Progesterone Receptor

Norethisterone, also known as 19-nortestosterone derivative, is primarily progestational rather than androgenic, with some oestrogenic and anti-oestrogenic activity. It lacks a C19 methyl group and has C17 ethinyl substitution. (Source: ) Progesterone receptor binding and transactivation activities are two times stronger in NET compared to Org 2058 (100%) and five to eight times weaker in NET. 3.2 and 1.1%, respectively, are the binding and transactivation activities of NET for the androgen receptor (5α-dihydrotestosterone 100%), none for the estrogen receptor (estradiol 100%), and below 1% for the glucocorticoid receptor (dexamethasone 100%).[2] Serum-stimulated or oestradiol (0.1 nM)-induced MCF-7 proliferation is inhibited by norethisterone (1 nM) by 41% and 34%, respectively.[/3] Significant effects on rat osteoblast proliferation, differentiation, and mineralization processes are induced by norethisterone (50 nM), which is mediated by the estrogen receptor and mimics the effects of estradiol.[4]

Norethisterone displays hormonal properties in vivo. MNorethisterone s.c.'smeanactive dose (MAD) in the progestagenic test (McPhail), androgenic test (Hershberger), estrogenic test (Allen–Doisy), and in a progestagenic and estrogenic test (ovulation inhibition test) is, respectively, 0.63 mg/kg, 2.5 mg/kg, 4 mg/kg, and 0.235 mg/kg.When taken orally, the MAD is 0.25 mg/kg, 20 mg/kg, 8 mg/kg, and 12 mg/kg. **[2]** Both bone resorption and formation are influenced by norethisterone. In SO and OVX mice, norethisterone (80 μg/day) reduced bone resorption while promoting estradiol-stimulated endosteal bone formation. (5) In castrated mice, norethisterone at the dose used in hormonal therapy for osteoporosis prevention has a minor protective effect against bone mineral loss. (6)

In assay kit medium, 96-well plates are seeded with roughly 1000 MCF-7 cells per well. The cells are then incubated for three days in a medium containing serum that has been treated with dextran and charcoal. After that, the wells are filled solely with norethisterone, and they are incubated for seven days. The cells are treated with a combination of 0.1 nM oestradiol and 0.1 nM norethisterone for seven days in order to simulate continuous combined HRT. An ATP-chemosensitivity test is used to quantify cell proliferation following a seven-day incubation period. To put it briefly, the bioluminescence reaction of luciferine in the presence of ATP and luciferase is measured to determine the amount of light emitted during proliferation.

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
Following a single oral dose of norethindrone, the peak plasma concentration (Cmax) ranges from 5.39 to 7.36 ng/mL, with a time to peak concentration (Tmax) of 1 to 2 hours. The AUC0-24 value after a single oral dose is approximately 30 to 37 nghr/mL. The oral bioavailability of norethindrone is approximately 64%. When administered transdermally, norethindrone is well absorbed through the skin, reaching steady-state concentrations within 24 hours, with a steady-state peak plasma concentration (Cmax) of 617 to 1060 pg/mL. Norethindrone is usually formulated as norethindrone acetate, which is completely and rapidly deacetylated to norethindrone after oral administration—the distribution of norethindrone acetate in vivo is identical to that of oral norethindrone. After administration of radiolabeled norethindrone, slightly more than 50% of the administered dose is excreted in the urine, and 20-40% is excreted in the feces. The volume of distribution of norethindrone is approximately 4 L/kg. Sulfate metabolites and a small amount of the original drug are distributed into breast milk. The plasma clearance of norethindrone is estimated at 0.4 L/hr/kg, with an intrinsic clearance of approximately 73-81 L/h. Norethindrone binds 36% to sex hormone-binding globulin (SHBG) and 61% to albumin. The volume of distribution of norethindrone is approximately 4 L/kg. The plasma clearance of norethindrone is approximately 0.4 L/hr/kg. After subcutaneous implantation of a sustained-release tablet containing 40% norethindrone and 60% cholesterol in 25 BALB/c mice for 76-77 weeks, the estimated absorption of norethindrone was 3.6 to 15.9 μg/day (mean 7.7 μg/day). Rabbits primarily excrete norethindrone metabolites via urine… while rats excrete 80% via bile… For more complete data on the absorption, distribution, and excretion of norethindrone (8 items in total), please visit the HSDB record page. Metabolism/Metabolites
Norethindrone is extensively metabolized, primarily in… Norethindrone is partially or completely reduced in the liver via the A ring to a variety of metabolites. The main enzymes involved in this process are 3α- and 3β-hydroxysteroid dehydrogenases (HSD) and 5α- and 5β-reductases. 5α-reduced metabolites, including 5α-dihydronorethindrone and its derivatives, appear to be biologically active, while 5β-reduced metabolites appear to be inactive. Norethindrone and its metabolites are also widely present in conjugates—most plasma metabolites are sulfate conjugates, while most urinary metabolites are glucuronide conjugates. The main metabolites in plasma are the disulfate conjugate and monosulfate conjugate of 3α,5α-tetrahydronorethindrone, while the main metabolites in urine are glucuronide and/or sulfate conjugates of 3α,5β-tetrahydronorethindrone. Norethindrone is also metabolized to some extent by the cytochrome P450 enzyme system, primarily catalyzed by CYP3A4, with less catalytic activity from CYP2C19, CYP1A2, and CYP2A6. The metabolites produced by these reactions are not fully elucidated. Norethindrone undergoes extensive biotransformation, mainly through reduction reactions followed by sulfate and glucuronide conjugation. The circulating metabolite is primarily sulfate, while the urinary metabolite is mainly glucuronide. Norethindrone undergoes extensive A-ring reduction reactions to produce dihydronorethindrone and tetrahydronorethindrone metabolites, which can undergo conjugation reactions; it can also undergo aromatization. Postmenopausal women experienced lower serum ethinylestradiol levels after oral administration of relatively large doses of norethindrone acetate or norethindrone. Based on the measured area under the curve (AUC) values for ethinylestradiol and norethindrone, the results indicated that the average conversion rate of norethindrone to ethinylestradiol was 0.7% and 1.0% at 5 mg and 10 mg doses, respectively. The authors calculated that this equates to approximately 6 μg of ethinylestradiol per mg of norethindrone acetate orally. Similarly, the study showed that oral administration of 5 mg of norethindrone is equivalent to approximately 4 μg of ethinylestradiol per mg of norethindrone.
Incubation of norethindrone with canine liver microsomes yielded a 4β,5β-epoxide of norethindrone and a 6-oxonorethindrone derivative as minor metabolites…
Rabbit liver homogenate…catalyzed the deynylation of norethindrone to generate the metabolite estradiol-4-en-3,17-dione.
For more complete metabolite/metabolite data on norethindrone (7 metabolites in total), please visit the HSDB record page.
The known human metabolites of norethindrone include norethindrone-O-glucuronide.
It is primarily metabolized in the liver. Norethindrone is extensively metabolized, mainly through reduction reactions. It also undergoes sulfate and glucuronide conjugation. The circulating metabolite is primarily sulfate, while the urinary metabolite is primarily glucuronide.
Elimination pathway: Norethindrone is primarily excreted in the form of metabolites in urine and feces.
Half-life: 8.51 ± 2.19 (after a single dose in healthy women)
Biological half-life
The estimated half-life of norethindrone is between 8 and 10 hours.
The mean terminal elimination half-life of norethindrone after a single dose of AYGESTIN is approximately 9 hours.
Plasma half-life, maximum clearance (MCR), and plasma metabolite levels were investigated at different time intervals in 6 women following intravenous injection of 3H-norethindrone acetate. The disappearance curve of norethindrone acetate showed that it disappeared rapidly in the initial phase, with a mean half-life of 7.5 minutes, followed by slow disappearance with a half-life of 51.5 hours. The mean metabolic clearance (MCR) of norethindrone acetate from plasma was 495 L/day. Following intravenous injection, norethindrone acetate was rapidly metabolized. The mean half-life of the major metabolite, norethindrone, from plasma was 34.8 hours. At all time intervals within 24 hours, the concentration of norethindrone was higher than that of norethindrone acetate, reaching equilibrium between 24 and 48 hours. The elimination half-life (two-component model β phase) ranged from 4.8 to 12.8 hours (mean 7.6 hours), with no significant difference between oral and intravenous administration.

Toxicity Summary
Progestins can freely diffuse into target cells and bind to progesterone receptors. Target cells include the female reproductive tract, mammary glands, hypothalamus, and pituitary gland. Once bound to receptors, progestins slow the release frequency of hypothalamic gonadotropin-releasing hormone (GnRH) and suppress the pre-ovulatory luteinizing hormone (LH) surge. Interactions When assessing contraceptive failure, the concurrent use of antibiotics and oral contraceptives should be considered. This article presents and discusses a case of unintended pregnancy in an 18-year-old woman with a severe staphylococcal skin infection and underlying chronic granulomatous disease. She had been treated with semi-synthetic penicillin (500 mg oxacillin sodium every 6 hours) for 6 weeks and reported a 40-day absence of menstruation. She was taking oral contraceptives at the time (1 mg norethindrone/0.035 mg estradiol). Serum β-subunit human chorionic gonadotropin (hCG) testing confirmed her pregnancy. A careful review of her birth control pill packaging and antibiotic prescription confirmed that she had indeed taken both medications strictly as prescribed. She, her boyfriend, and family all received counseling and underwent therapeutic abortions. For adolescents taking antibiotics long-term, alternative methods of contraception or additional contraceptive measures are recommended. ...In a randomized, two-way crossover study, 20 healthy female participants received either Group A or Group B treatment. Group A treatment consisted of a single dose of OrthoNovum containing 1 mg of norethindrone and 35 mcg of ethinylestradiol. Group B treatment consisted of taking bosentan 125 mg twice daily for 7 days, with both norethindrone and ethinylestradiol taken concurrently on day 7. Plasma concentrations of norethindrone and ethinylestradiol were measured during the use of oral contraceptives. In the absence of bosentan, the pharmacokinetic characteristics of norethindrone and ethinylestradiol were as follows: Cmax and AUC0-∞ values (95% CI) were 9.8 (8.1, 11.9) ng/mL and 72.9 (57.0, 93.1) ng·hr/mL, and 53.0 (47.0, 59.9) pg/mL and 758 (655, 878) pg·hr/mL, respectively. Concomitant bosentan did not affect Cmax but significantly reduced the AUC of norethindrone and ethinylestradiol, decreasing by 13.7% (-23.5, -2.6) and 31.0% (-40.5, -20.2), respectively. The maximum reduction in AUC of norethindrone and ethinylestradiol in individual subjects was 56% and 66%, respectively. Bosentan reduces the AUC of norethindrone and ethinylestradiol in healthy female subjects. The possibility of reduced efficacy of hormonal contraceptives should be considered in patients receiving bosentan treatment. This study investigated the effect of phenytoin sodium treatment on plasma norethindrone (NET) concentrations in seven healthy female rhesus monkeys. Before starting phenytoin sodium treatment, each monkey received an oral dose of 0.5 mg NET, followed by an intravenous injection of the same dose two weeks later. Plasma NET concentrations were frequently measured within 24 hours in both experiments. Monkeys received oral phenytoin sodium daily for more than four weeks. Phenytoin sodium absorption was confirmed by plasma phenytoin sodium concentration measurements. During continued phenytoin sodium treatment, monkeys again received an oral dose of 0.5 mg NET, followed by an intravenous injection of NET two weeks later, with repeated blood sampling. Plasma NET concentrations remained lower than pre-treatment levels throughout the phenytoin sodium treatment period. The area under the plasma concentration-time curve (AUC) decreased to 55% of the pre-treatment AUC, regardless of whether the medication was administered intravenously or orally. No changes in plasma half-life were observed during phenytoin sodium treatment. These results suggest that women taking phenytoin sodium for epilepsy should also take a higher dose of oral contraceptive to ensure contraceptive effectiveness. This study investigated the pharmacokinetics of norethindrone in eight women during and one month after treatment with rifampin (450-600 mg/day). Results showed that rifampin significantly reduced the AUC of a single 1 mg norethindrone dose from 37.8 ± 13.1 ng/mL·hr to 21.9 ± 5.9 ng/mL·hr (p < 0.01). The plasma half-life (β phase) of norethindrone also decreased from 6.2 ± 1.7 hours to 3.2 ± 1.0 hours (p < 0.0025). In another woman who had been taking oral contraceptives long-term, rifampin reduced the 12-hour plasma norethindrone concentration from 12.3 ng/mL to 2.3 ng/mL. Rifampin significantly increased antipyrine clearance, 6β-hydroxycortisol excretion, and plasma gamma-glutamyl transferase activity, but there was no significant correlation between these changes in hepatic microsomal enzyme induction parameters. During rifampin treatment, there was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethindrone AUC. Changes in norethindrone pharmacokinetics during rifampin treatment were consistent with the known enzyme-inducing effects of rifampin. For more complete data on interactions of norethindrone (a total of 8), please visit the HSDB record page. Non-human toxicity values: Oral LD50 in mice: 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
AYGESTIN is an oral synthetic contraceptive; a synthetic progestin. It is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance, excluding organic lesions such as submucosal fibroids or uterine cancer. AYGESTIN is not indicated, recommended, or approved for use concurrently with estrogen therapy in postmenopausal women to protect the endometrium. /Included on US product label/ Oral contraceptives are indicated for women who choose to use this product as a method of contraception to prevent pregnancy. /Included on US product label/ Oral contraceptives containing only progestin are indicated for the prevention of pregnancy. /Included on US product label/ For more complete data on the therapeutic uses of norethindrone (6 types), please visit the HSDB record page. Drug Warnings Veterinary Use: Maleization of fetuses has been observed in labeled rats, monkeys, and dogs, similar to the situation in humans. Overdose during pregnancy may also result in fetal death, teratogenicity, and delayed delivery. Smoking increases the risk of serious cardiovascular side effects from oral contraceptives. This risk increases with age and heavy smoking (15 cigarettes or more per day), particularly in women over 35. Smoking is strongly advised for women taking oral contraceptives. Norethindrone, like other progestins, can cause breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, cervical erosion and changes in discharge, edema, weight gain or loss, cholestatic jaundice, allergic rashes with or without itching, melasma or pregnancy mask, and depression. Breakthrough bleeding or irregular vaginal bleeding during norethindrone treatment should raise suspicion of nonfunctional causes. A thorough diagnostic procedure should be performed for patients with unexplained vaginal bleeding. For more complete data on drug warnings for norethindrone (44 in total), please visit the HSDB records page.

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Pharmacodynamics
Norethindrone 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, norethindrone acts similarly to endogenous progestins, but with significantly higher potency. It acts in the pelvic cavity, altering the function of the cervix and endometrium, and influencing follicle maturation and ovulation by suppressing pituitary hormones. Patients taking combined oral contraceptives have a slightly increased risk of breast cancer, and some evidence suggests a similar risk with progestin-only contraceptives. Therefore, patients starting hormonal contraceptives should be informed of this risk and perform regular breast self-exams to check for any lumps.

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

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)

Solubility in Formulation 1: 2.5 mg/mL (8.38 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)