Progesterone Receptor

炔诺酮，也称为 19-去甲睾酮衍生物，主要是孕激素而非雄激素，具有一些雌激素和抗雌激素活性。它缺少 C19 甲基并具有 C17 乙炔基取代。 （来源：）与 Org 2058 (100%) 相比，NET 中的黄体酮受体结合和反式激活活性强两倍，比 NET 弱五到八倍。 NET对雄激素受体（5α-二氢睾酮100％）的结合和反式激活活性分别为3.2％和1.1％，对雌激素受体（雌二醇100％）没有结合和反式激活活性，对糖皮质激素受体（地塞米松100％）低于1％ ).[2]血清刺激或雌二醇 (0.1 nM) 诱导的 MCF-7 增殖被炔诺酮 (1 nM) 分别抑制 41% 和 34%。[/3] 对大鼠成骨细胞增殖、分化和矿化过程产生显着影响通过炔诺酮 (50 nM)，它由雌激素受体介导并模仿雌二醇的作用。 [4]

炔诺酮在体内表现出激素特性。孕激素试验 (McPhail)、雄激素试验 (Hershberger)、雌激素试验 (Allen–Doisy) 以及孕激素和雌激素试验（排卵抑制试验）中 MNorethisterone sc 的平均活性剂量 (MAD) 分别为 0.63 mg/kg 、2.5mg/kg、4mg/kg和0.235mg/kg。口服时，MAD为0.25mg/kg、20mg/kg、8mg/kg和12mg/kg。 **[2]** 骨吸收和形成均受炔诺酮的影响。在 SO 和 OVX 小鼠中，炔诺酮（80 μg/天）可减少骨吸收，同时促进雌二醇刺激的骨内骨形成。 (5) 在去势小鼠中，用于预防骨质疏松症的激素治疗剂量的炔诺酮对骨矿物质流失具有轻微的保护作用。 (6)

在测定试剂盒培养基中，96 孔板每孔接种大约 1000 个 MCF-7 细胞。然后将细胞在含有已用葡聚糖和木炭处理过的血清的培养基中孵育三天。之后，孔中仅填充炔诺酮，并孵育 7 天。将细胞用 0.1 nM 雌二醇和 0.1 nM 炔诺酮的组合处理 7 天，以模拟连续联合 HRT。 ATP 化学敏感性测试用于量化 7 天潜伏期后的细胞增殖。简而言之，通过测量荧光素在 ATP 和荧光素酶存在下的生物发光反应来确定增殖过程中发出的光量。

Rats: Individual caged Sprague-Dawley female rats (200-210 g), with six of them acting as controls, are housed in a brightly lit animal room from 9:00 a.m. to 9:00 p.m. For two weeks, each of the seven rats given norethindrone acetate is fed 35 μg per day. There is an abundance of water and the high-carb rat chow available.

Absorption, Distribution and Excretion
The Cmax of norethisterone following oral administration of a single dose ranges from 5.39 to 7.36 ng/mL with a Tmax of 1-2 hours. AUC0-24 values following single oral doses range from approximately 30 to 37 ng*hr/mL. The oral bioavailability of norethisterone is approximately 64%. When applied transdermally, norethisterone is well-absorbed through the skin, reaches steady-state concentrations within 24 hours, and has a Cmax ranging from 617 to 1060 pg/mL at steady state. Norethisterone is often formulated as norethisterone acetate, which is completely and rapidly deacetylated to norethisterone following oral administration - the disposition of norethisterone acetate is indistinguishable from that of orally administered norethisterone.
Following administration of radio-labeled norethisterone, slightly more than 50% of the administered dose was eliminated in the urine and 20-40% was eliminated in the feces.
The volume of distribution of norethisterone is approximately 4 L/kg. Sulfated metabolites of norethisterone, as well as small quantities of parent drug, have been shown to distribute into breast milk.
The plasma clearance of norethisterone has been estimated as 0.4 L/hr/kg, and the intrinsic clearance is approximately 73-81 L/h.
Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is about 4 L/kg.
Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg.
In 25 BALB/c mice implanted subcutaneously with pellets containing 40% norethisterone and 60% cholesterol for 76-77 wk, absorption of norethisterone was estimated to be between 3.6 and 15.9 ug/day (mean, 7.7 ug/day).
Rabbits excrete norethisterone metabolites predominantly in the urine ... while rats excrete them to 80% in bile ... .
For more Absorption, Distribution and Excretion (Complete) data for NORETHINDRONE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Norethisterone is extensively metabolized, primarily in the liver, to a number of metabolites via partial and total reduction of its A-ring. The enzymes predominantly involved are 3α- and 3β-hydroxysteroid dehydrogenase (HSD) as well as 5α- and 5β-reductase. The 5α-reduced metabolites, including 5α-dihydronorethisterone and its derivatives, appear to carry biological activity while the 5β-reduced metabolites appear inactive. Norethisterone and its metabolites are also extensively conjugated - most of the plasmatic metabolites are sulfate conjugates, while most of the urinary metabolites are glucuronide conjugates. The major metabolites in plasma are a disulfate conjugate of 3α,5α-tetrahydronorethisterone and a monosulfate conjugate of 3α,5β-tetrahydronorethisterone, while the major metabolite(s) in the urine are comprised of glucuronide and/or sulfate conjugates of 3α,5β-tetrahydronorethisterone. Norethisterone has also been observed to undergo some degree of metabolism via the cytochrome P450 enzyme system, predominantly by CYP3A4 and, to a much lesser extent, by CYP2C19, CYP1A2, and CYP2A6. The metabolites generated by these reactions have not been fully characterized.
Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.
Norethisterone undergoes extensive ring A reduction to form dihydro- and tetrahydronorethisterone metabolites that undergo conjugation; it can also be aromatized. Low serum levels of ethinylestradiol have been measured in postmenopausal women following oral administration of relatively large doses of norethisterone acetate or norethisterone. On the basis of the area-under-the-curve (AUC) values that were determined for ethinylestradiol and norethisterone, it was shown that the mean conversion ratio of norethisterone to ethinylestradiol was 0.7 and 1.0% at doses of 5 and 10 mg, respectively. The authors calculated that this corresponds to an oral dose equivalent of about 6 ug ethinylestradiol/ mg of norethisterone acetate. Similarly, it was shown that a dose of 5 mg norethisterone administered orally was equivalent to about 4 ug ethinylestradiol/mg norethisterone.
After incubation of norethisterone with dog liver microsomes the 4beta,5beta-epoxide of norethisterone and a 6-oxygenated norethisterone derivative were obtained as minor metabolites ... .
Rabbit liver homogenates ... catalyze the deethinylation of norethisterone, giving rise to the metabolite oestr-4-ene-3,17-dione.
For more Metabolism/Metabolites (Complete) data for NORETHINDRONE (7 total), please visit the HSDB record page.
Norethindrone has known human metabolites that include Norethindrone-O-glucuronide.
Hepatic. Norethindrone is extensively metabolized, primarily via reduction. It also undergoes sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.
Route of Elimination: Norethindrone is excreted in both urine and feces, primarily as metabolites.
Half Life: 8.51±2.19 (when a single dose is given to healthy women)

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Biological Half-Life
The half-life of norethisterone has been variably estimated as 8-10 hours.
The mean terminal elimination half-life of norethindrone following a single dose administration of AYGESTIN is approximately 9 hours.
The plasma half-life, MCR and plasma metabolite levels at various time intervals have been studied in six women after an intravenous injection of 3H-norethindrone acetate. The disappearance curve due to norethindrone acetate showed an initial rapid disappearance of 3H with an average half-life of 7.5 minutes and a subsequent slow disapperance with a half-life of 51.5 hours. Norethindrone acetate was cleared from the plasma with an average MCR of 495 L/day. Norethindrone acetate is rapidly metabolised after an intravenous injection. Norethindrone, the main metabolite, disappears from the plasma with an average half-life of 34.8 hours. Norethindrone maintains a high level compared with norethindrone acetate at all time intervals up to 24 hours and an equilibrium is reached between the two at 24 to 48 hours.
The half-life (of the beta phase of a two-component model) of elimination ranged from 4.8 to 12.8 hr (mean, 7.6 hr) with no significant differences between oral and intravenous administration.

Toxicity Summary
Progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge.

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Interactions
The concomitant use of antibiotics and oral contraceptives should be included in the assessment of contraceptive failure. A case of unwanted adolescent pregnancy in an 18-year-old female who had a severe staphylococcal skin infection and an underlying chronic granulomatous disease is presented and discussed. She had been receiving semisynthetic penicillin (500 mg. of oxacillin sodium every 6 hours) for 6 weeks and reported not having a menstrual period for 40 days. She was also on an oral contraceptive (1 mg. norethindrone/0.035 mg. estradiol). Results of a beta subunit human chorionic gonadotropin in serum test confirmed that she was pregnant. Careful review of her contraceptive package and antibiotic prescription suggests that indeed she had faithfully followed directions with both medicines. She and her boyfriend and the family received counseling; a therapeutic abortion was done. Advising a different contraceptive method or an additional contraceptive modality may be indicated in adolescents taking longterm antibiotic medication.
... In a randomized, 2-way crossover study, 20 healthy female subjects received Treatments A and B. Treatment A consisted of a single dose of OrthoNovum containing 1 mg norethisterone (norethindrone) and 35 microg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration. In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by Cmax and AUC0-infinity values (95% CI) of 9.8 (8.1, 11.9) ng/mL and 72.9 (57.0, 93.1) ng x hr/mL, and 53.0 (47.0, 59.9) pg/mL and 758 (655, 878) pg x hr/mL, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (-23.5, -2.6) and 31.0% (-40.5,-20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively. Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered.
The effects of phenytoin treatment on plasma concentrations of norethisterone (NET) was studied in 7 healthy female rhesus monkeys. Before phenytoin treatment was started each monkey received an oral dose of 0.5 mg NET and 2 weeks later the same dose was given intravenously. On both occasions, plasma concentrations of NET were measured at frequent intervals during 24 hours. The monkeys were given phenytoin daily orally for more than 4 weeks. The absorption of phenytoin was confirmed by plasma determinations of phenytoin. While still on phenytoin treatment, the monkeys were again given 0.5 mg NET orally and 2 weeks later i.v. and blood sampling was repeated. During phenytoin treatment, plasma NET concentrations were always below those found before treatment. Both at iv and oral administration, the areas under the plasma concentration vs time curve (AUC) were reduced to 55% of the pretreatment AUCs. No difference in plasma half-life was found during phenytoin treatment. The results of this study may suggest that women on antiepileptic treatment with phenytoin should be given an oral contraceptive with a comparatively high dose of the steroids to provide contraceptive efficacy.
The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450--600 mg/day). Rifampicin caused a significant reduction in the AUC of a single dose of 1 mg norethisterone from 37.8 +/- 13.1 to 21.9 +/- 5.9 ng/mL X hr (p less than 0.01). The plasma norethisterone half life (beta-phase) was also reduced from 6.2 +/- 1.7 to 3.2 +/- 1.0 hr (p less than 0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/mL to 2.3 ng/mL. Rifampicin caused a significant increase in antipyrine clearance, 6 beta-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there was no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone AUC during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.
For more Interactions (Complete) data for NORETHINDRONE (8 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse oral 6 g/kg

[1]. Maturitas . 2003 Dec 10:46 Suppl 1:S7-S16.

[2]. J Steroid Biochem Mol Biol . 2000 Nov 15;74(4):213-22.

[3]. J Br Menopause Soc. 2003 Mar;9(1):36-8.

[4]. J Endocrinol . 2007 Jun;193(3):493-504.

[5]. J Bone Miner Res . 1993 Feb;8(2):219-30.

[6]. Prague Med Rep . 2006;107(4):401-8.

Therapeutic Uses
Contraceptives, Oral, Synthetic; Progestational Hormones, Synthetic
AYGESTIN is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. AYGESTIN is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection. /Included in US product label/
Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception. /Included in US product label/
Progestin-only oral contraceptives are indicated for the prevention of pregnancy. /Included in US product label/
For more Therapeutic Uses (Complete) data for NORETHINDRONE (6 total), please visit the HSDB record page.

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Drug Warnings
VET: MARKED RAT, MONKEY, & DOG FETAL MASCULINIZATION HAS BEEN OBSERVED AS IN HUMAN. EXCESSIVE DOSAGE DURING PREGNANCY MAY ALSO CAUSE FETAL DEATH, TERATOGENICITY, & DELAYED PARTURITION.
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Norethindrone, like other progestins, may cause breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, changes in cervical erosion and secretions, edema, weight gain or loss, cholestatic jaundice, allergic rash with or without pruritus, melasma or chloasma, and mental depression.
When breakthrough bleeding or irregular vaginal bleeding occurs during norethindrone therapy, nonfunctional causes should be considered. Adequate diagnostic procedures should be performed in patients with undiagnosed vaginal bleeding.
For more Drug Warnings (Complete) data for NORETHINDRONE (44 total), please visit the HSDB record page.

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Pharmacodynamics
Norethisterone is a synthetic oral progestin used for contraception or to treat other hormone-related conditions such as menopausal symptoms and endometriosis. As a synthetic progestin, norethisterone acts similarly to endogenous progesterone but with a much higher potency - it acts at the pelvic level to alter cervical and endometrial function, as well as via the inhibition of pituitary hormones that play a role in follicular maturation and ovulation. A small increase in the risk of developing breast cancer has been observed in patients using combined oral contraceptives, with some evidence also implicating progestin-only pills - patients starting hormonal contraception should be advised of this risk and should employ routine breast self-examinations to check for evidence of any developing masses.

C20H26O2

298.4192

298.193

C, 80.50; H, 8.78; O, 10.72

68-22-4

Norethindrone (Standard);68-22-4;Norethindrone-d6;2376036-05-2

6230

White to off-white solid powder

1.2±0.1 g/cm3

447.0±45.0 °C at 760 mmHg

205-206 °C(lit.)

190.5±21.3 °C

0.0±2.5 mmHg at 25°C

1.577

3.38

37.3

1

2

1

22

594

6

O([H])[C@@]1(C#C[H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])C(C([H])([H])C([H])([H])[C@]4([H])[C@@]3([H])C([H])([H])C([H])([H])[C@@]21C([H])([H])[H])=O

VIKNJXKGJWUCNN-XGXHKTLJSA-N

InChI=1S/C20H26O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,12,15-18,22H,4-11H2,2H3/t15-,16+,17+,18-,19-,20-/m0/s1

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

Utovlan; Norethindrone; 19-nor-17α-ethynyltestosterone; Norethisterone

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)

DMSO: 25~60 mg/mL (83.8~201.1 mM)
Ethanol: ~5 mg/mL (~16.8 mM)

配方 1 中的溶解度: 2.5 mg/mL (8.38 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (8.38 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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配方 3 中的溶解度: ≥ 2.5 mg/mL (8.38 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 储备液加入到 900 μL 玉米油中并混合均匀。

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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。