Pharmacokinetics of 19-nortestosterone esters in normal men

Belkien, L.; Schürmeyer, T. H.; Hano, R.; Gunnarsson, Per Olof; Nieschlag, Eberhard

doi:10.1016/0022-4731(85)90215-8

Cited by 50 publications

(21 citation statements)

References 21 publications

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“…Testicular tissue was homogenized in 1 mL 150 mmol/L NaCl and extracted with ether. The ether was evaporated to dryness, and after redissolution in n-hexane-isopropanol, T and DHT were separated by high pressure liquid chromatography, as previously described (22). For determinations of T the assay described above was used.…”

Section: Hormone Determinationsmentioning

confidence: 99%

Testosterone Prevents Complete Suppression of Spermatogenesis in the Gonadotropin-Releasing Hormone Antagonist-Treated Nonhuman Primate (Macaco, fascicularis)*

Weinbauer

Göckeler

Nieschlag

1988

The Journal of Clinical Endocrinology & Metabolism

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We studied the effects of administration of a GnRH antagonist combined with testosterone (T) as an approach to male contraception as well as the role of intratesticular androgens in spermatogenesis using a nonhuman primate model. Three groups of five adult cynomolgus monkeys (Macaca fascicularis) received daily sc injections of 420-460 micrograms/kg GnRH antagonist ([Ac-D2Nal1,D4ClPhe2,DPal3,Arg5,DGlu6(AA), DALa10]GnRH) for a period of 15 weeks. T supplementation, commencing on the first day of GnRH antagonist administration, was provided by single im injection of 40 mg (group 2) or 200 mg (group 3) of the long-acting testosterone ester testosterone-trans-4-n-butylcyclohexancarboxylate (20-Aet-1). Serum LH bioactivity was undetectable within 1 week of GnRH antagonist administration in all monkeys. GnRH antagonist administration alone (group 1) reduced serum T levels into the castrate range. Forty milligrams of 20-Aet-1 maintained serum T levels in the upper range of normal monkeys, while 200 mg 20-Aet-1 maintained serum T levels about 1.5-fold above normal. The response to electroejaculation was fully maintained in all T-treated monkeys. Sperm counts in the ejaculates dropped to zero among group 1 animals within 7-10 weeks of GnRH antagonist administration. In groups 2 and 3 consistent azoospermia could not be induced, and the sperm counts were significantly (P less than 0.05) higher in group 3 than in group 2. Histologically, spermatogenesis in group 1 was arrested at the spermatogonial level in 75% of seminiferous tubules. In group 2, spermatogenesis proceeded to spermatocytes in 50% of tubules and to elongated spermatids in 10% of tubules, while in group 3 elongation of spermatids occurred in 75% of tubules. The mean T and dihydrotestosterone concentrations in baseline testicular biopsies (n = 15) were 43.8 +/- 6.8 (+/- SE) and 5.7 +/- 1.5 ng/g, respectively. After GnRH antagonist with or without T administration, the mean (n = 15) intratesticular T and dihydrotestosterone levels were reduced to 20.3 +/- 4.9 and 3.2 +/- 0.5 ng/g, respectively, and differed little among the three groups. No correlation, however, could be established between testicular androgen levels and spermatogenic status (P greater than 0.30) or sperm counts (P greater than 0.60). These results demonstrate that administration of a GnRH antagonist in the presence of constant serum T levels does not induce consistent azoospermia, and that the supporting effects of T on spermatogenesis cannot be explained exclusively on the basis of the testicular androgen concentrations.

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Section: Hormone Determinationsmentioning

confidence: 99%

Testosterone Prevents Complete Suppression of Spermatogenesis in the Gonadotropin-Releasing Hormone Antagonist-Treated Nonhuman Primate (Macaco, fascicularis)*

Weinbauer

Göckeler

Nieschlag

1988

The Journal of Clinical Endocrinology & Metabolism

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“…Kinetics of metabolism and excretion of xenobiotic nandrolone or norsteroids in man have been well studied (Bjorkhem and Ek 1982;Belkien et al 1985;Bergink et al 1985;Minto et al 1997;Bhasin et al 2003). The results point out to a faster excretion of these substances as compared to testosterone.…”

Section: Resultsmentioning

confidence: 92%

“…They have been extensively studied in both animals and humans for the last five decades (Birch 1950;Engel et al 1958;Dimick et al 1961;Schu¨rmeyer et al 1984;Belkien et al 1985;Dumasia et al 1989;Minto et al 1997;Bhasin et al 2003). They are also obligatory intermediates in estrogen biosynthesis, in both animals and man (Short 1961;Skinner and Akhtar 1969;Berkowitz et al 1984;Courtot et al 1984;Bergink et al 1985;Dumasia et al 1989;Garrett et al 1991).…”

Section: Resultsmentioning

confidence: 96%

“…However, under these basal conditions and with the same techniques, notwithstanding the particular technical difficulties attached to its preparation, 19-NE was more elusive to detect in human urine up to 1998, due to particular interferences depending on the urinary matrix studied, in the area where 19-NE is eluted. Finally, it was reported to be assayed at 20-50 pg ml )1 urine Le Bizec et al 2002;Schmitt et al 2002), whereas it was easily detectable, and detected, after controlled administration of nandrolone or norsteroids (Belkien et al 1985;Hatton and Catlin 1987;Masse et al 1985;Scha¨nzer 1996). Indeed, this is confirmed by the thousands of controls practiced each year by IOC's accredited antidoping laboratories on competing athletes where neither nandrolone metabolite was ever reported as detectable at the limit of 200 pg ml )1 urine unless a doping offence was reported and accepted (Tables 1 and 2).…”

Section: Research Evolution In the Detection Of Nandrolone And Norstementioning

confidence: 97%

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Update on nandrolone and norsteroids: how endogenous or xenobiotic are these substances?

Bricout

Wright

2004

European Journal of Applied Physiology

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Norsteroids are xenobiotics with androgenic and anabolic properties known since as far back as the 1930s. In doping controls, the use of the banned xenobiotic norsteroids is detected in the competitor's urines by the measurement of norandrosterone (19-NA) and noretiocholanolone (19-NE), which are the main metabolites for nandrolone (NT) and most norsteroids with anabolic properties. In 1996, the IOC subcommission "Doping and Biochemistry of Sport" informed the Heads of the "IOC Accredited Laboratories" that the recommended cut-off limit for reporting an offence was to be 1-2 ng ml(-1) urine for either 19-NA or 19-NE. We will discuss how technical progress in gas chromatography coupled to high-resolution mass spectrometry permitted a dramatic increase in sensitivity with a detection limit of 1 pg ml(-1) urine, or less, and an assay limit of 20-50 pg ml(-1) urine, for either 19-NA or 19-NE. As a paradox, norsteroids have been known for decades as not only xenobiotics but also obligatory endogenous intermediates in the biosynthesis of estrogens from androgens in all species, man included. It is this biochemical observation which fed the active scientific and medical controversy initiated in 1998 over the possibly endogenous production of nandrolone and metabolites well over the new IOC's recommended cut-off limit of 2 ng ml(-1) urine. Notwithstanding the particular technical difficulties attached, we will provide data and discuss the minute endogenous levels detected and measured in man either at rest, after performance or training and compare them to the relatively high levels reported in male athlete's doping controls today. We will also discuss data on the pharmacological effects of some contraceptive therapies containing norsteroids in women. In view of the well-documented noxious effects repeatedly observed after anabolic steroid misuse, the confirmation and implementation of technically proven procedures for reporting norsteroid abuse in sports seems an important enough goal to protect athlete's health against such abuses and justifies up dating the review of the patent scientific and medical experience and knowledge gained over the last 50 years on nandrolone and its minor production in man and woman.

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“…Testosterone and DHT in serum and testicular tissue extracts were separated by high-performance liquid chromatography (2). Serum and testicular testosterone and DHT were then determined by specific ra dioimmunoassays as described previously [23].…”

Section: Hormone Determinationsmentioning

confidence: 99%

Testosterone and Dihydrotestosterone, but Not Estradiol, Selectively Maintain Pituitary and Serum Follicle-Stimulating Hormone in Gonadotropin-Releasing Hormone Antagonist Treated Male Rats

Arslan

Weinbauer²,

Khan³

et al. 1989

Neuroendocrinology

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Recently it has been found that testosterone can maintain and restimulate serum and pituitary follicle-stimulating hormone (FSH) in the gonadotropin-releasing hormone (GnRH) antagonist treated adult male rat. The present investigation was undertaken to determine (1) which metabolite of testosterone, dihydrotestosterone (DHT), or estradiol accounts for the effects of testosterone in GnRH antagonist suppressed rats and (2) whether these effects of testosterone are influenced by other testicular factors. Eight groups of 6–8 adult male Sprague-Dawley rats were subjected to the following treatments: vehicle, GnRH antagonist (75 µg/day s.c), testosterone-filled Silastic implants (3 × 5 cm, s.c), DHT-filled Silastic implants (3 × 5 cm, s.c), estradiol ben-zoate (15 µg/day s.c), and combined administration of GnRH antagonist with either steroid. In addition, the GnRH antagonist/ testosterone treatment regimen was applied to rats orchidectomized 72 h prior to initiation of treatments. After 3 weeks of treatment, serum was analyzed for concentrations of luteinizing-hormone (LH), FSH, testosterone, DHT, and estradiol. Pituitary extracts were analyzed for LH and FSH content. Except for the vehicle-treated groups, serum and pituitary LH concentrations were markedly suppressed by all treatments. In intact rats treated with GnRH antagonist alone and/or estradiol, the pituitary FSH level was reduced by more than 70% relative to controls, while both testosterone and DHT maintained pituitary FSH. Similarly, testosterone and DHT, but not estradiol, delayed the decline of serum FSH induced with GnRH antagonist alone. In orchidectomized animals, testosterone was also capable of preventing a reduction of pituitary FSH despite concomitant GnRH antagonist administration. It is concluded that testosterone and DHT selectively maintain FSH in the GnRH antagonist treated male rat. This paradoxical stimulation of FSH occurs in the absence of other testicular factors.

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Pharmacokinetics of 19-nortestosterone esters in normal men

Cited by 50 publications

References 21 publications

Testosterone Prevents Complete Suppression of Spermatogenesis in the Gonadotropin-Releasing Hormone Antagonist-Treated Nonhuman Primate (Macaco, fascicularis)*

Testosterone Prevents Complete Suppression of Spermatogenesis in the Gonadotropin-Releasing Hormone Antagonist-Treated Nonhuman Primate (Macaco, fascicularis)*

Update on nandrolone and norsteroids: how endogenous or xenobiotic are these substances?

Testosterone and Dihydrotestosterone, but Not Estradiol, Selectively Maintain Pituitary and Serum Follicle-Stimulating Hormone in Gonadotropin-Releasing Hormone Antagonist Treated Male Rats

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