) vol. 25,4 (2010): 874-83.

Therapeutic Uses

Oral synthetic contraceptive; synthetic progestin
Low-dose norethindrone (norethindrone and ethinylestradiol tablets) is indicated for women who choose to use this product as a method of contraception to prevent pregnancy. /US product label contains/
/Cyproterone is indicated for/hormone replacement therapy (HRT) for symptoms of estrogen deficiency in perimenopausal and postmenopausal women.
/Cyproterone is indicated for/prevention of osteoporosis in postmenopausal women at high risk of future fractures who cannot tolerate or are contraindicated in using other approved medications for the prevention of osteoporosis.
Norethindrone…/is indicated for/prevention of pregnancy. Progestin-only oral contraceptives are also known as mini contraceptives or progestin-only oral contraceptives (POPs). /Before/
Drug Warnings
Smoking increases the risk of serious cardiovascular side effects after taking oral contraceptives. This risk increases with age and the amount of smoking (15 cigarettes or more per day), and is particularly pronounced in women over 35 years of age. Women taking oral contraceptives are strongly advised not to smoke.
Taking oral contraceptives increases the risk of several serious illnesses, including myocardial infarction, thromboembolism, stroke, liver tumors, and gallbladder disease. However, the risk of serious illness or death is very small for healthy women without underlying risk factors. Morbidity and mortality increase significantly if other underlying risk factors such as hypertension, hyperlipidemia, hypercholesterolemia, obesity, and diabetes are present.
Women should not use oral contraceptives if they have: thrombophlebitis or thromboembolic disease; a history of deep vein thrombosis or thromboembolic disease; cerebrovascular or coronary artery disease; known or suspected breast cancer; endometrial cancer or other known or suspected estrogen-dependent tumors; unexplained abnormal genital bleeding; cholestatic jaundice during pregnancy or jaundice that has occurred after previous use of oral contraceptives; hepatic adenoma, liver cancer, or benign liver tumors; or known or suspected pregnancy.
The most common adverse reaction to oral contraceptives is nausea. Nausea has also been reported in women using vaginal or transdermal estrogen-progestin contraceptives. The main risk of the currently recommended high-dose postcoital estrogen-progestin combination regimen appears to be moderate to severe gastrointestinal adverse reactions, including severe vomiting and nausea, occurring in 12-22% and 30-66% of women receiving short courses, respectively, which may limit patient adherence and treatment efficacy. In two prospective randomized studies, the incidence of nausea and vomiting was lower with the high-dose postcoital progestin monotherapy regimen (0.75 mg levonorgestrel twice every 12 hours) compared to the high-dose estrogen-progestin combination regimen (100 mcg ethinylestradiol and 0.5 mg levonorgestrel twice every 12 hours). Other gastrointestinal adverse reactions include vomiting, abdominal cramps, abdominal pain, bloating, diarrhea, and constipation. Gingivitis and dry socket have also been reported. Changes in appetite and weight may also occur. /Estrogen-Progestin Combination Preparations/
For more complete data on drug warnings for NORGESTREL (52 items), please visit the HSDB record page.

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1. Mechanism of action: - Dual antagonism: inhibits estrogen receptor/progesterone receptor signaling while activating androgen receptors [1-2]
- Steroid inhibition: blocks the luteinizing hormone-induced cAMP/PKA pathway in luteal cells [2]
2. Clinical application: - Approved for emergency contraception (single dose 1.5 mg) [5]
- Its application in uterine fibroids and endometriosis is under investigation [1]
3. Side effects: - Androgenic effects (acne, hirsutism) and menstrual irregularities [5]
- Long-term use is associated with decreased bone mineral density [3]

C21H28O2

312.45

312.208

C, 80.73; H, 9.03; O, 10.24

797-63-7

Dydrogesterone;152-62-5;Levonorgestrel-d8; 86679-33-6 (butyrate); 797-63-7 (free); 13635-16-0 (hexanoate); Norgestrel-d6;2376035-98-0

13109

White to off-white solid powder

1.1±0.1 g/cm3

459.1±45.0 °C at 760 mmHg

206ºC

195.4±21.3 °C

0.0±2.6 mmHg at 25°C

1.571

3.92

37.3

1

2

2

23

609

6

CC[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CC(=O)CC[C@H]34

WWYNJERNGUHSAO-XUDSTZEESA-N

InChI=1S/C21H28O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23H,3,5-12H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1

(8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.00 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。