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Different patterns of metabolism determine the relative anabolic activity of 19-norandrogens
K Sundaram1, N Kumar, C Monder
1Center for Biomedical Research, Population Council, New York, NY 10021, USA.
Abstract:
Testosterone, the principal androgen secreted by Leydig cells, exerts a wide range of actions including growth of the male reproductive tract (androgenic effects) and growth of non-reproductive tissues such as muscle, kidney, liver, and salivary gland (anabolic effects). As androgenic steroids were discovered some were found to have relatively more anabolic than androgenic activity. The results reviewed in this report suggest that these differences result, in part, from the differential metabolism of the steroids in individual tissues and the varied activities of the individual metabolites. In the accessory sex organs (e.g. the prostate) testosterone is 5 alpha-reduced to dihydrotestosterone (DHT) which, due to its higher affinity for androgen receptors (AR), amplifies the action of testosterone. In contrast, when 19-nortestosterone (NT) is 5 alpha-reduced, its affinity for AR decreases, resulting in a decrease in its androgenic potency. However, their anabolic potency remains unchanged since significant 5 alpha-reduction of the steroids does not occur in the muscle. 7 alpha-methyl-19-nortestosterone (MENT) does not get 5 alpha-reduced due to steric hindrance from the 7 alpha-methyl group. Therefore, the androgenic potency of MENT is not amplified as happens with testosterone. These metabolic differences are responsible for the increased anabolic activity of NT and MENT compared to testosterone. Part of the biological effects of testosterone are mediated by its aromatization to estrogens. The fact that MENT is also aromatized to 7 alpha-methyl estradiol, a potent estrogen, in vitro by human placental and rat ovarian aromatase suggests that some of the anabolic actions of MENT may be mediated by this estrogen.
Insights
Testosterone metabolism varies by tissue, affecting its anabolic and androgenic effects. Novel steroids like MENT show increased anabolic activity due to altered metabolism and potential estrogenic pathways.
Area of Science:
- Endocrinology
- Pharmacology
- Biochemistry
Background:
- Testosterone, the primary androgen, drives both reproductive (androgenic) and non-reproductive (anabolic) tissue growth.
- Androgenic steroids exhibit varied anabolic versus androgenic potencies, influenced by tissue-specific metabolism and metabolite activity.
- Differential metabolism of androgens in target tissues significantly modulates their biological effects.
Purpose of the Study:
- To explore how tissue-specific metabolism of androgens influences their anabolic and androgenic activities.
- To investigate the mechanisms behind the differential potency of testosterone, 19-nortestosterone (NT), and 7 alpha-methyl-19-nortestosterone (MENT).
- To examine the potential role of estrogenic metabolites in the anabolic actions of MENT.
Main Methods:
- Review of existing research on androgen metabolism and receptor binding affinities.
- Analysis of 5 alpha-reduction pathways for testosterone, NT, and MENT in various tissues.
- In vitro studies on MENT aromatization using human placental and rat ovarian aromatase.
Main Results:
- Testosterone is 5 alpha-reduced to dihydrotestosterone (DHT) in accessory sex organs, amplifying androgenic effects.
- 19-nortestosterone (NT) and MENT exhibit reduced androgenic potency due to limited 5 alpha-reduction in accessory organs, while anabolic potency in muscle remains high.
- MENT's 7 alpha-methyl group sterically hinders 5 alpha-reduction, preserving its anabolic activity and preventing androgenic amplification seen with testosterone.
- MENT is aromatized to 7 alpha-methyl estradiol, suggesting a potential estrogen-mediated contribution to its anabolic effects.
Conclusions:
- Tissue-specific metabolism, particularly 5 alpha-reduction, is a key determinant of androgenic and anabolic potencies.
- Steroids like NT and MENT demonstrate enhanced anabolic activity compared to testosterone due to favorable metabolic profiles.
- The estrogenic activity of MENT metabolites may contribute to its overall anabolic effects, offering a novel therapeutic avenue.