Rat v. Human, re: inhibition of neurosteroids -- Allopregnanolone, THDOC and dihydroprogesterone

[3pm]

With respect to Finasteride’s inhibition of neurotransmitters such as Allopregnanolone, THDOC and dihydroprogesterone, is there any evidence that they are affected in humans like in the rat studies? Reason I really ask is that I want to start approaching law firms with my data, but I feel inadequately prepared without direct evidence that finasteride has been demonstrated to have a significant effect in humans.

I’m sorry if this is a bit of a moot point but I’m definitely focused on pinpointing this. It might also be worth discussing anyways.

[Mew]

Regarding rat vs human Finasteride inhbiition of 5AR – I have read that in rats Finasteride inhibits 5ARI and II equally, but in humans predominantly 5AR-II (irreversibly) and extremely low levels of 5AR-I (reversibly) probably not even worth being concerned about – see my post here regarding 5AR I:

propeciahelp.com/forum/viewtopic.php?t=1119

I will have to dig up the rat vs human scientific materials when I have the chance, I know I read it somewhere.

[3pm]

If Finasteride only slightly - to a point of irrelevance - inhibits the type I 5AR, how then can this website claim it interferes with Progesterone’s neurosteroids in Propecia users? That factor would be just as insignificant, wouldn’t it?

BTW, has anyone here been tested, or is it possible to test for GABA and other neurosteroids in the brain? Determining if we post-fin sufferers have been impacted in this way seems crucial, since I haven’t found any human trial studies discussing Finasteride’s influence on neurostransmitters.

Since, however, I know I’ve experienced the negative mental impacts of finasteride, maybe those experiencing such problems had type II creating neurosteroids in the brain? I realize I’m grasping at straws, but its hard to make sense of this without proper studies done.

[Mew]

If Finasteride only slightly - to a point of irrelevance - inhibits the type I 5AR, how then can this website claim it interferes with Progesterone’s neurosteroids in Propecia users? That factor would be just as insignificant, wouldn’t it?

How can this website claim it interferes with Progesterone’s neurosteroids in Propecia users?

From:
blackwell-synergy.com/doi/pd … 06.00053.x

In addition to catalyzing the rate-limiting step in the reduction of testosterone, [Size=4]both isoforms of the 5alpha-reductase enzyme [/size] are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively.

Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission.

Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior.

Results of some preclinical studies and clinical observations with finasteride are described in this review article.

The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

Since Fin predominantly inhibits 5AR2 in humans, judging by the above quoted materials (“both isoforms of the 5alpha-reductase enzyme are responsible for the reductionof progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC)”), it would seem neurosteroid inhibition would still take place. And since numerous men experience profound depression and anxiety while on the drug, it would seem this is likely true… as evidenced here:

PAGE 6:

“[b]Finasteride crosses the blood-brain barrier, and thus can be used to inhibit 5a-reductase activity in the CNS /b. Given this finding, there has been speculation that finasteride might be useful to inhibit progesterone metabolism, and the concomitant synthesis of neuroactive steroids in the brain. Thus, the remainder of the review will focus on recent preclinical and clinical data that are consistent with the notion that finasteride alters brain function and behavior via its ability to inhibit the formation of GABAergic neuroactive steroids, with particular emphasis on 3a,5a-THP”

On the author hand, however, the authors also concede:

“While these studies report that finasteride was very effective
at treating symptoms of the disease, the mechanism by which finasteride could alter aspects of sexual behavior in humans is not presently known.”

“Likewise, finasteride has been used to discern the contribution of 3á,5á-THP to aspects of sexual behavior in female rodents that are predominantly mediated by progesterone. The ability of finasteride to robustly inhibit rodent female sexual behavior differs from data in clinical trials, which have reported that sexual side effects occurred in a small proportion of males and females treated with finasteride (typically 5%). As the putative mechanism by which finasteride might affect human sexual behavior is not presently known, it is difficult to generalize the results from the preclinical studies to the clinical data.”

Also FYI, found more material that mentions equal inhibition of 5AR I and II in rat: propeciahelp.com/forum/viewtopic.php?t=1402

In more detail: jbc.org/cgi/reprint/267/12/8577.pdf

[3pm]

Ah, that was just the info I needed, thanks Mew. So basically, we’re dealing with a drug they’re selling that will definitely interfere with Progesterone’s neurosteroids? Funny, Merck fails to inform that 5AR type-II has functions in my CNS and brain beyond creating DHT. Would have loved to have been properly informed of the drug’s action BEFORE taking it.

[Mew]

So basically, we’re dealing with a drug they’re selling that will definitely interfere with Progesterone’s neurosteroids?

Well the major difference here is that 5AR1 is found predominantly in the brain, which in rats is equally inhibited by Finasteride, but in humans, far less (and reversibly I might add). Nonetheless, as mentioned in my previous post, it would seem that yes, we are dealing with a drug that does what you mention – interferes with the 5AR reduction of:

• Progesterone --> 5a-DHP --> Allopregnanolone
• Deoxycorticosterone --> 5a-DHDOC --> 5a-THDOC.
• Testosterone --> 5a-DHT --> Androstanediol

See page of 3 for diagram: blackwell-synergy.com/doi/pd … 06.00053.x

Further indirect evidence of these neursteroid inhibiting effects IN HUMANS:

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated [reduced] by Finasteride
nature.com/npp/journal/v30/n … 0688a.html

"In this study, we also examined the effects of finasteride, a 5AR inhibitor, on the subjective response to a moderate dose of alcohol in social drinkers. As hypothesized, finasteride reduced a number of the self-reported stimulant effects of alcohol, as measured by two subscales of the Alcohol SS (ie the Central-Stimulant and Dynamic-Peripheral Subscales), as well as the Stimulation Subscale of the BAES. These findings are consistent with the results of studies in rodents, which show that the pregnane neuroactive steroids, especially ALLO, mediate some of the effects of acute alcohol administration (Morrow et al, 1999, 2001). "

Nonetheless, there are caveats to the study:

The findings reported here must nonetheless be viewed in the context of the study’s limitations. Although of interest in relation to alcoholism risk, the GABRA2 polymorphism that was examined in this study as a moderator of alcohol’s effects has not been shown to be functional; the variation in this gene that underlies the association with alcohol dependence remains to be determined. Although finasteride is a potent antagonist of type 2 5AR, it has modest antagonist activity at type 1 5AR (Tian et al, 1994; Tian, 1996), the predominant isoform in the mature human brain (Poletti et al, 1998; Stoffel-Wagner et al, 1998). To compensate for the lower antagonist activity of finasteride at the human brain type 1 5AR, we administered a high dose of the drug (ie a total of 200 mg over 24 h, which is 40 times the standard daily dose). Human studies using lower doses of finasteride, which inhibit only peripheral 5AR, would help to define the relative contribution of central or peripheral effects of finasteride on the subjective effects of alcohol in humans. Further, the lack of a placebo alcohol condition limited our capacity to ascertain whether the impact of finasteride on subjective responses was pharmacological or psychological (eg reflecting expectancies), or to determine the subjective effects produced by finasteride alone.

Since the literature on the effects of neuroactive steroids in humans is limited to ALLO (Torres and Ortega, 2003, 2004), we have focused primarily on that compound as a potential mediator of the observed effects of finasteride. However, we did not measure peripheral neuroactive steroid concentrations, so it is possible that the observed effects of finasteride were mediated by changes in other brain steroids. For example, changes in testosterone concentration may have mediated the observed subjective effects, consistent with a recent finding that testosterone concentrations are elevated in both men and women following acute alcohol intake (Sarkola and Eriksson, 2003; Sarkola et al, 2000). Although alcohol may also have increased levels of 5b-reduced steroids, such as pregnanolone, finasteride blocks the conversion of progesterone and deoxycorticosterone to the 5a-reduced metabolites, with no effect on the concentration of 5b-reduced metabolites. This makes it unlikely that changes in concentration of the 5b-reduced steroids provide an adequate explanation for the observed subjective effects.

Although the primary outcome measures used in the study were based on participants’ self-report, the instruments that were chosen are used widely to evaluate alcohol-induced subjective effects. In this study, A-allele homozygotes were more sensitive to the subjective effects of alcohol. However, it is possible that the presence of the G-allele changed the threshold at which subjects experienced alcohol’s effects, which may also have limited the potential effects of finasteride in the G-allele group. A study design in which the dose of alcohol is varied could be used to test this hypothesis by determining the concentration at which G-allele carriers experience substantial subjective effects. Subsequent studies of the impact of a 5AR inhibitor on a behavioral measure of alcohol’s effects in humans should also include a physiological measure that is sensitive to alcohol effects, such as static ataxia, or by using an operant paradigm to measure alcohol self-administration.

The comparatively small number of subjects in this study, in particular the fact that only seven individuals were homozygous for the A-allele, raises the possibility that the findings occurred by chance. In addition, because only two individuals were homozygous for the G-allele, we were able to test only for a dominant effect of the G-allele by comparing carriers (ie AG or GG genotypes) with A-allele homozygotes. A larger sample would make it possible to examine an additive effect of the alleles by using all three genotype groups to examine both the response to alcohol and its modification by finasteride. In addition, the functional effects of the allelic variation at GABRA2 are not understood (Edenberg et al, 2004; Covault et al, 2004), so that additional research is required to elucidate the potential mechanism by which the gene influences the response to alcohol.

Now, even though they admit to the various limitations of their study, it is nonetheless interesting to note their conclusions:

Despite these limitations, the results of this study provided support for the hypothesis that GABRA2 alleles moderate the stimulating effects of alcohol, and that these effects can be attenuated by finasteride. The effects of finasteride observed here are consistent with findings from an extensive animal literature and a growing human literature that implicate neuroactive steroids as mediators of some of the effects of alcohol. Further investigations of neuroactive steroid interactions with GABAA receptor variants and their potential role in determining risk of alcohol dependence are warranted.

Also of note is the fact they used massive doses of Finasteride in their study. Despite the fact that the drug has a near flat-dose response, there is a point where it does begin to start inhibit 5AR1 far more at higher concentrations. I don’t have the literature in front of me to say at what point this might start to happen… but just something to keep in mind.

[Mew]

Furthermore.

2nd image from PAGE 2 – medind.nic.in/ibi/t01/i1/ibit01i1p51.pdf

[Mew]

dialogues-cns.org/brochures/ … ge=103PAGE 109

[Size=4]Effects of ethanol on neuroactive steroids in humans[/size]

---

… Finasteride reduces the formation of both 3α,5α-
THP and 3α,5α-THDOC by inhibiting the reduction of
progesterone and DOC to intermediate precursors.Indeed, finasteride pretreatment blocked subjective
effects of alcohol using three different scales to measure
the activating, sedating, anesthetic, and peripheral
dynamic aspects of alcohol actions.

…The ability of finasteride
to reduce the subjective effects of alcohol was not
observed in individuals carrying the GABAA α2 subunit
polymorphism associated with alcoholism, suggesting
that individuals carrying this polymorphism have reduced
sensitivity to both alcohol and finasteride.95

…Humans, but not rodents, synthesize multiple 5β-reduced
neuroactive steroids including 3α,5β-THP and 3α,5β-
THDOC. 3α,5β-THP levels are comparable to those of
3α,5α-THP in human plasma and cerebrospinal fluid.15,16

…These neuroactive steroids also modulate GABAergic
transmission,8,13,14 but have not been measured in humans
after ethanol administration.

…Additionally, the primary stress steroids in humans are cortisol and 11-deoxycortisol, while progesterone and corticosterone are the primary
stress steroids in rodents.

…3α,5β-reduced cortisol is a negative
modulator of GABAA receptors,17 and could contribute
to the subjective effects of ethanol in humans.Thus,
the combined effects of 3α,5α- and 3α,5β-reduced neuroactive
steroids may contribute to the effects of ethanol
in humans and nonhuman primates.These steroids have
never been measured following ethanol, stress, or HPA
axis activation in humans or nonhuman primates.

…Other GABAergic 3α,5α- and 3α,5β-reduced neuroactive
steroids, derived from DOC, dehydroepiandrosterone
(DHEA), and testosterone, are known GABAergic modulators100-
102 that may be elevated by HPA axis activation
in humans. Unfortunately, simple inexpensive analytic
methods to measure these steroids are not available.

The ability of finasteride to block the subjective effects of
ethanol in humans may be due to its ability to prevent
the formation of any or all of these neuroactive steroids.

[Mew]

jneurosci.org/cgi/content/full/27/9/2155#B25

Neurosteroid Synthesis-Mediated Regulation of GABAA Receptors: Relevance to the Ovarian Cycle and Stress

---

"…We have shown that elevations in neurosteroid levels associated with an acute stressful episode induce alterations in GABAARs, which may function to maintain the balance between excitation and inhibition after stress.

The duration of neurosteroid exposure and the rate of decline of neurosteroid levels may be critical for the regulation of GABAARs. The key to the regulation may be a relatively rapid rise and fall in neurosteroid levels, because long-term exposure to positive allosteric modulators such as benzodiazepines, alcohol, and even neurosteroids result in a downregulation of receptor function (Bateson, 2002; Krystal et al., 2006; Reddy, 2006).

Disruption in the regulation of GABAARs in response to stress may underlie the stress-induced exacerbation of many psychiatric and neurological disorders.

The upregulation of GABAAR subunit expression after an acute stressful episode may be a protective mechanism to prevent an imbalance in neuronal excitability. Our results demonstrate that, in addition to the direct allosteric modulation of GABAARs, neurosteroids also regulate GABAARs on a longer timescale by altering the expression of specific GABAAR subunits.

[Size=4]This may have implications on the clinical use of neurosteroid synthesis inhibitors such as finasteride (Propecia), because certain neurological disorders related to steroid hormone changes may be worsened by finasteride treatment [/size](Herzog and Frye, 2003)."

[derekjrt]

Very unteresting I have to show it to my endocrynologist who thinks the whole problem is neurological.

[YaEatChickenSOWHAT]

VERY INTERESTING.

“exacerbating underlying psychiatric disorders”

This adds credence to the neurotransmitter theory that finasteride has created an imbalance of dopamine hormones and raised serotonin levels. Why? Possibly because there was some pre-existing condition in us that was exacerbated by propecia’s use.

Just a theory, but adds merit.

[derekjrt]

Pre-existing condition… what do you mean?

[Mew]

works.bepress.com/cgi/viewconten … l_rogawski

"… Abrupt withdrawal from progesterone-derived neurosteroids [ie, allopregnanolone or THDOC], as is believed to occur around the time of menstruation in humans, can be induced either by ovariectomy or by injection of a 5a-reductase inhibitor that blocks neurosteroid synthesis.

[Size=4]Such neurosteroid withdrawal is associated with a marked enhancement in anxiety-like behaviors and seizure susceptibility[/size].

We have proposed that the period of heightened seizure susceptibility represents a model of human perimenstrual catamenial seizure exacerbations.

[Mew]

[Size=4]It’s official:[/size]

[Size=4]December 2010 – Depression has been added by Merck USA as an officially reported post-marketing side effect from Propecia (Finasteride) use.

Read Details: viewtopic.php?f=24&t=4666[/size]