So, we know that by taking Finasteride, we induces a state of surrogate 5AR2 defiency/lack of DHT, by changing our hormonal profile to match that of a 5AR2-deficient pseudohermaphrodite.
Proof of above claim:
- Attached image at bottom of post, PAGE 27, from fda.gov/cder/foi/nda/97/2078 … CORRES.PDF
The text is from Merck – proclaiming the safety of Fin to the FDA, using the biological model of 5AR2 deficiency (pseudohermaprodites) they based the drug’s design on.
5AR2 defiency and pseudohermaphroditism involve mutations in the 5AR2 enzyme that prevent it from operating correctly. Most pseudo’s are raised as girls, but may have micropenis or other male characteristics that emerge during puberty. Their Testosterone and LH levels are usually elevated, however, due to lack of negative feedback from DHT (unlike many here post-Fin).
Regardless, since many here report a shrinkage of penis/testes after quitting the drug – and since 5AR2 defiency is associated with microphallus/ambigious/female genitalia, and 5AR2 is predominantly found in genital skin – to me this is very interesting as a potential point of investigation (5AR2 mutation).
What if by taking Finasteride and instilling a surrogate state of 5AR2 defiency, that our bodies adapted to this while on the drug (ie, having 70% less DHT/loss of 5AR2) and “learnt” this new homeostasis accordingly? Then when we quit, and DHT came flooding back as 5AR2 supposedly regenerated, body sensed this extra DHT, shut down T production to compensate, and subsequently either 1. permanently downregulated 5AR2 activity, or 2. 5AR2 mutated/loss of function post-Fin to maintain the “newly learnt”, Fin-induced pseudohermaphrodite state?
I admit this theory has holes because some guys have tried TRT and even Proviron (synthetic DHT) post-Fin, and not had much luck… and serum DHT blood values seem to show high levels of DHT for some guys here… thus, perhaps this points to an androgen receptor issue (AR not utilizing T/DHT correctly post-Fin, due to desensitization/downergulation)… OR possibly the fact that it is the actual 5AR2 reduction process of T --> DHT that is critical for it to exert it’s effects (unsure about this)…
Regardless, the fact that Finasteride inhibits 5AR2 (when taking it), that in pseudohermaphrodites 5AR2 mutation induces enzyme loss of function, 5AR2 is found in genital skin, and 5AR2 defiency can lead to microphallus – adding it all up, it just seems to match a lot of the symptoms we are experiencing “down there”.
Also, remember that Fin binds with NADPH – and NADPH is required for the enzyme to operate correctly, as noted here:
propeciahelp.com/forum/viewtopic.php?t=1401
Below is a study on the genetics of 5AR2 deficiency/pseudohermaphrodites – note the key points highlighted (including the bit on NADPH).
Molecular Genetics of Steroid 5a-Reductase 2 Deficiency
pubmedcentral.nih.gov/picren … obtype=pdf
"…To gain insight into correlations between a particular mutation and the
severity of the disease (i.e., degree of femaleness in 46,XY individuals)
and structure-function relationships in the enzyme, two mutations were produced and analyzed in an expressible cDNA for 5a-reductase 2 (Table III, Fig. 5). "
“…The mutant cDNAs and a normal control were transfected
into cultured human embryonic 293 cells and assayed in whole
cells and cell lysates for 5a-reductase activity. As shown in
Table III, the Gl 96S mutation reduced enzyme activity in
whole cells to 8.3% of normal, while the G34R mutation reduced
activity to - 1.7% of normal.”
Immunoblotting of lysates from the transfected cells indicated
that essentially equal amounts of 5a-reductase protein
were produced from the transfected cDNAs (Fig. 5 A), suggesting
that the mutations did not affect the expression or the stability
of the enzyme. The G196S mutation reduced the affinity of
the enzyme for NADPH but did not alter the apparent Km for
testosterone (Table III). In contrast, the G34R mutation drastically reduced the affinity of the mutant protein for testosterone
but did not affect the NADPH Km.
… "In two subjects analyzed at the biochemical level and in
affected individuals from the Dominican Republic described
in another study (Thigpen, A. E., et al., submitted for publication),
there appears to be a correlation between the severity of
manifestations and the severity of the impairment of enzyme
function. Thus, the GI 96S mutation identified in a boy (5R2-
New Haven) with a predominant male phenotype reduces enzyme
activity to - 8% of normal when assayed in transfected
whole cells (Table III). [b][u]The mechanism by which this mutation
decreases enzyme activity is presumably related to the
- 15 fold decrease in affinity of the enzyme for NADPH[/u][/b]. The
effect of this mutation on the catalytic activity ofthe enzyme in
vivo is difficult to estimate because intracellular concentrations
of NADPH vary between 50 and 400 ,uM (42). It is therefore
conceivable that the level of 5a-reductase activity in the anlage
of the external genitalia in this subject was sufficient to induce
partial virilization."
"… The acidic pH optimum may represent an artifact associated
with cell lysis or reflect localization of the type 2 enzyme
within an acidic subcellular compartment. The G34R and
G1 96S mutations appear to alter the conformation of the
membrane-bound enzyme in such a manner that the requirement
for an acid environment is reduced. The acidic pH optimum
of the normal enzyme may thus reflect an activation
requirement."
“…5a-Reductase deficiency leading to male pseudohermaphroditism
is a rare autosomal recessive disorder whose frequency
has not been directly measured. The finding that almost
half of the subjects analyzed here are known or presumed
compound heterozygotes suggests that the carrier frequency of
mutations in the type 2 gene may be quite high. The reasons
behind and the effects of a putative high carrier frequency of
mutations in the Sa-reductase type 2 gene are not known. The
apparent recurrent mutations identified here (Fig. 4) suggest
the possibility of mutational hotspots (43) in the gene that
might lead to an increased carrier frequency. Alternatively,
there may be an as yet unidentified selective advantage to heterozygous
carriers.”
Mutations leading to subtle abnormalities in the enzyme
may underlie some forms of commonly encountered urogenital
birth defect in males such as hypospadias or microphallus.
Along these same lines, regulatory defects in the type 1 or type
2 genes may underlie a wide variety of androgen-dependent
disorders such as male pattern baldness, acne, hirsutism, and
benign or cancerous growth of the prostate. The availability of
DNA probes for both genes should allow the future definition
of the genetic role of Sa-reductase in these diseases.
