Background
Finasteride is sold for hairloss under the brand name Propecia (fincar, finpecia as generics in India). It is a competitive 5alpha Reductase Type 2 inhibitor, it also inhibits 5beta Reductase. As a result it blocks the production of Dihydrotestosterone in the scalp and prostate and elsewhere, it also inhibits the production of all the 5alpha reduced metabolites in the body, including important neurosteroids in the brain. It also inhibits liver enzymes as a result of its actions upon 5beta reductase.
As a result Finasteride alters the hormone profile to be same as 5AR2 deficient pseudohermaphrodites [0]. Low serum DHT and low levels of other 5aR metabolites.
The members of Propeciahelp.com are the real world examples of the post marketing side effects of Finasteride.
Typically someone with issues will experience erectile dysfunction and loss of libido, known side effects of androgen deprevation [00]. After stopping finasteride things typically get worse, a full endocrine 'crash' followed by a host of symptoms normally found in men with low levels of testosterone, these include fatigue, problems concentrating, depression and even muscle loss plus many more. These side effects are permanant and continue despite all and any attempts to allieviate them (even supra-physiological levels of testosterone will not always work). A low quality of life results for those suffering this miserable condition.
It must be accepted that the 'post finasteride syndrome' is a novel form of iatrogenically induced hypogonadism. The underlying mechanism of which is not known.
Blood tests on these individuals show a consistent set of results:
Low to normal Testosterone levels
Normal DHT levels
Very low 3adiolG levels (the actual marker of intracellular DHT activity)
Low ratios of other 5aR reduced metabolites, especially 5a-Tetrahydrocortisol, but not as low as when using Finasteride.
Effects on DHEA-S, Androstenedione and other hormones
Low to normal LH and FSH,
Low Vitamin D
The syndrome is a mystery, why do these symptoms persist despite normal T? Why such low levels of 3adiolG despite normal T and DHT levels?
Some, including serious and educated endocrinologists and neuroendocrinologists (in the USA and Europe) who have seen a number of sufferers have come to the conclusion that they have developed a form of acquired androgen insensitivity.
I think there is one better explination, that reflects the fact such symptoms do not persist in those undergoing full androgen deprevation therapy. I will now provide my own theory.
Feedback is very welcome.
Theory
The 'Phantom DHT' theory or the 'Increased Testosterone Metabolism Theory'
(1) Fin inhibits 5-beta-Reductase, which controls the hepatic cyp3a4 enzyme involved in the metabolism of androgens and xenobiotics [1]. Fin is both a xenobiotic and a synthetic androgen [10], thus the reduced cyp3a4 enzyme is taxed to metabolise it.
(2) As fin inhibits its own metabolism there may be v.high serum levels and higher chances of side-effects, especially if taken with other drugs, alcohol.
(3) When fin usage ends, 5-beta-reductase will regenerate thus creating more cyp3a4 enzyme. I theorise this could lead to permanant increase in the metabolation of androgens as well. (this has been discussed in relation to the gulf war syndrome [9])
(metabolism = deactivation before being made water soluble for urination. Androgens can also be made water soluble for urination w/out deactivation from cyp3a4)
(4) higher testosterone metabolism will lead to more deactivated hydroxytestosterone (especially 6beta-hydroxy testosterone '6bOHT') in serum. [2]
(5) the body should compensate for metabolism with more T production via LH [3] (possibly resulting in altered LH profile)
(6) the sudden metabolism and gap before T production catches up could lead to the 'crash'. If T production never catches up T levels will be permanantly lowered.
(7) I theorise that a higher serum ratio of hydroxytestosterone/testosterone could interfere with the heomeostatis of testosterone in the body leading to symptoms of hypogonadism. (ie competing for the androgen receptor [7], transport throughout the body)
(8) 6bOHT is an excellent substrate of 5aR.[4] Thus higher levels of this will also inhibit normal production of dihydrotestosterone throughout the body. High levels of 6bOHT will create higher serum levels which interfere with 5aR throughout the body, not just the liver.
(9) 6bOHT is NOT an inhibitor of 5aR. Thus its reduction via 5aR will only take place where T normally produces its metabolites. It will NOT inhibit 5aR conversions of neurosteroids in the brain for example, or stop other 5ar metabolites.
(10) I propose the product of 6bOHT and 5aR is: 6b-hydroxy-5a-dihydrotestosterone, a deactivated version of DHT [5]
(11) I theorise that 6b-hydroxy-5a-dihydrotestosterone is detected in the blood as normal DHT. Due to the fact it is a difficult chemical to determine due to its unique properties (as was found in this paper [5]) and because the normal test for DHT seems insensitive (andractim & proviron also detected as DHT for example[8]). Thus the DHT found in blood tests is a 'Phantom DHT'.
(12) The result of point (11) is apparantly normal DHT but v. low 3adiolG (lower even than when on fin) due to both T AND DHT being effected.
(13) Blood tests will show inhibition of other 5aR reduced metabolites due to 'competion' over 5aR in the liver.
(14) A urinary or blood test to determine the ratio of Hydroxy-Testosterone to Testosterone will discover if this has happened, or prehaps other markers of cyp3a4 induction.[6]
(15) Also...this enzyme, cyp3a4, will also increase metabolism of androgens such as DHEA and Androstendione as well as T (although T is metabolised most).
The body will compensate with LH to create more T & Androstendione from the testes and ACTH to create more DHEA from the adrenals. However, since each are also steps in the steroid pathway, this disruption can lead to altered levels (particularly DHEA as it has only one precursor and comes before Androstendione & T)
A pretty solid theory. Symptoms & Blood tests results match with the theory.
Proof of all of this, apart from the 'theories' claims, in the references below.
[0]
C19 and C21 5 beta/5 alpha metabolite ratios in su... [J Clin Endocrinol Metab. 1990] - PubMed result
[1]
http://onlinelibrary.wiley.com/doi/1...157.x/abstract
[2]
The Contribution of Hepatic Inactivation of Testosterone to the Lowering of Serum Testosterone Levels by Ketoconazole — Toxicol Sci
[3]
http://www.ncbi.nlm.nih.gov/pubmed/9...?dopt=Abstract
[4]
ScienceDirect - Archives of Biochemistry and Biophysics : Inhibition of steroid 5?-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450*1
[5]
http://onlinelibrary.wiley.com/doi/1....tb00389.x/pdf
[6]
The increase in urinary excretion of 6 beta-hydrox... [Br J Clin Pharmacol. 1989] - PubMed result
[7] I assume there will be some interference as 6bOHT enters a cells cytoplasm to react with 5aR.
[8] I assume hydroxytestosterone does not show up as normal testosterone in a blood test.
[9]
Inhibition and Activation of the Human Liver Microsomal and Human Cytochrome P450 3A4 Metabolism of Testosterone by Deployment-Related Chemicals — DMD
[10]
http://www.wiley-vch.de/books/sample/3527306501_c01.pdf
[00] Erdemir F, Harbin A, and Hellstrom WJG. 5-alpha reductase inhibitors and erectile dysfunction: The connection