Perhaps 3a-hydroxysteroid dehydrogenase/3b-hydroxysteroid dehydrogenase worth investigating

[Mew]

Perhaps another area worth investigating and testing… 3α-hydroxysteroid dehydrogenase/3b-hydroxysteroid dehydrogenase levels and function.

---

Steroid 5α-reductases and 3α-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism
linkinghub.elsevier.com/retrieve … 0X01901204

Androgen action in mammals can be regulated at the pre-receptor level by the intracellular formation and degradation of potent androgens, such as 5α-dihydrotestosterone (5α-DHT).

In androgen target tissues (e.g. prostate), 5α-DHT is formed from circulating testosterone by the action of the type 2 steroid 5α-reductase (5α-R) and its action is terminated by the action of a reductive 3α-hydroxysteroid dehydrogenase (3α-HSD) which forms the weak androgen 3α-androstanediol.

Oxidative 3α-HSD isoforms, however, can provide an alternative source of potent androgens by converting 3α-androstanediol to 5α-DHT. Working in concert, 5α-Rs and 3α-HSDs determine the amount and the type of androgen available for the androgen receptor and hence affect transcription of genes under androgen control.

In peripheral tissues (e.g. liver), type 1 5α-R and reductive 3α-HSD isoforms work consecutively to eliminate androgens and protect against hormone excess. Thus, different 5α-R and 3α-HSD isoforms participate in distinct anabolic and catabolic processes and their important roles in androgen action render them drug targets for the treatment of androgen-dependent diseases.

Androgen Metabolism in Human Prostate

Studies in rat (17, 18, 19), dog (11, 20, 21, 22, 23), and marsupials (24, 25) show that [b]DHT may also be formed from the inactive androgen 5-androstane-3,17ß-diol (3-diol) by an unknown oxidative 3-hydroxysteroid dehydrogenase(s) /b

The formation of DHT from either the reduction of testosterone by type 2 5-reductase or by the oxidation of 3-diol (back reaction) by an oxidative 3-HSD are shown. One source of circulating 3-diol is the hepatic metabolism of DHT by AKR1C4. Inhibition of type 2 5-reductase with finasteride and the inhibition of the oxidative 3-HSD is also indicated as therapeutic targets for prostate diseases. RED, Reductase; OX, oxidase.

IMAGE: mend.endojournals.org/cgi/conten … 0/2/444/F1

Regulating the levels of DHT by hormonal ablative therapy is achieved either by surgical castration to remove the testis and hence remove its precursor testosterone or by directly blocking the intracrine formation of DHT within the prostate by targeting type 2 5-reductase with the mechanism-based inactivator finasteride

Other sources of DHT include reduction of testosterone by type 1 5-reductase, which may be up-regulated in the diseased prostate (32), and oxidation of 3-diol, which can potently stimulate the growth of prostate across species (19, 20, 23, 25). Because 3-diol has a low affinity for the AR [dissociation constant (Kd) = 10–6 M[;rsqb];, it was concluded that 3-diol is converted back to DHT by an unidentified oxidative 3-HSD.

Furthermore, administration of 3-diol, but not its epimer 5-androstane-3ß,17ß-diol (3ß-diol), resulted in the induction of prostate growth in castrated beagles (20, 23). Administration of [3H]3-diol in human males suggests a human oxidative 3-HSD exists because approximately 65% and 50% of the radioactivity was found to be [3H]DHT in the plasma and prostate, respectively (33, 34). These data suggest that the back reaction could be an important source of DHT in humans and a potential therapeutic target for treating prostate diseases.

Attached images from:

books.google.com/books?id=alYapO … 4#PPA21,M1

[Mew]

books.google.ca/books?hl=en&lr=& … w#PPA14,M1

[to.robin]

In my case there is a problem converting Androstenedione to Testosterone, at least according to the saliva tests. This involves 17B-hydroxysteroid dehydrogenase, the nutritionist interpreting the results said maybe finasteride had damaged this enzyme.
My test results were: Androstenedione 557 (151-350) and Testosterone 31 (50-80)

[Mew]

In my case there is a problem converting Androstenedione to Testosterone, at least according to the saliva tests. This involves 17B-hydroxysteroid dehydrogenase, the nutritionist interpreting the results said maybe finasteride had damaged this enzyme.
My test results were: Androstenedione 557 (151-350) and Testosterone 31 (50-80)

Very interesting that you have a high Androstenedione:Testosterone ratio. You are correct that this involves the 17B-hydroxysteroid dehydrogenase pathway.

Researching this ratio, I came across the following (warning, graphic photo of genitalia):

ijp.it/articoli/2004/vol-1-04/Bertelloni.pdf

17β-hydroxisteroid-dehydrogenase deficiency is a rare autosomal recessive form of male pseudohermaphroditism, due to mutations in the 17β-hydroxisteroid-dehydrogenase type 3 gene. Mutated genes encode an abnormal enzyme with absent or reduced ability to convert Δ4-androstenedione to testosterone in the testis.

The hallmark of 17β-HSD3 deficiency is an abnormally
low testosterone to Δ4-androstenedione (T: Δ4-A) ratio
due to increased concentrations of Δ4-androstenedione
and impaired synthesis of testosterone in affected
patients This imbalance is biochemically evident
following hCG stimulation in affected infants and children.

…So 17B-hydroxysteroid deficiency leads to a form of pseudohermaphroditism. Since many here are experiencing shrinking genitals/scrotum etc thanks to Finasteride, this almost seems to parallel what might be the result of 17B-hydroxysteroid deficiency-induced pseudohermaphroditism.

---

The other thing I came across is this, as it relates to both 17Beta & 3Beta issues (this thread’s main theory):

Corticosterone impairs the mRNA expression and activity of 3b- and 17b-hydroxysteroid dehydrogenases in adult rat Leydig cells

article.pubs.nrc-cnrc.gc.ca/ppv/ … &volume=84

“Clinical and experimental studies, including our own observations, have shown the adverse effects of excess glucocorticoids on testicular steroid hormone production.”

…"For in vitro studies, purified Leydig cells (7.5 106 cells) of control rats were plated in culture flasks and exposed to different concentrations (50, 100, 200, 400, and 800 nmol/L) of corticosterone for 24 h. At the end of incubation, total RNA was isolated from cultured Leydig cells, and the mRNA of 3b- and 17b-HSDs was quantified by RT–PCR. A significant reduction in the activities and levels of 3b-HSD type-I and 17b-HSD type-III mRNAs in Leydig cells were observed. In vitro studies demonstrated a dose-dependent significant impairment in both the activity and mRNA expression of these enzymes.

These results suggest that corticosterone might have a direct effect on the transcription of the genes of 3b- and 17b-HSD. It is inferred from the present in vivo and in vitro studies that one of the molecular mechanisms by which excess corticosterone decreases the steroidogenic potency of Leydig cells is by suppressing the mRNA expression of 3b-HSD type-I and 17b-HSD type-III enzymes."

…

High levels of glucocorticoids due to Cushing’s syndrome/disease (McKenna et al. 1979), therapeutic administration (MacAdams et al. 1986; Veldhuis et al. 1992), and stress (Monder et al. 1992; Orr et al. 1994; Maric et al. 1996) decrease plasma testosterone. These reciprocal changes in the levels of steroid hormones have immense physiological
consequences, which include [Size=4]muscular atrophy and gonadal dysfunctions [/size](McKenna et al. 1979; Sapolsky 1985).

…

Our in vivo study clearly demonstrates that elevated levels
of corticosterone resulting from exogenous administration
decreased testicular 3b-HSD type-I and 17b-HSD type-
III mRNA expression. Glucocorticoids impair Leydig cell
function indirectly via a defective hypothalamo-pituitary
axis and by acting directly on Leydig cells through their receptors
(Dubey and Plant 1985; Rosen et al. 1988; Hales
and Payne 1989; Orr et al. 1994; Maric et al. 1996). Testicular
testosterone output was shown to be markedly reduced
following levels of glucocorticoids that were elevated as a
result of Cushing’s syndrome/disease, stress, and exogenous
administration (Veldhuis et al. 1992; Orr et al. 1994; Horiba
1997). 3b- and 17b-HSDs are the 2 important enzymes involved in testosterone biosynthesis.

I suggest you read the whole study as it is very interesting.

---

Based on the above study, my point is this:

- Finasteride can be considered as a synthetic corticosteroid, according to propeciahelp.com/forum/viewtopic.php?t=589

“The current case confirms rapidly reversible myopathy as a possible adverse effect of finasteride treatment, [Size=4]attributable to its structural affinity to corticosteroids[/size].”

…and from fda.gov/ohrms/dockets/ac/97/ … 3352t1.rtf

Also, in this year, there is a report showing that in a patient treated for benign prostatic hyperplasia, there is an occurrence of severe reversible myopathy associated with finasteride use, and this was clinically and histologically resembling glucocorticoid-induced myopathy.

So, if Finasteride in fact acted as a corticosteroid/glucocorticoid while we were taking it, and had an effect on adrenal/testicular steroid metabolism, then perhaps it interfered with 3Beta hydroxysteroid AND 17Beta hydroxysteroid metabolism, leading to the issues listed in the above study on rats… the result of which is a form of Fin-induced 17B/3B pseudohermaphroditism in adulthood.

I believe testing for the 3Beta (and 3Alpha) and 17Beta pathways should be considered.

---

Additional info on the Molecular Endocrinology of Hydroxysteroid Dehydrogenases, including deficiencies:
edrv.endojournals.org/cgi/content/full/18/3/281

[italysideeffect]

i did a new test about androstenedione becouse the last one was wrong… I have it high too…out of range .

3,35 ng/ml RANGE 0,7----2,5

if these enzyme are damaged is it possible to reverse it?

my testo seems to be in range.

[worried]

This is interesting. Well, if damage to these pathways were really the case, wouldn’t that mean that our problems would be alleviated with testosterone injections (TRT)? Some have done TRT, but have seen no improvement…

[italysideeffect]

I did TRT but this is the problem i think…at least for me…

when doc put me on TRT he prescribed me testingel 1 dose each 2 days…
doing like this i had my test when i was on TRT and what i can see is that my testosterone total and free were both high…but also my estrogens were so fucking high …cause aromatasi .
i remember they were 3 times more out of range…because???

because he gave me Testosterone he did’nt give me some anti aromatasi or anti estrogens…

so my T grow up but my E too…than i didn’t feel nothing .

could it be right this theory?

[italysideeffect]

another question if this was our real problem…is it reverseble? is possible to reverse enzyme function?

and…nobody more had a androstenedione test?

[Mew]

is it reverseble? is possible to reverse enzyme function?

I don’t know, I’m not an endocrinologist. Would have to research more, but I believe likely treatment would be androgen replacement (TRT). Something else I came across was this (hypospadia is an undeveloped penis)… but note the pathways involved, some of which are discussed in this thread already:

---

Defects of the Testosterone Biosynthetic Pathway in Boys With Hypospadias

linkinghub.elsevier.com/retrieve … 4701648936

Purpose
We determined the incidence of defects in 3 enzymes, namely 3 beta-hydroxysteroid dehydrogenase, 17 alpha-hydroxylase and 17,20-lyase, on the testosterone biosynthetic pathway in boys with hypospadias.

Materials and Methods
We evaluated 30 boys with a 46,XY karyotype, fully descended testes and penoscrotal or proximal shaft hypospadias. Serum concentrations of the metabolites mediated by these enzymes were measured, from which the precursor-to-product ratios were calculated. Seven patients underwent adrenocorticotropic hormone stimulation. Findings were compared to previously published data on age matched normal boys.

Results
A total of 11 boys had evidence of impaired function of 3 beta-hydroxysteroid dehydrogenase alone or in combination with impaired 17,20-lyase or 17 alpha-hydroxylase activity. An additional 4 boys had evidence of isolated 17,20-lyase deficiency. Thus, of the 30 boys studied 15 (50%) had evidence of a testosterone biosynthetic defect. The effect of adrenocorticotropic hormone stimulation varied with widening of the precursor-to-product ratios in some boys and narrowing in others.

Conclusions
A high incidence of 3 beta-hydroxysteroid dehydrogenase and 17,20-lyase deficiency was found in boys with proximal hypospadias. The response to adrenocorticotropic hormone stimulation suggests that enzymes in the adrenal glands and testes may be affected independently. Our findings support the hypothesis that hypospadias is the result of fetal endocrinopathy.

[to.robin]

If we take some form of TRT, is Testosterone going to increase with this damaged or greatly reduced 17B-HSD enzyme?
And if it did increase wouldn’t this only be temporary- whilst on TRT ?
We would need to take artificial Testosterone for the rest of our lives, not good for our health I believe ?
A lot of questions I know, but I had to get it of my chest.

[solonjk]

.

[to.robin]

I got the saliva tests done through the representatives of Diagnos-Techs here in the UK, the Red Apple Clinic - wasn’t it you solonjk who advised me to get tests done by Diagnos-Techs? I can’t remember now. They probably have representatives in other countries, you’re in Greece as I recall?

Androstenedione comes under the Male Hormone Panel. My Testosterone level was 31 (50-80pm/ml for 31-40 age range). They send you a diagram of the Androgen Pathway with results for Progesterone, Androstenedione, Testo, Estrone and DHT.

The problem is I’ve had these results since July last year but can’t find anyone interested in looking at them! What a waste.

Cheers

[solonjk]

.

[to.robin]

Yes, Solonjk, I’ll certainly take all my test results to Chrousos.
I posted my saliva test results, including DHEA and cortisol, in my thread ‘My Blood Test Results’ Page 4 in the section Hormone & Blood Tests. the last ones were last summer 2008.

[kazman]

Just wanted to add to this thread and indicate that I too have excessive Androstenedione. I had both blood and urine testing done earlier this year, after being on clomiphene citrate for several weeks (see My Recovery via Clomid later pages).

Androstenedione was 297 ng/dL on a range of 30 to 260. I will need to fin the urine results but they are over normal range as well.

[anonnn1]

I have excess androstandione as well…my last test on jan. 14 shows a value of

342 Range: (0-50)

maybe we all have adrenal fatigue and our bodies are forced to exert other hormones or exhaust them.
I dont know, just a theory I suppose.

[kazman]

Maybe we should have a Sticky thread similar to the Adiol-G thread of “Post your Androstenedione levels here” as it sure seems like everyone that has posted is above the range.

[Fanjeera]

I don’t know what to think of this theory. Not many of us have low T values, me included. It’s rather high. Though, my androstenedione is out of ranges high. But my low LH still indicates that everything is okay in the making of testosterone in the Leydig cells.

[Luckfax]

@Fanjeera

I don’t know what to think of this theory. Not many of us have low T values, me included. It’s rather high. Though, my androstenedione is out of ranges high. But my low LH still indicates that everything is okay in the making of testosterone in the Leydig cells.

[b]

[/b]

[golf]

Is there particular testing for 3α-hydroxysteroid or 17bhydroxysteroid deficiencies?