| Reference | [1]. Steroids. 2003 Nov;68(10-13):907-13. doi: 10.1016/s0039-128x(03)00140-5.<br />
Nestorone: clinical applications for contraception and HRT.<br />
Sitruk-Ware R(1), Small M, Kumar N, Tsong YY, Sundaram K, Jackanicz T.<br />
Author information: (1)Center for Biomedical Research, Population Council, Rockefeller University, 1230 York Avenue, Weiss Bldg., 6th Floor, New York, NY 10021, USA. [email protected]<br />
The 19-nor derivatives of progesterone are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) without interfering with receptors of other steroids. In this category is Nestorone, which has strong progestational activity and antiovulatory potency with no androgenic or estrogenic activity in vivo. These properties make it highly suitable for use in contraception and hormonal therapy (HT). Due to its high potency, very low doses of Nestorone may be delivered via long-term sustained-release delivery systems. Nestorone, 75 or 100 microg per day, released by vaginal ring has suppressed ovulation in women, with inhibition of follicular maturation. A vaginal ring releasing both 150 microg of Nestorone and 15 microg of ethinyl estradiol per day has effectively suppressed ovulation for 13 consecutive cycles. Nestorone has also been used effectively in a single implant for contraception in breastfeeding women and shows promise for use in transdermal systems as a contraceptive or for HT when combined with estrogen.<br />
DOI: 10.1016/s0039-128x(03)00140-5 PMID: 14667982<br />
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[2]. Brain Res. 2019 Feb 1;1704:161-163. doi: 10.1016/j.brainres.2018.10.014. Epub 2018 Oct 12.<br />
Beyond contraception and hormone replacement therapy: Advancing Nestorone to a neuroprotective drug in the clinic.<br />
Tuazon JP(1), Sitruk-Ware R(2), Borlongan CV(3).<br />
Author information: (1)Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. (2)Population Council, Center for Biomedical Research, 1230 York Avenue, New York, NY 10065, USA. (3)Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. Electronic address: [email protected].<br />
Republished in Brain Res. 2019 Sep 15;1719:285-287.<br />
Neurological diseases such as ischemic stroke can be debilitating and have limited treatments available. The progestin Nestorone® (segesterone acetate) has been evaluated for use in birth control and hormone replacement therapy due to its potency and high affinity for the progesterone receptor. Interestingly, Nestorone also exerts neuroprotection in animals afflicted with various central nervous system diseases, including stroke, which implicates its potential for treating these maladies in clinical settings. In fact, a recent Brain Research paper by Tanaka and colleagues demonstrates Nestorone's ability to reduce infarct sizes and preclude functional impairments in rats subjected to ischemic stroke. This commentary highlights Nestorone's properties as a progestin, its neuroprotective capabilities in animal studies, and how the Tanaka team's findings and previous clinical trials contribute to Nestorone's translation into a therapeutic agent for stroke and other neurological diseases.<br />
DOI: 10.1016/j.brainres.2018.10.014 PMID: 30321495<br />
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[3]. CNS Neurosci Ther. 2021 Apr;27(4):464-469. doi: 10.1111/cns.13538. Epub 2020 Dec 24.<br />
Nestorone(®) , a 19nor-progesterone derivative boosts remyelination in an animal model of demyelination.<br />
El-Etr M(1), Akwa Y(1), Rame M(1), Schumacher M(1), Sitruk-Ware R(2).<br />
Author information: (1)Disease and Hormones of the Nervous System", U1195 Inserm-Université Paris Saclay, Le Kremlin-Bicêtre, France. (2)Population Council and Rockefeller University, New York, NY, USA.<br />
INTRODUCTION: We previously showed that Nestorone® (NES), a synthetic progestin structurally related to progesterone, stimulated remyelination of the corpus callosum in a Cuprizone (CUP) mouse model of demyelination in intact females by promoting replenishment with mature oligodendrocytes (OL) (Glia. 2015;63:104-117). Here, we further investigated the underlying mechanisms of this promyelinating effect. METHODS: We explored whether NES, applied subcutaneously through Alzet mini-osmotic pumps, regulates specific transcription factors involved in oligodendrocyte progenitor cell (OPC) proliferation and their differentiation into mature OL, using RT-qPCR and Western Blot analysis. RESULTS: Our present data show that in comparison to controls, a one-week treatment with NES, through Alzet mini-osmotic pumps, enhanced the production of three relevant transcription factor mRNAs encoding Olig2, Myt1, and Sox17. After 3 weeks, NES treatment reversed the effect of CUP on the levels of corresponding Olig2, Myt1, and Sox17 proteins. Moreover, in mice receiving NES + Estradiol (E2) co-treatment, levels of Olig2, Myt1, and Sox17 proteins did not change as compared to NES alone. CONCLUSION: NES alone or with E2 increased the levels of transcription factors, essential for myelin synthesis.<br />
DOI: 10.1111/cns.13538 PMCID: PMC7941173 PMID: 33369182<br />
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[4]. Steroids. 2000 Oct-Nov;65(10-11):629-36. doi: 10.1016/s0039-128x(00)00119-7.<br />
Nestorone: a progestin with a unique pharmacological profile.<br />
Kumar N(1), Koide SS, Tsong Y, Sundaram K.<br />
Author information: (1)Center for Biomedical Research, Population Council, 1230 York Avenue, New York, NY 10021, USA. [email protected]<br />
Nestorone(R) (Nestorone 16-methylene-17alpha-acetoxy-19-norpregn-4-ene-3,20-dione), formerly referred to as ST 1435, is a potent progestin when given parenterally via sustained release formulations. The pharmacological profile of Nestorone was compared with that of levonorgestrel and 3-keto-desogestrel by steroid receptor binding studies and by in vivo bioassays in rats and rabbits. 3-Keto-desogestrel showed the highest binding affinity to progesterone receptors (PR) followed by Nestorone, levonorgestrel, and progesterone. The binding affinity of Nestorone to androgen receptors (AR) was 500- to 600-fold less than that of testosterone. However, both levonorgestrel and 3-keto-desogestrel showed significant binding (40 to 70% of testosterone) to AR. None of the progestins bound to estrogen receptors (ER). The progestational activity of Nestorone, levonorgestrel, and progesterone was compared using McPhail index in immature rabbits and pregnancy maintenance and ovulation inhibition tests in rats after subcutaneous (s.c.) administration. In all three tests, Nestorone was the most potent progestin. The progestational activity of Nestorone was also compared after oral and s.c. administration in rabbits. The potency of Nestorone was over 100-fold higher upon s.c. administration than via the oral route. The androgenic activity of progestins, based on the stimulation of ventral prostate (androgenic target) and levator ani (anabolic target) growth in castrated immature rats, showed good correlation with their binding affinity to AR. Nestorone showed no androgenic or anabolic activity. Nestorone did not bind to sex hormone binding globulin (SHBG), whereas both levonorgestrel and 3-keto-desogestrel showed significant binding to SHBG. The estrogenic/antiestrogenic activity of Nestorone was investigated in immature ovariectomized rats. In contrast to estradiol and levonorgestrel, Nestorone showed no uterotropic activity in ovariectomized rats. Despite significant binding to glucocorticoid receptors (GR), Nestorone showed no glucocorticoid activity in vivo. It is concluded that a strong progestational activity, combined with lack of androgenic, estrogenic, and glucocorticoid-like activities, confer special advantages to Nestorone for use in contraception and hormone replacement therapy.<br />
DOI: 10.1016/s0039-128x(00)00119-7 PMID: 11108869<br />
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[5]. Brain Res. 2019 Sep 15;1719:288-296. doi: 10.1016/j.brainres.2018.09.022. Epub 2018 Sep 20.<br />
Nestorone exerts long-term neuroprotective effects against transient focal cerebral ischemia in adult male rats.<br />
Tanaka M(1), Ogaeri T(2), Samsonov M(3), Sokabe M(4).<br />
Author information: (1)Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. Electronic address: [email protected]. (2)Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. (3)R-Pharm, Moscow 123317, Russia. (4)Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. Electronic address: [email protected].<br />
Progesterone (P4) exerts long-term neuroprotective effects in animal models of stroke, and P4 receptors play a crucial role in this neuroprotection. However, it currently remains unclear whether the activation of P4 receptors alone is sufficient to exert long-term neuroprotection because P4 exhibits other steroidogenic and GABAergic activities via several of its metabolites. Nestorone is a potent selective P4 receptor agonist without other steroidogenic and GABAergic activities. Therefore, we examined the effects of nestorone in adult male rats subjected to transient middle cerebral artery occlusion (MCAO). The dose-response relationship of nestorone showed that the 6-h post-ischemic administration of 10 μg/kg nestorone resulted in greater reductions in infarct sizes 48 h after MCAO than the other two doses tested (5 and 80 μg/kg), and this dose of nestorone significantly decreased astrocyte activation in the peri-infarct cortical region. Moreover, 10 μg/kg nestorone significantly prevented functional impairments on the 28th and 29th days and slightly reduced infarct size on the 30th day after MCAO. The present results suggest that the activation of P4 receptors alone is sufficient to exert neuroprotection against transient cerebral ischemia in adult male rats; therefore, nestorone is a promising agent in post-stroke treatment due to its potent progestational effects without other steroid-related activities.<br />
DOI: 10.1016/j.brainres.2018.09.022 PMID: 30244019
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