Finasteride Warning, FYI

[Stef]

Hello All,

This just came my way at NORD, from a medical-legal online journal called AboutLawsuits.com.

Anyone considering using finesteride (aka "Propecia"), please take heed --

Propecia Sexual Problems May Last for Years After Use of Drug: Study

Posted: 13 Jul 2012 08:10 AM PDT

A new study appears to confirm the mounting concerns that sexual dysfunction caused by Propecia can pose a long-term problem for men who used the hair-loss drug, despite prior warnings provided by the manufacturer.

According to research published online by the Journal of Sexual Medicine on July 12, a George Washington University researcher found that most men who report sexual problems after using Propecia appear to show no signs of recovering, suggesting that the side effects might be permanent.

Propecia (finasteride) is a prescription medication that is marketed to help restore natural hair loss that occurs in some men. However, side effects of Propecia have been linked to sexual problems for some users, including reports of erectile dysfunction, decreased libido, genital shrinkage and problems with cognition. These issues have also been linked to severe depression and at least one man has reportedly committed suicide due to the Propecia problems.
Sexual Problems from Propecia May Be Permanent

Until recently, the warning label for Propecia suggested that sexual side effects caused by the medication were only temporary and typically resolve once the drug is no longer used.

This latest study looked at 54 men already diagnosed with persistent sexual issues after taking Propecia to see if the side effects would continue over a long period of time. The men involved in the test were otherwise healthy, young and had no previous sexual dysfunctions.

The findings indicate that after 9 to 16 months nearly all (96%) of the men involved in the study still reported sexual side effects from Propecia and 89% qualified as having a sexual dysfunction. How long they took Propecia and how long the sexual problems had lasted appeared not to be a factor.

The lead researcher, Michael S. Irwig, MD, of George Washington University?s Center for Andrology and Division of Endocrinology, concluded that in most men who suffer Propecia sexual dysfunction for longer than three months after their final dose of Propecia can expect those symptoms to continue for months or even years.
Propecia Warning Label Updated

In April 2012, the FDA announced that Merck had agreed to update the Propecia warning label in the United States to indicate that sexual side effects caused by the medication may be permanent, continuing even after the drug is no longer used.

Although Merck updated the warning label in several other countries several years ago to include reports that some men suffered persistent sexual side effects after the medication was discontinued, they continued to suggest in the prior warnings provided in the United States that problems reported during clinical trials resolved after the medication was discontinued.

Merck currently faces a growing number of Propecia lawsuits filed by men who continue to suffer from long-term sexual problems, alleging that the drug maker failed to adequately research the medication or warn about the risk of side effects.

Plaintiffs allege that if they had been provided with accurate information about the risk of long-term sexual dysfunction, they never would have chosen to take a prescription drug to help improve their appearance by restoring hair loss.


Stef

[Starsky]

Yes, thank you for your care. Thats the reason why i have not already tried it to lower the semen volume. I was thinking about it years ago as i suffered from hair loss but then I decided not to try: POIS + this crap is not good idea. POIS cure was for me important than a few hair on my head.

[demografx]

Stef, thank you for the finasteride/Propecia warning!

[Vincent M]

About Propecia, I'd actually be glad to get the sexual dysfunction side effect haha. However I wouldn't risk it because of the other more serious (in my opinion) side effects including the loss of cognition mentioned. I've read claims of persistent exhaustion and joint and muscle pains as well and I think some other side effects of the drug that appear to be more common than they should be.

In the past I've learned that attempting to reduce my sex drive with drugs isn't a good idea. When I took effexor for a couple weeks the lowered libido was a blessing for me, but the other side effects increased virtually all of my POIS symptoms.

I know my post here doesn't apply to most of our cases, but I guess it doesn't hurt to share it.

[Daveman]

About Propecia, I'd actually be glad to get the sexual dysfunction side effect haha. However I wouldn't risk it because of the other more serious (in my opinion) side effects including the loss of cognition mentioned. I've read claims of persistent exhaustion and joint and muscle pains as well and I think some other side effects of the drug that appear to be more common than they should be.

In the past I've learned that attempting to reduce my sex drive with drugs isn't a good idea. When I took effexor for a couple weeks the lowered libido was a blessing for me, but the other side effects increased virtually all of my POIS symptoms.

I know my post here doesn't apply to most of our cases, but I guess it doesn't hurt to share it.

On the contrary, I thnk it's very applicable. I've heard many here who seek reduced libido, and you help expose our problem, it's not just as simple as reducing libido.

I swear, that some day we'll find a cure that permits a full and enjoyable sex life with very few restrictions. Having seen that it IS possible ableit only in some, it still shows, that IT IS POSSIBLE.

[Nightingale]

I SAW THIS!! I was watching TV on vacation last week and heard this and it caught my attention, especially the part about "mental fogginess."

I've learned that the main cause of male hair loss is Prostoglandin D2 (PGD2) in high concentrations in the scalp.  PGD2 is the SAME THING that causes niacin's flush!  It doesn't explain a whole lot, but I think that it might tie POIS to these Propecia side effects.

Here is the news report: http://www.youtube.com/watch?v=mHQMjZUTna8

What's confusing is that Propecia doesn't work directly on PGD2 but rather on a complex form of testosterone.  Still, this doesn't mean it's not affecting PGD2.  I wonder if the doctor in this video would be interested to hear from us?

[Daveman]

I'm sure he would......

[fernab]

Hi all,

This comment from dopamine about 'PFS' (Post finasteride syndrome) draw my attention powerfully.

One of my POIS symtoms is feeling strong palpitations. They are very particular palpitations, because I feel them with a strange difficulty for breathing. I mean, these palpitations are very characteritic. And they are totally different to the ones you feel when you stop suddenlly after a sprint when running, for instance. Or to the ones you feel when someone hits you with a big scare. Completely different.

And, in my case, I used finasteride during two complete years. After which I decided to stop taking it. And i would swear that a few months after I stopped It, I felt for the first time in my life, those characteritic palpitations. Without any other POIS symtoms.

What I am trying to say here, is that maybe, side effects of using finasteride for a long period may have any relation with POIS itself. Finasteride if i am not wrong can cause on the long term hormonal problems. And curiously, hormonal imbalance is a possible cause for POIS.

Of course, this is only a suspicion.

[Mr_GG]

I developed POIS at the same time that I was taking finasteride (5 years ago), and I suspect that I might have post-finasteride syndrome (PFS).

Does anyone else think PFS might have brought on their POIS?

Does anyone have any ideas about how these two syndromes might be related?

[drop247]

Yes, I also started having POIS at the same time I used Propecia.

[Prospero]

Someone tells me: "Finasteride upregulates ERa [estrogen receptors] and permanently messes up with neurosteroids. There were a lot of guys with POIS after finasteride usage and with PFS."

[Progecitor]

PEA (Palmitoylethanolamide) and possibly other PPARA agonists are potential treatments for post-finasteride syndrome.

We report two cases of infertile patients with azoospermia or severe oligospermia who showed significant improvements in sperm concentrations 6 months after the discontinuation of finasteride. In one case, improvement in semen parameters prevented the need for testicular biopsy and corrected the azoospermia. Stopping finasteride in the infertility population may improve semen parameters, and may allow for less invasive fertility treatments.
https://www.sciencedirect.com/science/article/abs/pii/S001502820703169X

Since 5a-dihydrotestosterone (5a-DHT) plays a key role in erectile physiology, including activation of nitric oxide synthase (NOS) and increasing blood flow in penile tissue, inhibition of 5a-Rs by finasteride or dutasteride contributes to erectile dysfunction (ED). Studies in the animal models demonstrated decreased biosynthesis and circulation of 5a-DHT, reduced expression and activation of endothelial (eNOS) and neural (nNOS) nitric oxide synthases, thus attenuating penile tissue relaxation and resulting in ED. In addition, absence of or reduced levels of 5a-DHT result in penile trabecular smooth muscle cells death concomitant with increased deposition of connective tissue leading to alterations in penile tissue histoarchitecture and impeding its compliance, thus, contributing to ED. The consequence of these pathophysiological changes is fibrosis (scarring) of penile tissue, leading to poor tissue compliance, venous leakage and ultimately ED.
Indeed, several studies have assessed the concentrations of neuroactive steroids in cerebrospinal fluid (CSF) of patients who were former finasteride users and exhibited persistent symptoms. These studies demonstrated a significant reduction in 5a-DHT concomitant with increased testosterone and 3a-diol derivatives and decreased progesterone metabolites such as 5a-dihydroprogesterone (DHP) and 5a, 3a, tetrahydroprogesterone (5a, 3a, THP; allopregnenolone) concomitant with increased levels of substrate precursor, such as pregnenolone. These findings suggest that alteration in neuroactive steroids, may be associated with depression symptoms in patients who were treated with finasteride and/or discontinued finasteride use.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0015028219325993

Allopregnanolone (Allo) can be produced de novo from progesterone in glutamatergic neurons of the cortex, hippocampus, and basolateral amygdala by the dual action of 5a-reductase type I (5a-RI) and 3a-hydroxysteroid dehydrogenase (3a-HSD). Given that PPARA is widely distributed in glutamatergic corticolimbic neurons, it is conceivable that PPARA activation by PEA or other PPARA agonists (e.g., fenofibrate) may induce Allo biosynthesis in corticolimbic neurons, which are involved in the regulation of emotion.
Hence, it is conceivable that PEA-induced Allo and Allo-S upregulation may act in concert, on one hand by potentiating GABAA receptor–mediated inhibition, and on the other by inhibiting NMDA-mediated excitatory neurotransmission. In kind, recent findings have shown that PEA improves neurological (e.g., normalization of astrocytic function and glutamatergic transmission) and behavioral abnormalities in animal models of PTSD, traumatic brain injury, and Alzheimer’s disease.
In SI mice, decreased Allo levels correlate with the downregulation of the rate-limiting step enzyme 5a-RI in cortical and hippocampal pyramidal neurons. This conforms to human studies that show that 5a-RI is downregulated in the prefrontal cortex of depressed male patients. In PTSD, a gender-dependent disruption in the Allo biosynthetic enzyme pathway was found at the level of 3ahydroxysteroid dehydrogenase in women and 5a-R (5a-RI and II could not be differentiated) in men. Our study shows that PEA normalizes the decreased 5a-RI hippocampal expression in SI mice; we did not, however, investigate possible parallel effects on 5a-RII—a potential focus for future studies.
Remarkably, in our studies, the effects of PPARA agonists on neurosteroidogenesis appeared 1 hour after administration. This relatively fast effect could be supported by the evidence that activation of PPARA by agonists induces the upregulation of “early response genes,” including Fos, Junb, Jun, Jund, and Myc, which can be activated and transcribed within minutes, without requiring de novo protein synthesis.
https://www.researchgate.net/profile/Graziano-Pinna/publication/331078884_Stimulation_of_PPAR-a_by_N-palmitoylethanolamine_engages_allopregnanolone_biosynthesis_to_modulate_emotional_behavior/links/5cf54264a6fdcc847501a0dc/Stimulation-of-PPAR-a-by-N-palmitoylethanolamine-engages-allopregnanolone-biosynthesis-to-modulate-emotional-behavior.pdf

These peripheral or secondary effects have undesirable consequences that are collectively becoming known as Post-Finasteride Syndrome. Symptoms range from minor to severe. Physical effects can include chronic fatigue, gynecomastia (the development of breasts), muscle atrophy, thinning skin, and penile and scrotal shrinkage. Sexual changes include: decreased libido, intermittent erectile dysfunction, and impotence. Cognitive effects include: a difficulty in maintaining attention and an overarching “brain fog.” Psychological effects also include emotional sensitivity, depressed affect, and excessive anxiety leading to functional decline.
Depression has also been associated with the dysregulation of neurosteroids and androgen deficiency.
Finasteride is well tolerated because the side effects are extremely rare, and even when they occur due to increased Oestrogen levels, caused by partial conversion of testosterone in estradiol through the aromatase enzyme, they become easily reversible after suspension of the drug. The increased Oestrogen levels can lead to problems like water retention, adiposity, Gynecomastia and increased risk of breast cancer infection, while low levels of DHT can lead to sexual dysfunction (reduced libido, reduction in amount of ejaculated semen and erection problems). Depression, ocular symptoms, alterations in lipid metabolism and increased cardiovascular risk, have also occasionally been reported.
However, there is a drug called Dustasteride is currently being studied to treat Androgenic Alopecia (AGA). It is found to be 3 times stronger as Propecia in inhibiting type II 5-alpha-resuctase isoenzym and 100 times stronger in inhibiting type I.
Androgens, especially testosterone increases the libido. So any drug, which interferes with the action of
androgens, is therefore assumed, by the layperson, to induce impotence. However, the precise role of androgen in penile erection needs to be fully elucidated. Even an individual with low testosterone levels can achieve erection, also, androgens, visual, olfactory, tactile, auditory, and imaginative stimuli influence the libido. The penile erection is mainly under the control of parasympathetic nervous system. Ejaculation and detumescence require an intact sympathetic system.
The enzyme, 5a-reductase converts testosterone to DHT and exists in two isoenzyme forms: type I is predominant in liver and type II is predominant in prostate, seminal vesicles, epididymes, hair follicles, and liver.
The only causal relation between Finasteride and sexual adverse effects is decreased ejaculatory volume because of predominant action of DHT on prostate.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Assessing+the+quality+of+life+and+health+outcomes+of+Androgenic+Alopecia+patients+using+Propecia&btnG=

Here, we advance the concept that blockade of 5a-reductases by finasteride or dutasteride in a mechanism-based, irreversible, inhabitation of 5a-DHT biosynthesis results in a novel state of androgen deficiency, independent of circulating testosterone levels.
We suggest that long-term use of finasteride and dutasteride may be associated with health risks including NAFLD, IR, T2DM, dry eye disease and potential kidney disease.
We have advanced the hypothesis that irreversible inhibition of 5a-Rs by finasteride or dutasteride may interfere not only with the metabolism and clearance of androgens and glucocorticoids but also impedes downstream signaling of androgens and glucocorticoids via their downstream receptor signaling and therefore adversely affect cellular metabolic function.
Dutasteride resulted in increased blood glucose, glycosylated hemoglobin A, total cholesterol, and low-density lipoprotein cholesterol levels. In addition, dutasteride treatment increased activities of liver alanine aminotransferase and aspartate aminotransferase, suggesting dysregulation of liver metabolism.
Androgen deficiency produces pathophysiological changes manifested in reduction of tear production and evaporative dry eye conditions.
Finasteride treatment increased the expression of B-72, interleukin (IL)-1B, IL-4, IL-6, IL-10, matrix metalloproteinase-8, Fas ligand, tumor necrosis factor (TNF)-a and metalloproteinase inhibitor 1 levels in the lacrimal gland of the dry eye model.
Finasteride also altered the apoptotic/proliferating ratio of nephron cells and the increased lymphocytes infiltrations into the area of pathologically altered convoluted tubules were accompanied by impaired androgen/estrogen homeostasis.
The wide expression and distribution of 5a-Rs in many tissues and organs suggests that although T is the main circulating androgen, its conversion to the high affinity 5a-DHT in many of these tissues is responsible for regulating tissue and cellular metabolism and function. Binding of 5a-DHT to AR results in activation and transformation of the AR into a higher affinity complex for DNA and induces its translocation from the cytoplasm to the nucleus where it interacts with the androgen response elements. This high affinity binding to a specific DNA sequences, result in recruitments of AR co-activators or co-repressors, resulting in regulating specific gene expression. This results in changes in cellular metabolism and function.
Reduction of spermatogenesis progression is impaired in men lacking 5a-R type 2 isozyme, suggesting that 5a-DHT is critical for spermatogenesis, as well as the structure of seminiferous tubules/spermatocysts and Sertoli cells are affected by loss of 5a-DHT, since the Sertoli cells support germ cells' development, and the structure of the seminiferous tubules concomitant with maintenance of the blood-testis barrier.
A third example for the relevance of 5a-DHT instead of total T is the effects of 5a-DHT on scalp hair growth. In absence of 5a-DHT baldness pattern was observed in men as determined in men with mutations in the 5a-R type 2 gene resulting in no expression of 5a-R type 2 enzyme even though there were not changes in total T levels. In the scalp, the presence of 5a-DHT induces hair miniaturization by converting terminal hairs into vellus hairs. This specific 5a-DHT-mediated biological event prompted the development of finasteride for treatment of AGA.  A fourth example is the recent observations that treatment of animals with finasteride or dutasteride results in dry eye disease within a very short period of time.
Therefore, inhibition of 5a-DHT biosynthesis by synthetic inhibitors acting via a mechanism-based (irreversible) inhibition of 5a-RS (suicide substrates) induce a novel form of tissue specific androgen deficiency and results in pathophysiological conditions that are not fully recognized.
In addition, since finasteride and dutasteride act via a mechanism-based inhibition (slow dissociation rate) rendering the reaction nearly irreversible, once bound to the active site, finasteride and dutasteride are tightly bound to the enzyme resulting in inactivation of the enzyme. Furthermore, with the advent use of dutasteride which inhibits both types, this drug brings about complete inhibition of both isozymes.
Traish et al have advanced a framework by which androgens modulate mitochondrial function. In this schema, the authors suggested that androgens increase the expression of PPARG coactivator 1a, which in turn increases mitochondrial transcription factor A (Tfam) expression as well as mitochondrial biogenesis. The increase in mitochondrial biogenesis increases levels of nuclear respiratory factor 1, which in turn increases oxidative phosphorylation. Androgens increase Tfam expression as well as serine-threonine kinase (Akt) phosphorylation, both of which decrease apoptosis leading to an increase in oxidative phosphorylation. Androgens stimulate lipolysis and down-regulates lipoprotein lipase activity and increases expression of fatty acid-binding protein leading to an increase in fatty acid oxidation and in oxidative phosphorylation. Androgens increase expression of pyruvate dehydrogenase, which increases production of oxaloacetate and acetyl-CoA leading to a stimulation of the tricarboxylic acid cycle (TCA). Androgens also increase expression of succinate dehydrogenase and aconitase, also upregulating TCA and increasing oxidative phosphorylation. Finally, androgens increase the expression of cytochrome c oxidase, which leads to an increase in oxidative phosphorylation. The increase in oxidative phosphorylation leads to a decrease in reactive oxygen species and an increase in insulin sensitivity. Yialamas et al have demonstrated that acute androgen withdrawal reduces insulin sensitivity in young healthy men with idiopathic hypogonadotropic hypogonadism. The acuity T deficiency and absence of changes in BMI or leptin levels suggest that androgens modulate insulin sensitivity in the absence of apparent or detectable changes in body composition. Pitteloud et al demonstrated that low T levels were associated with an adverse metabolic profile and proposed a novel unifying mechanism that low T levels impair mitochondrial function and promote insulin resistance (IR). T deficiency may promote IR by altering fatty acid metabolism and reduced expression of genes involved in oxidative metabolism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308241/

[drop247]

Thank you so much for posting that. I've ordered some Palmitoylethanolamide to trial.

[Progecitor]

Thank you so much for posting that. I've ordered some Palmitoylethanolamide to trial.

Well I just hope it helps!
Anyway I saw you mention in a post that another 5a-reductase, namely fenugreek helped you which makes me wonder as it seems contradictory. Others have also pointed out that saw palmetto is another 5a-reductase. Have you tried saw palmetto and if so have you had any positive experience with it as well?
In my case 5a-reductase probably doesn't play a big role as fenugreek was not really beneficial. A few years ago I also tried saw palmetto, but I don't remember any major effect. However I also have sparse hair on my forehead with vellus hairs in between. I always thought it was a genetic issue and well it could be, but it probably means I have a high level of 5a-DHT in my scalp.
I also took some silicon dioxide capsules a few years ago and I think my hair was much stronger and the vellous hair also seemed to grow somewhat if I remember well. It didn't help my POIS however.
By the way I recently tried the GABA supplement and it proved to be moderately beneficial, although I couldn't perceive any benefit on depression and it mainly worked as an anti-inflammatory or pain reducing agent. I could best compare its effectiveness to niacinamide (B3).

[drop247]

I haven't tried Saw Palmetto recently, no. I suspect Fenugreek helps my POIS not because of its 5AR inhibition but because of its mast cell stabilizing flavonoids. I'm starting to trial the palmitoylethanolamide and have some encouraging intial results, again I suspect due to its mast cell stabilizing properties. I will update if I achieve significant improvement from it.