Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Norprogesterones”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1996

The antigonadotropic activity of progestins (19-nortestosterone and 19-norprogesterone derivatives) is not mediated through the androgen receptor.

To further study the mechanism of the antigonadotropic activity of progestins, the effects of a 19-nortestosterone derivative, norethisterone acetate (NETA), and a 19-norprogesterone derivative, nomegestrol acetate (NOMA), were compared. The aim was to assess whether their action is exerted via the androgen receptor. Ten healthy postmenopausal women were treated for five monthly periods of 24 days separated by 10 days in a randomized cross-over design. Transdermal estradiol, Estraderm TTS (25 micrograms; one patch every 3 days), was given from days 1-24 during the five periods. On the last 12 days, of each estradiol treatment, they all received a placebo, NOMA (5 mg/day), NOMA in association with the nonsteroidal antiandrogen, flutamide (FLU; 250 mg, twice a day), NETA (10 mg/day), or NETA plus FLU. On the other hand, three castrated patients with complete androgen insensitivity (CAI) received NOMA and NETA for two periods of 12 days separated by 3 weeks. In postmenopausal women, the effects of NOMA and NETA on metabolic parameters were studied. Only NETA decreased high density lipoprotein cholesterol. Plasma LH, FSH, and estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their responses to exogenous GnRH was observed with NOMA and NETA treatments compared to placebo (P < 0.001). The pulsatile frequency, but not the amplitude, of LH was significantly decreased during both treatments. Interestingly, the effects of both progestins on gonadotropins were not antagonized by FLU administration. In the patients with CAI, the pulsatile study of gonadotropins was performed before and on day 12 of NOMA and NETA treatments. As in postmenopausal women, both progestins induced similar decreases in LH and FSH. In conclusion, a 19-nortestosterone derivative, NETA, and a 19-norprogesterone derivative, NOMA, have similar antigonadotropic activities. This effect, not antagonized by FLU and observed in patients with CAI, is not mediated via the androgen receptor. The absence of deleterious effects of 19-norprogesterone derivatives on metabolic parameters should favor the therapeutic use of these compounds.

Cholesterol, HDL↗
PubMed1991

Identification of 19-norprogesterone in pregnant rat urine.

The existence of biosynthetic pathways leading to the formation of 19-nor-androgens and corticoids have been established in animals and humans. The exact biologic function of the products of these pathways in vivo has yet to be established; however, it has been shown that they possess pronounced biologic activity when administered exogenously. This report describes the identification of 19-nor-progesterone isolated from the urine of pregnant rats. The procedures used included isolation as the underivatized material and methoxime derivative by thin-layer and high-performance chromatography. The identity was further confirmed by gas chromatography/mass spectral analysis of the isolated product as the 3,20-bis-methoxime derivative. The spectra obtained from the urinary product and the authentic 19-norprogesterone-3,20-bis-methoxime were identical. A possible biologic role for 19-norprogesterone or its precursors is discussed.

Animals↗
PubMed1991

Preclinical evaluation of a positron emitting progestin ([18F]fluoro-16 alpha-methyl-19-norprogesterone) for imaging progesterone receptor positive tumours with positron emission tomography.

Three 21-fluoro-progestins were investigated as potential imaging agents for the in vivo assessment of human progesterone receptor positive neoplasms with positron emission tomography. In competitive binding assays these compounds demonstrated high specificity, competing only for progesterone receptors. Binding to other steroid receptor types was negligible. Based on its high affinity binding, 21-fluoro-16 alpha-methyl-19-norprogesterone was selected for further evaluation in vivo. Tissue distribution studies in immature estrogen primed female rats revealed high uterine uptake of 21-[18F]fluoro-16 alpha-methyl-19-norprogesterone ([18F]FMNP). At 60 min after injection the ratio of uptake of radioactivity by uterine tissue to that of blood was 7. This ratio increased to 24 at 180 min. A selective decrease in uterine uptake was observed after administration of [18F]FMNP with excess unlabelled progestin. Rats bearing hormone responsive MT-W9A mammary adenocarcinomas were used to examine [18F]FMNP for tumour uptake. Animals were used irrespective of the phase of the estrous cycle. At 180 min the uterus to blood ratio and the tumour to blood ratio ranged from 3 to 20 and 3 to 17, respectively. Uterine and tumour tissue was assayed for cytosolic estrogen and progesterone receptors using a dextran-coated charcoal method and Scatchard plot analysis. The results indicate that the in vivo uptake of [18F]FMNP by uterine and mammary tumour tissue correlates well with the progesterone receptor concentration (rs = 0.98 and rs = 0.88, respectively). It is concluded that the uptake of [18F]FMNP by progesterone receptor positive tissue in vivo is primarily receptor related and that this uptake is attributable to the progesterone receptor. The study demonstrates the potential applicability of [18F]FMNP and positron emission tomography for imaging progesterone receptor positive neoplasms.

Animals↗
PubMed1988

21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone: synthesis and target tissue selective uptake of a progestin receptor based radiotracer for positron emission tomography.

We have synthesized 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP), a high affinity ligand for the progesterone receptor, labeled with the positron-emitting radionuclide fluorine-18 (t1/2 = 110 min). The synthesis proceeds in two steps from 21-hydroxy-16 alpha-ethyl-19-norprogesterone and involves [18F]fluoride ion displacement of the 21-trifluoromethanesulfonate (21-triflate). This material is purified by HPLC and is obtained in 4-30% overall yield (decay corrected) within 40 min after the end of bombardment to produce [18F]fluoride ion. The effective specific activity, determined by competitive radioreceptor binding assays, is 700-1400 Ci/mmol. In vivo, [18F]FENP demonstrates highly selective, receptor-mediated uptake by the uterus of estrogen-primed rats; the uterus to blood and uterus to muscle ratios were respectively 26 and 16 at 1 h and 71 and 41 at 3 h after injection. The high target tissue selectivity of this uptake suggests that this compound may be useful for the in vivo imaging of progestin target tissues and receptor-rich tumors (such as human breast tumors) by positron emission tomography.

Animals↗
PubMed1994

Metabolism of a [18F]fluorine labeled progestin (21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone) in humans: a clue for future investigations.

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone ([18F]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [18F]FENP to image PR with PET. Our present study on the in vivo metabolism of [18F]FENP in humans demonstrates a rapid clearance and biotransformation of the compound. Results of incubation experiments suggest that the metabolic conversion of [18F]FENP is not restricted to the liver, but also occurs in blood cells (presumably the erythrocytes) and tumors (breast carcinomas and meningiomas). The predominant metabolite of [18F]FENP in plasma during the rapid distribution phase and in tumors is identified as 20-dihydro-[18F]FENP. The conversion of [18F]FENP to its 20 alpha- or 20 beta-hydroxy metabolite has a deleterious effect on the binding affinity for PR. Our findings do not justify a conclusion as to the extent of in vivo extrahepatic biotransformation of [18F]FENP, or its significance in the ineffectiveness of [18F]FENP as an imaging agent for PR. On the other hand, the ability of breast carcinomas and meningiomas to metabolize [18F]FENP avidly appears to preclude selective imaging of PR in these tumors during the time of a PET examination. It is imperative to evaluate the metabolic stability of a [18F]fluorine labeled progestin in an early stage of future screening procedures.

Animals↗
PubMed1992

[Lack of mutagenicity and teratogenicity of 16-methylene-17 alpha-acetoxy-19-norprogesterone].

16-Methylene-17 alpha-acetoxy-19-norprogesterone (ST-1435) is a new antifertility agent. ST-1435 silastic capsule was implanted sc in the nuchal region of rats on d 6 of gestation at 75, 300, and 600 mg.kg-1. The rats were killed on d 20. In comparison with the control, the treated groups showed no significant differences in maternal body weights, number of corpora lutea, and the development of embryos and fetuses. The number of dead fetuses decreased and live fetuses increased slightly. ST-1435 did not affect the frequency of micronucleated polychromatic erythrocytes, nor induce chromosomal aberrations in cultured CHL cells, or increase the revertants of Salmonella typhimurium TA97, TA98, TA100, and TA102 in Ames test. The results suggested that ST-1435 had neither teratogenicity nor mutagenicity.

Animals↗
PubMed1991

Assessment of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas.

We have used 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP) for imaging progestin receptors by PET in patients with primary carcinoma of the breast. In vitro binding and in vivo tissue distribution studies in rats have shown that FENP has high specific activity, high affinity for progestin receptors, and receptor-mediated uptake in target tissues. Eight patients with primary breast carcinoma were studied. Breast carcinoma was identified correctly in 50% of the patients with progestin-receptor-positive tumors; however, the FENP uptake was not correlated with progestin-receptor levels. We noted a low target-to-background ratio in humans, with high relative activity in the spine, blood pool, and normal breast tissue. Our findings indicate that FENP is not a suitable agent for imaging progestin receptors in humans.

Breast Neoplasms↗
PubMed1987

Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships.

19-Norprogesterone (19-NOR-P) is a potent progestagen in mammals by s.c. injection, but is almost inactive when given p.o. In the rat, 19-NOR-P also shows marked salt-retaining and hypertensive effects, consistent with its high affinity for mineralocorticoid receptors (MR). We synthetized recently some p.o. active 19-NOR-P derivatives, and have examined the extent to which the structural changes made on the parent compound can modify the affinity for MR and the salt-retaining potency. Compared with aldosterone, 19-NOR-P has a 47% affinity for rat renal cytosolic MR, decreasing to 13% with alpha-hydroxylation on C-17 (17 alpha-OH-19-NOR-P). The addition of a methyl group combined with the formation of a double bond at C-6 led to nomegestrol, the relative affinity of which was 1.2%. Binding was almost abolished completely (0.23%) by acetylation of the 17 alpha-OH group (nomegestrol-acetate). A single s.c. injection of 19-NOR-P, 20 micrograms/animal, induced a marked decline of [Na+]/[K+] ratio in urine of adrenalectomized male rats. The antinatriuretic effect was still observed after a 11-day period of daily administrations of the same dosage. 17 alpha-OH-19-NOR-P decreased the [Na+]/[K+] ratio only at a high p.o. dose (2500 micrograms/animal). NOM-Ac did not affect the [Na+]/[K+] ratio after a single s.c. or p.o. administration, but increased it at the end of a 11-day p.o. treatment. Thus, the chemical modifications that lead to potent p.o. active progestins derived from 19-NOR-P induce stepwise reductions in the affinity for MR and of the mineralocorticoid effects of the parent compound.

Adrenalectomy↗
PubMed1991

[Antifertility effect of the implant containing 16-methylene-17 alpha-acetoxy-19-norprogesterone (ST-1435)].

The silastic capsules containing ST-1435 (0.5, 1, 2, 4, 6 or 8 mg) showed "burst effect" with a peak value of 4-15 micrograms.h-1 after incubation in vitro. A constant release rate was gradually approached within 1-2 wk. After the capsules were subcutaneous implanted or vaginally administrated, the rats manifested diestrus within 24-48 h. The normal estrus cycles and fertility were restored as soon as the release rate of implants decreased to 10 micrograms.d-1 in vitro. ST-1435 did not inhibit the superovulation induced by PMSG and HCG in immature female rats, but blocked the ovulation induced by LHRH in mature rats.

Animals↗
PubMed1995

Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity.

The estrogenic activity of various 19-norprogestin derivatives has been identified by several laboratories. We have previously hypothesized that the estrogenic activity of these compounds stems from the absence of a methyl group at the 19 position, as various progestins that have a methyl group at this position are not estrogens. To test this hypothesis more directly, we now compare the progestin megestrol acetate against its 19-nor analogue nomegestrol acetate. We also compare these compounds to known estrogens (estradiol, norgestrel, RU486) as well as compounds known to be devoid of estrogenic activity at concentrations as high as 10(-6) M (medroxyprogesterone acetate, R5020, ICI 182780). In growth assays using the MCF-7 and T47D:A18 human breast cancer cell lines, we find that only estradiol, norgestrel and RU486 stimulate proliferation, and this effect can be blocked by the pure antiestrogen ICI 182780. Furthermore, in transient transfection studies using a luciferase reporter construct containing three tandem copies of the Xenopus vitellogenin A2 estrogen response element, estradiol, norgestrel and RU486 can stimulate transcription, while none of the other compounds act as estrogens. Transcriptional stimulation by the estrogenic compounds can be blocked by ICI 182780. Our results demonstrate that the lack of a 19-methyl is not the major determinant for estrogenic activity in 19-norprogestins. We suggest that the 17-hydroxyl group more accurately defines estrogenic action.

Animals↗