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Dear Dr Jacobs,

Don´t waste your time trying to find the causes of this severe problem. The real cause is demyelination of the motor neurons in the spinal chord,not only the mental side effects but also the sexual side effects are a result of the neurological damage from finasteride.

You can read it here:


And here:


"Demyelination just happend because of a lack of allopregnanolone which is synthesized by 5AR2 (yes, type 2 and only type 2!!) in the spinal chord and not because of an immune response"

"But neurodegeneration can happen over many years. And I bet they didn't check for demyelination. I think that most people taking finasteride over the years will experience neurological damage (demyelination) in the spinal chord. It's just that for some it happens in a shorter timeframe and for others it develops during several years"

"The brain has 5AR1 but the spinal chord has mainly 5AR2. Finasteride only inhibits 5AR2. I said the CONDITION at the spinal chord is the same. It's not a real case of MS though since the brain is not as strongly affected of 5AR2 inhibition as the spinal chord. But I personally still think the brain is somewhat affected from peripheral neurosteroid inhibition although not as much as the spinal chord neurons.

This also explains why these neurological effects appear years after finasteride usage. It takes a longer period of time of allopregnanolone depletion for neurodegeneration to occur.

The symptoms of "brain fog" are definitely the same as demyelination of spinal chord motor neurons, as written in my first post. "


This theory is from Alex Miller who is a biologist (specialization track: neurology and neurological sciences). I have tried to find his contact info but have had no success. As you may know finasteride side effects are not well-known yet there are no direct scientific studies about this theory but there is strong evidence and arguments that support it, so anyone who conducts a study about this theory will prove well. Even using other scientific studies (Poletti et al. 2003), (William H. Theodore, MD; Clinical Epilepsy Section NIH Bethesda, MD) will reach to the same conclusion:

Here it is the theory that Alex Miller and others are supporting:

Before starting the research, I already knew that 5-alpha-reductase (5AR) has important functions in the central nervous system (CNS). So inhibiting it (by finasteride) might induce some side effects there. I will not address the possible sexual side effects but only the neurological ones. I will explain to you all what I have come up with so far. And guys: this is not looking good at all.

First of all, 5AR exists in two different isozymes: 5AR type 1 (5AR1) and 5AR type 2 (5AR2). 5AR1 is present mainly in the brain, muscle, liver and in sebaceous glands. 5AR2 is referred to as the "peripheral 5AR" since it is present mainly in the prostate, seminal vesicles, liver and hair follicles. Finasteride is a specific type 2 inhibitor and doesn't inhibit 5AR1 in significant amounts. But here comes something that not many people know: 5AR type 2 is also expressed in very significant amounts in spinal chord motor neurons, actually in similar amounts found in the prostate (Poletti et al. 2003) and could have (damn it!: WILL have) an effect there. What kind of effect this is, will be explained soon.

Something else, that many people don't know: Both isozymes of 5AR have more functions than just Testosterone (T) -> Dihydrotestosterone (DHT) conversion. They do the following conversions:

1. Testosterone -> Dihydrotestosterone
2. Progesterone -> Dihydroprogesterone
3. Deoxycorticosterone -> Dihydrodeoxycorticosterone

The latter two conversions are also inhibited by finasteride and so the production of neuroactive steroids is inhibited, since their metabolic pathway continues like this:

Dihydroprogesterone -> Tetrahydroprogesterone or also called Allopregnanolone.
Dihydrodeoxycorticosterone -> tetrahydrodeoxycorticosterone

These converions are catalyzed by an enzyme called 3-alpha hydroxysteroid dehydrogenase (3-alpha HSD).

You can read about these neuroactive steroids on wikipedia in order to get a rough idea about them:


Altough it states there, that Tetrahydrodeoxycorticosterone is synthesized by 5AR1 in the brain, this is only partially true since, as explained above 5AR2 is also present in the CNS namely in the motor neurons of the spinal chord.

Now we come to the REAL concern: The inhibition of Allpregnanolone production. Altough Allopregnanolone can be produced in the brain by 5AR1, the CNS is also dependent on peripheral 5AR2. I quote from "Implications of neuroimaging for the treatment of epilepsy":

"Allopregnanolone formed in peripheral tissues readily enters the brain where it acts to enhance activation of GABA. A receptors" (William H. Theodore, MD; Clinical Epilepsy Section NIH Bethesda, MD).

Now to repeat again: Finasteride definitely inhibits allopregnanolone production in spinal chord motor neurons where mainly 5AR2 is present and also reduces allopregnanolone levels in the brain and other parts of the CNS since these parts are dependent on peripheral 5AR2 conversion of progesterone to dihydroprogesterone which is then converted to allopregnanolone by 3-alpha HSD.

The question is what the result of long-term allopregnanolone depletion is. Before you have to understand what the myelin-sheath of neurons is. The axon of neurones (both, peripheral neurons and neurons in the CNS) are surrounded by an electrically insulating layer: the myelin sheath. This is vital for fast and efficient impulse propagation on the neurons. I don't want to go into details here. Fact is: Allopregnanolone has vital function in the myelination of neurons as seen in the following studies:

When you read these, you'll see that the metabolic pathway of progesterone (inhibited by finasteride...) is vital for myelination and other functions in the CNS. In fact there are dozens of studies about the effects of progesterone metabolism and allopregnanolone on myelination.

1. Progestins and antiprogestins: mechanisms of action, neuroprotection and myelination (Link)

2. Progesterone: Therapeutic opportunities for neuroprotection and myelin repair (Link)

Quote: "Progesterone and its metabolites promote the viability of neurons in the brain and spinal cord. ".

Oh damn it! Didn't we say just before, that the motor neurons of the spinal chord expresses mainly 5AR type 2 (inhibited by finasteride)? So there will be a negative effect of myelination there for sure!

2. Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of niemann-pick C mice (Link)

3. There is also a study of Goumari et al. (didn't find it on the net) that shows the function of allorpegnanolone in myelination. Quote: "... allopregnanolone accelerated myelination ..." (Ghoumari et al. 2003b)

Alright. Let's see what the effects of demyelination are: Read Myelin . The most worrying effect is again demyelination of the motor neurons of the spinal chord which will be the effect of long term finasteride use:

"Sub-acute combined degeneration of the spinal cord secondary to pernicious anaemia can lead to anything from slight peripheral nerve damage to severe damage to the central nervous system affecting speech, balance and cognitive awareness. When myelin degrades, conduction of signals along the nerve can be impaired or lost and the nerve eventually withers."

Do you see those symptoms? Speech is affected, balance and cognitive awareness. This is exactly what you call brain fog here. The question is wheter this effect is reversable if you take finasteride for years. I certainly hope so for my friend altough, you know, neurogegeneration can really be irreversible.

It has to be said, that these effects are of LONG-TERM use but probably WILL eventually happen after years of finasteride use.


Here there are some studies that talk about demyelination and the lack of Allopregnanolone:

1) http://www.springerlink.com/content/k540755q22168672/
Progestins and antiprogestins: mechanisms of action, neuroprotection and myelination

2) http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBG-4P0KP3F-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=958176063&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=37eaacdd1fe4dc713d703a481446a5a5
Progesterone: Therapeutic opportunities for neuroprotection and myelin repair

3) http://cat.inist.fr/?aModele=afficheN&cpsidt=17334014
Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of niemann-pick C mice


Sorry for the long post but I think it is necessary.




Michelle Rose

Help! I have thyroid resistance and can not find a doctor in the Cincinnati area, or Ohio in general who will take this issue on full force. I keep going into mild states of rhabdo and honestly feel like I'm going to die if this keeps up. Is there anyone in the Ohio area you know of that can help me?????
Michelle Rose
michelle underscore rose 27 at vzw dot blackberry dot net


Dr. Jacobs,

While the poster above has good intentions, I did not find his comments of "Don´t waste your time trying to find the causes of this severe problem" helpful. For the above poster to state "the real cause is demyelination of the motor neurons in the spinal chord" is simply conjecture which has not been proven, nor does it explain why so many men acquire secondary hypogonadism and and possibly androgen resistance post-drug.

While neurosteroid inhibition occurs on the medication, it would be expected to resolve upon discontinuation. This has been found to be true in studies where men given the drug developed depression, discontinued use, accepted reintroduction and relapsed into depression once again. In other words, 5AR2 was no longer inhibited and thus our problem likely does not stem directly from permanently inhibited 5AR2 (although it may be a factor, if proven true). Low levels of Allopregnanolone are correlated with GABAergic-mediated mood disorders, Alzheimer's symptoms and depression, while low levels of THDOC contribute to GABAergic anxiety and seizures. For the vast majority of men suffering permanent side effects from Finasteride, these issues generally clear up within weeks of quitting the medication, although there are always exceptions.

Additionally, while both neurosteroids are inhibited by Finasteride while on the medication, they are NOT implicated in the clinical manifestations of hypogonadism and androgen deprivation therapy such as muscle wasting, penile atrophy, decreased semen volume, gynecomastia, complete loss of libido and the various other physical symptoms these men exhibit post-drug, likely further compounded due to a skewed androgen/estrogen ratio which has been documented to occur from use.


As you have noted, acquired secondary hypogonadism from Finasteride use is a real-world result of the drug's many mechanisms of action. As you have also alluded to, the problem likely lies at the Androgen Receptor, or even more likely beyond the Androgen Receptor (ie, gene expression). This is where investigation into this problem needs to be focused.

As can be seen here, http://www.propeciahelp.com/forum/viewtopic.php?f=4&t=2763

... many ex-Finasteride users have low levels of 3a-diol G. Considering low levels of 3a-diol G are found in genetic syndromes of 5AR2 deficiency, as well as androgen metabolism disorders and androgen insentivity syndromes, provides further evidence that the problem is first and foremost androgen-related.

Wether this is due to a malfunctioning 3a-HSD enzyme, mutated/downregulated AR, or altered AR gene expression remains unknown without further testing... which thus far has not been possible due to lack of interest from the medical community.



What is ultimately required is a research study in a lab (as you have alluded to previously) to ascertain:

- AR CAG repeat differences or similarities in these men vs. those who never took the drug

- AR binding/mutation/dissociation tests

- AR post-translational modification or protein-protein interactions (gene silencing) via mass spectrometry protein profiling techniques.

- AR gene expression testing via Microarray test

- 5AR2 deficiency testing via genital skin fibroblast cultures, 3a-diol-G, 5a/5b urinary metabolite ratios, and molecular 5AR2 deficiency (gene mutation) testing



Regarding all of the above, thus far 2 men from Propeciahelp.com have gotten AR binding and dissociation tests done, both of whom were found to be normal. Even though this is a small sample size, it suggests DHT binding to the AR is not the issue. This could suggest a post-receptor defect, in that the issue lies downstream from the AR itself (ie, gene transcription / expression). Without testing, however, we will be no closer to answers.

Finally, as to how acquired androgen resistance (if this is in fact what is occurring to us) might have occured from the drug's use: it is well known that anti-androgens and 5AR inhibitors given during prostate cancer only cause the cancer to temporarily regress. Within months or years, most prostate cancers mutate to an androgen-independant state and become resistant to androgen deprivation therapy. It is postulated this could be due to androgen receptor mutation, AR overexpression and AR hypersensitivity, or changes in AR ligand binding due to the presence of a low-androgen (ie low Testosterone or DHT) environment from such androgen deprivation medications.

Since Finasteride instills a surrogate state of genetic 5AR2 deficiency (male pseudohermaphroditism) by reducing DHT levels by ~70%, and considering low androgen environments select for AR mutation, AR overexpression and AR hypersensitivity (which has been found to persist despite discontinutation of the medication in some cases), perhaps it is plausible that Finasteride use (via DHT inhibition) has induced such molecular changes in us / our Androgen Receptors, despite us not having prostate cancer at the time. From that point forward, even after quitting these changes persist at the molecular level, as the body has adapted to an environment of low androgen while on the medication.

As to how this could trigger acquired secondary hypogonadism while on or (more typically) within weeks of quitting the medication, I am at a loss -- however, upon return of DHT after quitting, perhaps the hypothalamus (via overexpressed/hypersensitive AR) perceives this flood of DHT as too much androgen in the body and thus lowers GnRH output (and by consequence, LH/FSH levels) to compensate, leaving these men with both secondary hypogonadism and an acquired form of 5ARI-induced, persistent androgen resistance.



Dr. Jacobs, thank you for your interest in this problem. As you well know the drug's asctions are multi-factorial, but the core of the issue must stem from an underlying pathology shared amongst all men suffering from this problem. It is only through a scientific research study on these men vs. those who did not take the drug that the source of this problem will be found.

Perhaps through your efforts and resources, such a study involving research scientists, specialists in the androgen receptor and molecular genetics can be coordinated and accomplished -- the results of which could shed groundbreaking new insights into the mechanisms of androgen metabolism, AR and 5AR function, implications of 5AR inhibition, and new diagnostic tests and treatments for men affected by these and other conditions (ie, CAIS, PAIS, MAIS, 5AR2 deficiency) as well as pharmacogenetic testing prior to taking anti-androgens/5AR inhibitors to determine potential negative outcomes from use.

I would be happy to discuss this topic further with you, if possible. Thank you for your time.




I am a 53 year old woman who recently was prescribed propecia for hair loss. My doctor said that since I was not going to have any more children it would be safe. After reading your blog, I'm concerned. I have noticed a higher level of anxiety in the past few weeks but have not noticed a significant change in libido. What are your thoughts please?

glen jeffreys

Dr Jacobs, can you explain the mental side effects, such as decreased emotion, lack of motivation and loss of libido, don't these point to a dopaminergic malfunction? maybe the cause could lye in a failure of the adrenal - dopamine system, which would explain, these symptoms could this be due to adrenal fatigue?


Is it possible that saw palmetto can have the same long term effects on the body that finasteride has?


I have only skimmed through the various comments, but "permanent" sexual dysfunction caused by finasteride seems to be reversible in a fairly prominent number of cases. Many of the cases seems to occur fairly early in the finasteride treatment as well, as well as being more occurrent in genetically linked groups. I think there is little doubt that the cause is a genetic predisposition. The real question should, in my opinion, be one of dosage, considered the long half times of Finasteride derivates in the blood.

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