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PubMed1991

Development of a competitive enzyme immunoassay for 17 alpha-19-nortestosterone.

Because 17 beta-19-nortestosterone and its esters are frequently used anabolic steroids in cattle in Europe, there is a need for an assay that can also detect certain metabolites. The enzyme immunoassay described here involves the detection and quantitation of the major metabolite 17 alpha-19-nortestosterone in urine. The assay is based on the coating of an antibody raised in a rabbit against 17 alpha-19-nortestosterone-3-carboxy-methyloxime-bovine serum albumin (17 alpha-19-NT-3-CMO-BSA), the competitive incubation of 17 alpha-19-NT and the 17 alpha-19-nortestosterone-3-CMO-horseradish peroxidase label, followed by the detection of the blue colour developed by the action of the enzyme on tetramethylbenzidine. The 3-CMO conjugate of 17 alpha-19-nortestosterone was used to produce an antibody with selective affinity for the 17 alpha-epimer. For the optimization of the assay, different coatings and incubation conditions were tested. The standard curve ranged between 0.98 and 4000 pg per well, with a B/B0 50% of +/- 65 pg per well. Colour was measured with a microtitre plate reader. The method was validated by means of certified blank and spiked cattle urine samples.

Animals↗
PubMed1995

Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: II. T47D cell lines.

Two classes of progestagens, e.g. pregnane [Org 2058, progesterone (PROG), R5020, medroxyprogesterone acetate (MPA)] and 19-nortestosterone derived progestagens [norethisterone (NE), levonorgestrel (LNG), 3-ketodesogestrel (KDG), gestodene (GES), Org 30659] were studied for their effect on cell growth of two human breast tumor T47D cell lines of different origin, i.e. from ATCC (A) and Sutherland (S) et al. [Sutherland et al., Cancer Res. 48 (1988) 5084-5091]. The effect of estradiol (E2) and progestagens alone as well as the combined effect of E2 (10(-10) M) and progestagens were investigated at several dose levels. Compared with E2-induced growth at 10(-10) M, pregnane and 19-nortestosterone derived progestagens at 10(-6) M alone did enhance cell growth in T47D-A cells up to 25 and 100% respectively, whereas in T47D-S cells they did not influence growth. All these progestagens at 10(-6) M did not affect E2-induced growth in T47D-A cells, whereas in T47D-S cells they completely reduced cell proliferation at doses between 10(-10) and 10(-8) M. The involvement of progestagen (PR) and estrogen (ER) receptors with respect to growth stimulation was studied by using specific antihormones. In T47D-A cells, the antiprogestagens RU 38486 and Org 31710 could not block progestagen-induced growth. Antiestrogens, like 4-hydroxytamoxifen and ICI 164,384, inhibited the 19-nortestosterone derivative-induced cell growth by approx. 50%. Remarkably, both antiprogestagens alone could also inhibit E2-induced growth in T47D-A cells by about 50%. In T47D-S cells, E2-induced cell growth was completely blocked by both antiprogestagens and antiestrogens. Both antiprogestagens in T47D-S cells were equipotent to 4-hydroxytamoxifen and 10-fold more potent than ICI 164,384. In conclusion pregnane and 19-nortestosterone-derived progestagens stimulated cell growth in T47D-A cells at high unphysiological concentrations, whereas they did not affect cell growth in T47D-S cells. The 19-nortestosterone derivative induced growth in T47D-A cells could partially be inhibited by antiestrogens. In T47D-A cells, E2-induced cell growth was not influenced by both classes of progestagens, whereas in T47D-S cells all tested progestagens, antiprogestagens, and antiestrogens inhibited E2-induced cell growth completely. These results with T47D cells as well as those obtained previously with MCF-7 cells show that subclones of cell lines may respond differently to various types of progestagens in the presence and absence of estrogens.

Breast Neoplasms↗
PubMed1979

Competitive progesterone antagonists: receptor binding and biologic activity of testosterone and 19-nortestosterone derivatives.

Testosterone and 19-nortestosterone derivatives were evaluated in a developmental scheme designed to identify competitive progesterone antagonists having abortifacient activity. Compounds that displayed significant binding to the rabbit uterine progesterone receptor were followed in biologic tests for progestational, antiprogestational, and abortifacient activities. Of the seven compounds tested for both progestational and antiprogestational activity, only one, 5 alpha-dihydronorethindrone, behaved exclusively as an antagonist. Five other 19-nortestosterones (19-nortestosterone, 17 beta-hydroxyestra-4, 9(10)-dien-3-one, norethindrone, norethindrone acetate, and R 2323) proved to be mixed agonists/antagonists. 5 alpha-Dihydronorethindrone, norethindrone, and 19-nortestosterone terminated pregnancy during the postnidatory period in rats; in addition, the latter two compounds inhibited progesterone-supported pregnancy in spayed rats and curtailed pregnancy during the postnidatory period in hamsters. These results demonstrate that several 19-nortestosterone derivatives bind to the uterine progesterone receptor and behave either as antagonists or mixed agonists/antagonists.

Abortifacient Agents, Steroidal↗
PubMed1998

Nortestosterone: endogenous in urine of goats, sheep and mares?

For a number of species it is known that nortestosterone, either the alpha- or beta-epimer, can be of endogenous origin. For goats and mares similar results have not yet been published. As a follow-up on the experiments with cattle, a large number of urine samples per animal were collected from pregnant goats, sheep and mares. These samples were analysed for the presence of alpha- and beta-nortestosterone and alpha-estradiol using GC-MS. The results show that in the goats and mares studied alpha-nortestosterone is present during pregnancy. In this study no alpha-nortestosterone could be demonstrated in sheep. From our study and recently published data, however, it is proven that alpha-nortestosterone can occur endogenously.

Anabolic Agents↗
PubMed1982

Different binding of testosterone, 19-nortestosterone and their 5 alpha-reduced derivatives to the androgen receptor of the rat seminal vesicle: a step toward the understanding of the anabolic action of nortesterone.

Binding to the androgen receptor of rat seminal vesicle was studied in vitro using cell-free extract or minced tissue. Relative binding affinities of 5 alpha-dihydrotestosterone (DHT), 5 alpha-dihydro-19-nortestosterone (DHN), nortestosterone and testosterone were estimated from their competition with [3H]-DHT for the binding sites. In contrast with the conflicting results obtained with cell-free systems incubated at 0-15 degrees C, studies performed with vesicular mince at 37 degrees C proved to be useful to demonstrate characteristic differences in binding affinity and to gain information about binding both to cytosol and nuclear receptors. Competition data were graphically analyzed, and after correction for steroid metabolism the following relative competition indices were obtained: DHT = 1.00; nortestosterone = 0.32-0.4; testosterone = 0.1-0.2; DHN = 0.12. However, binding to cytosolic and nuclear receptors did not differ significantly. It is concluded that testosterone and 19-nortestosterone (which are equally good substrates for 5 alpha-reductase) are converted in the seminal vesicles to metabolites, of which DHT exhibits an affinity to the androgen receptor nearly one order of magnitude higher than that of DHN. On the other hand, in skeletal muscles that are practically devoid of 5 alpha-reductase activity, the 3-fold higher affinity of nortestosterone to the receptor, expectedly, results in a myotropic activity that is superior to that of testosterone.

Animals↗
PubMed1985

Gas chromatographic/mass spectrometric analysis of 19-nortestosterone urinary metabolites in man.

A sensitive and highly specific method based on capillary column gas chromatography/mass spectrometry has been developed for the detection of 19-nortestosterone (17 beta-hydroxy-4-estren-3-one) metabolites in urine. After intramuscular administration of 19-nortestosterone decanoate to man, urine samples were collected during several days and treated with Helix pomatia digestive juice. The free steroids were extracted and converted into O-methyl-oxime-trimethylsilyl or the trimethylsilyl ether derivatives and analysed by capillary column gas chromatography/mass spectrometry (GC/MS). Three isomeric metabolites were detected and identified as 3 alpha-hydroxy-5 alpha-extran-17-one (19-norandrosterone), 3 alpha-hydroxy-5 beta-estran-17-one (19-noretiocholanolone) and 3 beta-hydroxy-5 alpha-estran-17-one (19-norepiandrosterone). Packed column GC/MS was also employed in the selected ion monitoring mode for the specific detection of 19-norandrosterone, the most abundant urinary metabolite of 19-nortestosterone. These gas chromatographic/mass spectrometric methods are highly specific tests which can be used on a routine basis for the confirmation of 19-nortestosterone administration to athletes as well as for therapeutic monitoring following administration of the drug.

Estranes↗
PubMed1988

Aromatization of testosterone and 19-nortestosterone by a single enzyme from equine testicular microsomes. Differences from human placental aromatase.

A single enzyme in the stallion testis was able to aromatize both testosterone and nortestosterone. This enzyme had a much lower affinity for nortestosterone than for testosterone. In contrast to human placental estrogen synthetase, this enzyme aromatized testosterone and 19-nortestosterone with similar efficiency. The differences observed (effects of monovalent cations, inhibition of androstenedione aromatization by testosterone and 19-nortestosterone and, above all, rate of norandrogen aromatization) suggest that the aromatase in the horse testis is not the same as that in the human placenta.

Animals↗
PubMed1991

Identification and characterization of 19-nortestosterone in urine of meat-producing animals.

To monitor the illegal use of 19-nortestosterone as an anabolizing agent in meat-production, the Belgian Institute of Veterinary Expertise applies a strategy of urine control by radioimmunoassay, positive samples being confirmed by thin-layer chromatography. We have evaluated this control strategy, using gas chromatography-mass spectrometry to confirm the presence of 19-nortestosterone, or its metabolite oestrane-diol, in positive samples from radioimmunoassay. Our results show that the effective way of proceeding remains reliable in cattle, for mature and immature males as well as non-pregnant females, and in pigs, for pregnant and non-pregnant sows. The possible presence of endogenous 19-nortestosterone in cattle, in pregnant cows urine, and in pigs, in boars and in cryptorchid pigs, impedes the control of the use of 19-nortestosterone on these samples. False-positive (not confirmed by gas chromatography-mass spectrometry) results were produced by radioimmunoassay in the urine of castrated pigs and sheep.

Animals↗
PubMed1995

Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: I. MCF-7 cell lines.

The effects of two classes of progestagens, e.g. pregnane [Org 2058, medroxyprogesterone acetate (MPA), R5020, progesterone (PROG)] and 19-nortestosterone derived progestagens [3-ketodesogestrel (KDG), levonorgestrel (LNG), gestodene (GES), norethisterone (NE), Org 30659] on proliferation of three estradiol (E2)-dependent human breast tumor MCF-7 cell lines of different origin [Van der Burg (B), Litton bionetics (L) and McGrath (M)] were studied. The pregnane derivatives hardly stimulated cell growth at 10(-6) M in MCF-7 B and L cells except for Org 2058 in B cells, whereas in M cells a statistically significant growth induction was observed except for PROG. The 19-nortestosterone derivatives induced cell growth at doses at 10(-7) M or higher in all three cell lines. NE, GES and Org 30659 were more potent stimulators than KDG and LNG at 10(-7) M. E2 already showed maximal stimulation at 10(-10) M. For all three cell lines, the effects and ranking of the individual progestagens were similar. Antiprogestagens, like RU 38486 and Org 31710 could not block these stimulatory effects while antiestrogens like 4-hydroxytamoxifen and ICI 164,384 could. This suggests that cell growth by the above-mentioned progestagens occurs via an interaction with the estrogen receptor. Indeed, displacement studies with cytosol from MCF-7 M cells revealed that at very high concentrations NE, GES and Org 30659 were able to displace 50% of the radiolabelled E2, while KDG and LNG could not. Relative binding affinities (RBAs) were 0.010, 0.025 and 0.015% for NE, GES and Org 30659, respectively. The effect of the two classes of progestagens on cell proliferation was also investigated at several dose levels in combination with E2 (10(-10) M) in the MCF-7 B cell line. This resulted in a statistically significant inhibition of cell growth with R5020, MPA and most of the 19-nortestosterone derivatives at concentrations of 10(-8) M. Org 2058 and NE did not have any influence on E2-induced growth. The inhibitory effects could not be blocked by antiprogestagens. In summary these studies with 3 subclones of MCF-7 cells show that the pregnane derived progestagens stimulate growth only in one subclone, whereas the 19-nortestosterone derived progestagens do so in all three subclones. The progestagens possess estrogenic activity only at high pharmacological doses, being 10,000 times weaker than estradiol. In combination with estrogens most progestagens gave a reduction of E2-stimulated growth in the B subclone.

Adenocarcinoma↗
PubMed2003

Effect of embryonic 19-nortestosterone treatment and surgical bursectomy on plasma concentrations of reproductive hormones, on inhibin content in adrenals and gonads and on the histological appearance of the gonads in the young chicken.

Four-day-old chick embryos were hormonally treated with 19-nortestosterone in order to inhibit bursa development. At days 1, 4, 8, 15, 22, 29, and 36 of age, plasma, adrenals, and gonads from intact and hormonal treated chicks were collected. In embryonic nortestosterone treated males the appearance of a left 'ovotestis-like' gonad was observed. The occurrence of this ovotestis-like left gonad in the 19-nortestosterone treated male is probably a secondary effect of the in ovo treatment since surgically bursectomised chicks did not show the testicular morphology and histological changes as observed in 19-nortestosterone treated chicks. Additionally, both male and female hormonally or surgically treated chicks showed relatively enlarged adrenal glands. Hormonal bursectomy affected organ inhibin contents and plasma inhibin, testosterone, and FSH levels in males. Male hormonal treated chicks showed lower levels of plasma inhibin (p=0.0001), testosterone (p=0.01), and FSH (p=0.004), and a lower total testes inhibin content (p=0.0003) compared to intact chicks. However, none of these were significantly different between female intact and hormonal treated chicks, again indicating that the observed hormonal changes in males are not the result of the disappearance of the bursa but of the hormonal 19-NT treatment. The total adrenal inhibin content as well as the adrenal inhibin concentration were significantly higher in hormonally treated chicks than in intact chicks (p=0.0001), regardless of the sex.

Adrenal Glands↗
PubMed1988

In vitro metabolism of 7 alpha-methyl-19-nortestosterone by rat liver, prostate, and epididymis.

The in vitro metabolism of 7 alpha-methyl-19-nortestosterone (7 alpha-methyl-3-oxo-estr-4-ene-17 beta-ol) was investigated in male rat liver, ventral prostate, and epididymis. Three metabolites were recovered from the liver incubation: 7 alpha-methyl-estr-4-ene-3,17-dione, 7 alpha-methyl-5 beta-estrane-3,17 beta-diol, and 7 alpha-methyl-3-oxo-estr-4-ene-16,17 beta-diol, whereas prostate and epididymis did not perceptibly metabolize the steroid. The kinetics of metabolism in liver differed significantly from those of testosterone or 19-nortestosterone. About 85% of the 7 alpha-methyl-19-nortestosterone added was recovered at the end of 30 min of incubation. We conclude that the androgenic potency of 7-alpha-methyl-19-nortestosterone is not dependent on its further conversion to 5 alpha-dihydro-metabolites.

Animals↗
PubMed1979

Radioimmunoassay of nortestosterone and related steroids.

A radioimmunoassay of nortestosterone and related steroids, including its principal metabolities, is described and evaluated. Antisera against nortestosterone-17 beta-hemisuccinate- and nortestosterone-3-carboxymethyloxime-bovine serum albumin were raised in goats. By using a mixture of such antisera with different selectivity, the cross-reactions of several naturally occurring steroids can be reduced. The method can be applied for the detection of nortestosterone in both unprocessed or hydrolyzed urine extracts and also in plasma. It has been used as a screening test for anabolics in doping control.

Animals↗
PubMed1976

Comparison between the binding of 19-nortestosterone, 5alpha-dihydrotestosterone and testosterone in rat prostate and bulbocavernosus/levator ani muscle.

Specific binding of (3H)19-nortestosterone in the 100000 g cytosol of the rat bulbocavernosus/levator ani muscle (BCLA) and prostate was demonstrated by agargel electrophoresis at low temperature and compared qualitatively and quantitatively with the binding of tritiated testosterone and 5alpha-dihydrotestosterone (5alpha-DHT). Both tissues showed a greater binding affinity for 5alpha-DHT than for 19-nortestosterone, with testosterone binding the least well of the three. The relative binding affinities in the BCLA and prostate were: 19-nortestosterone:testosterone=1-4, 1.-nortestosterone: 5alpha-DHT = 0.7 The differences were statistically significant (P less than 0-02). The concentrations of receptor sites for 5alpha-DHT were 171 +/- 20 (S.D.) fmol/mg prostatic cytosol protein and 24 +/- 4 (S.D.) fmol/mg BCLA cytosol protein. The in-vitro metabolism of the three steroids in both tissues was aldo investigated by thin-layer chromatography. After incubating for 2 h at 0 degrees C the prostate was shown to reduce 26% of the 5alpha-DHT to androstanediols whilst the BCLA showed a 5% conversion. Testosterone was converted by the prostate to 5alpha-DHT (10%) and the androstanediols (6%) whilst the BCLA showed little activity in this respect. Comparing these in-vitro data with in-vivo findings from the literature, in both organs there is a positive correlation of the extent of binding in vitro to the stimulation of growth in vivo, bearing in mind that testosterone is metabolized to 5alpha-DHT in the prostate whilst in the BCLA, 5alpha-reductase is essentially absent.

Animals↗
PubMed1977

19-nortestosterone, a model for the use of anabolic steroid conjugates in raising antibodies for radioimmunoassay.

1. The raising of antibodies in Soay sheep to an immunogenic conjugate of 19-nortestosterone-3-(O-carboxymethyl)oxime with bovine serum albumin is described. 2. High titre plasma so obtained can be used for the radioimmunoassay of 19-nortestosterone. 3. Cross-reactivities of the antibody with endogenous steroids is confined to testosterone (20-25%) and 17beta-estradiol (1-2%). Cross-reactivities with a range of other 17beta-hydroxy synthetic anabolic steroids and with some potential 17beta-hydroxy metabolites of 19-nortestosterone vary between 2-3% for 5beta-estrane-3alpha,17beta-diol and 26% for 1-dehydrotestosterone. There is limited cross-reactivity (ca. 1-2%) with anabolic steroids with 17beta-hydroxy, 17alpha-methyl substituents. 4. 19-Nortestosterone (phenyl propionate) administered to a horse (1 mg/kg, intra-muscular) gives urinary metabolites readily detectable by radioimmunoassay, for more than 4 days.

Animals↗
PubMed1979

19-Nortestosterone in mouse kidney.

19-Nortestosterone was identified as a product of testosterone conversion in vitro in male mouse kidney. After incubation of [14C]testosterone with kidney slices of castrated male mice, 64% of the radioactivity was recovered as testosterone, about 6% as epitestosterone and 2.5% was identified as 19-nortestosterone. The renotrophic effect of 19-nortestosterone was at least as high as that of testosterone. Possible role of 19-nortestosterone in mouse kidney is discussed.

Animals↗
PubMed1986

Development of a gas chromatographic-mass spectrometric method using multiple analytes for the confirmatory analysis of anabolic steroid residues in horse urine. II. Detection of administration of 19-nortestosterone phenylpropionate to equine male castrates and fillies.

Esters of 19-nortestosterone form an important group of anabolic preparations used in veterinary practice. Based upon results from detailed metabolic studies for 19-nortestosterone in the horse, a method to confirm the administration of anabolic preparations of this steroid to castrated male horses and fillies is described; the method is based upon the use of multiple analytes. Following administration of the anabolic preparations, solid-phase extraction of urinary conjugates and the separation of the conjugate groups prior to hydrolysis allow for the determination of specific metabolites conjugated with either glucuronic acid or sulphate. Following hydrolysis of the conjugates, purification of the free neutral steroids on thin-layer chromatography, derivatisation and gas chromatographic-mass spectrometric analysis, the presence of the major metabolites, estrane-3,17 alpha-diol in the glucuronic acid fraction and 19-nortestosterone and two isomers of estrane-3,17-diol in the sulphate fraction, could be confirmed for 17-18 days after administration of Nandrolin (19-nortestosterone phenylpropionate).

Anabolic Agents↗
PubMed1985

Pharmacokinetics of 19-nortestosterone esters in normal men.

A reliable method for the isolation of 19-nortestosterone (NT), testosterone (T) and dihydrotestosterone (DHT) by high-performance liquid chromatography (HPLC) and quantitation of the individual steroids by radioimmunoassays is described. The method was used to measure serum concentrations of NT, T and DHT in a pharmacokinetic study and in a clinical trial for male fertility control. Following intramuscular injection of either 50 mg 19-nortestosterone-3-(p-hexoxyphenyl)-propionate (NP) or 50 mg 19-nortestosterone-decanoate (ND) serum NT increased rapidly to maximal concentrations of 4.6 +/- 3.2 and 2.0 +/- 1.3 nmol/l (+/-SD), respectively, in the 6 volunteers. The half-life time was 8 days for ND and 21 days for NP. Based on these findings a clinical trial with NP was performed. NP was given to 5 healthy men in doses of 100 mg/week for the first 3 weeks followed by 200 mg/week for 10 further weeks. Serum NT levels increased gradually and maximal concentrations were reached in the 13th treatment week (20.2 +/- 3.4 nmol/l). Measurable amounts of NT were detectable for 19 weeks after the last injection. The study shows that NT accumulates under this treatment regime and wider spacing of the injection intervals may be possible in future trials.

Adult↗
PubMed1993

7 alpha-Methyl-17 alpha-(E-2'-[125I]iodovinyl)-19-nortestosterone: a new radioligand for the detection of androgen receptor.

We have synthesized two gamma-emitting, 125I-labeled steroids, E- and Z-7 alpha-methyl-17 alpha-(2'-[125I]iodovinyl)-19-nortestosterone [125I](E- and Z-MIVNT) for specific labeling of androgen receptors. [125I]E- and [125I]Z-MIVNT were synthesized stereospecifically from E- and Z-7 alpha-methyl-17 alpha-(2'-tri-n-butylstannyl-vinyl)-19-nortestosterone. The tin adducts were prepared by addition of tri-n-butyltin hydride to 7 alpha-methyl-17 alpha-ethynyl-19-nortestosterone, and after purification they were converted in high yield to the [125I]MIVNT isomers by reaction with 125I (generated in situ by oxidation of [125I]iodide with chloramine T). The 125I-labeled products were purified by high-performance liquid chromatography, and their mass determined with an ultraviolet detector (specific activity of both, approximately 2,200 Ci/mmol). In rat prostate cytosol, [125I]E-MIVNT bound with high affinity to a single class of binding sites. Nonspecific binding in the presence of 5 alpha-dihydrotestosterone was relatively low, and compared favorably with that obtained in parallel studies with [3H]methyltrienolone (R1881). The E-isomer bound prostate cytosol with at least twice the affinity of the Z-isomer; therefore, the interaction of the E-isomer with the androgen receptor as well as other steroid receptors was studied in greater detail. Complexes of the androgen receptor with [125I]E-MIVNT as well as [3H]R1881 dissociate very slowly at 4C (kdiss for both = 0.04 h-1). Displacement studies showed that the interaction of [125I]E-MIVNT with the androgen receptor is highly specific. Competition studies showed that unlabeled E-MIVNT binds poorly to other steroid receptors in rat tissue cytosols. These binding properties make [125I]E-MIVNT a promising ligand for study of the androgen receptor, and [123I]E-MIVNT a potential imaging agent for the detection of androgen-dependent tumors, such as prostate cancer.

Animals↗