Antiestrogenic and antifertility actions of anordrin (2α,17ga-diethynyl-A-nor-5α-androstane-2β,17β-diol 2,17-dipropionate)

Mehta, Rajeev; Jenco, John M.; Chatterton, Robert T.

doi:10.1016/0039-128x(81)90086-6

Cited by 22 publications

(5 citation statements)

References 19 publications

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“…Estrogen-induced mitosis of EEC is required for embryo implantation11. Anordrin inhibits embryo implantation to elicit its contraceptive effects12. These clinical indications suggest that anordrin and tamoxifen might modulate the proliferation of EEC in the opposite manner.…”

Section: Resultsmentioning

confidence: 99%

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Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity

Sun

et al. 2017

Sci Rep

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Tamoxifen is administered for estrogen receptor positive (ER+) breast cancers, but it can induce uterine endometrial cancer and non-alcoholic fatty liver disease (NAFLD). Importantly, ten years of tamoxifen treatment has greater protective effect against ER+ breast cancer than five years of such treatment. Tamoxifen was also approved by the FDA as a chemopreventive agent for those deemed at high risk for the development of breast cancer. The side effects are of substantial concern because of these extended methods of tamoxifen administration. In this study, we found that anordrin, marketed as an antifertility medicine in China, inhibited tamoxifen-induced endometrial epithelial cell mitosis and NAFLD in mouse uterus and liver as an anti-estrogenic and estrogenic agent, respectively. Additionally, compared with tamoxifen, anordiol, the active metabolite of anordrin, weakly bound to the ligand binding domain of ER-α. Anordrin did not regulate the classic estrogen nuclear pathway; thus, it did not affect the anti-tumor activity of tamoxifen in nude mice. Taken together, these data suggested that anordrin could eliminate the side effects of tamoxifen without affecting its anti-tumor activity.

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Section: Resultsmentioning

confidence: 99%

“…Anordrin was marketed as a contraceptive medicine because it is a specific ER antagonist on uterus912, indicating that anordrin is an ER-α antagonist. Three ER-α variants, ER-α–66, -46 and -36, were reported to regulate classic estrogen nuclear pathway and MIES5671721.…”

Section: Discussionmentioning

confidence: 99%

Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity

Sun

et al. 2017

Sci Rep

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“…Many early studies have been reported (16)(17)(18)(19)28), but the results are all based on assay systems in vivo. The steroids anordrin (16,17) and 4-nitromethoxyes-1 x 10" 3 x 10" 9 1 x 10" trone (19) have been reported to possess some antiestrogenic activity in vivo. The steroids anordrin (16,17) and 4-nitromethoxyes-1 x 10" 3 x 10" 9 1 x 10" trone (19) have been reported to possess some antiestrogenic activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Prolactin Synthesis in Vitro by Estrogenic and Antiestrogenic Derivatives of Estradiol and Estrone*

Jordan

Koch

1989

Endocrinology

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The estrogenic and antiestrogenic activities of derivatives of estradiol and estrone were determined in vitro using the ability of primary cultures of immature rat pituitary cells to synthesize PRL. Estradiol derivatives were the most potent estrogens in the assay. Large ethinyl substitutions in the 17 alpha position generally caused a decrease in estrogenic potency (up to 1000-fold). The 3 phenolic hydroxyl was important, but not essential, for the estrogenic activity of the estradiol molecule. Estratriene was approximately 1000 times less potent than estradiol. However, significant estrogenic activity was observed with the compound anordin (EC50, 8 x 10(-9) M), which could potentially be converted to a dihydroxylated derivative but without an aromatic A ring. Similarly, the steroid androst-5-ene-3,17-diol was weakly estrogenic (EC50, 3 x 10(-8) M). Steriods with a ketone in the A and D rings were generally inactive as estrogens and antiestrogens. Estradiol derivatives with 17 beta amines were only weak estrogens. Estrone derivatives were less active than the corresponding estradiol derivatives. 4-Nitromethoxyestrone exhibited weak antiestrogenic properties; however, 4-nitroestrone and methoxyestrone were both estrogens. The reason for the antiestrogenic properties of 4-nitromethoxyestrone is obscure, as the compound does not have structural features similar to those of known nonsteroidal antiestrogens. Minor alterations to the estradiol molecule at the 11 beta (OH) or 6 (ketone) position had little effect on estrogenic potency; however, large substitutions at the 11 beta (RU 39,411) or 7 alpha (ICI 164384) position produced antiestrogenic compounds. RU 39,411 was approximately 10 times more active as an antiestrogen than 4-hydroxytamoxifen, whereas ICI 164,384 was approximately 10 times less active than 4-hydroxytamoxifen. A series of hypothetical models is proposed that could explain the antiestrogenic properties of RU 39,411 and ICI 164,384 by an interaction with the estrogen receptor steroid-binding site.

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“…Anordrin had very low estrogenic potency, depending on the estrogenic response measured [4], but also had antiestrogenic activity [4]. Anordrin given orally to mice during early gestation had an abortifacient action which was blocked by supplemental administration of estradiol [4]. If given before implantation, it prevented implantation and pregnancy in rats, mice, rabbits and dogs [3] and in one study [7] postovulatory administration to baboons resulted in luteolysis.…”

Section: Introductionmentioning

confidence: 99%

“…Biological and hormonal properties of anordrin were studied in detail in mice [3][4][5][6]. Anordrin had very low estrogenic potency, depending on the estrogenic response measured [4], but also had antiestrogenic activity [4].…”

Section: Introductionmentioning

confidence: 99%

Antiovulatory action of anordrin in the cynomolgus monkey (Macaca fascicularis)

Mehta

Chatterton

1991

Adv Contracept

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Anordrin (2 alpha, 17 alpha-diethynyl-A-nor-5 alpha-androstane-2 beta, 17 beta-diol dipropionate) was studied for its antiovulatory potency in the cynomolgus monkey. Anordrin, administered daily on days 9-13 of the menstrual cycle in doses of 4.0 and 8.0 mg/kg body weight, did not inhibit luteal activity in the cycle in which it was given, but delayed the development of ovarian follicles for 5 to 6 months. When a single low dose (0.1 or 0.2 mg/kg b.w.) was administered during the first 3 days of the menstrual cycle, follicular maturation was delayed such that luteal activity was not observed for an average of 26 and 39 days, respectively, and pregnanediol in the ensuing luteal phases was significantly decreased. Anordrin appears to inhibit follicular development when given during the stage of follicular recruitment.

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Antiestrogenic and antifertility actions of anordrin (2α,17ga-diethynyl-A-nor-5α-androstane-2β,17β-diol 2,17-dipropionate)

Cited by 22 publications

References 19 publications

Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity

Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity

Regulation of Prolactin Synthesis in Vitro by Estrogenic and Antiestrogenic Derivatives of Estradiol and Estrone*

Antiovulatory action of anordrin in the cynomolgus monkey (Macaca fascicularis)

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