Finasteride [5ARI] Induced/Associated Effects

[avanti]

Health Watch: Popular Drug Warning CBS Philly


PHILADELPHIA (CBS) – A grieving mother’s warning about a popular medication, taken by millions, that can cause devastating and long term side effects. 3 On Your Side Health Reporter Stephanie Stahl has exclusive details.

“I’m going to be living the rest of my life without my son,” said Rosemary of New Jersey. Her son Randy was just 22-years-old when he killed himself. His parents blame the hair loss drug PROPECIA. Randy was taking it because his curly red hair had started to recede.

“It is so not worth it,” said Rosemary.

The warning label says there can be sexual side effects, including lack of desire and difficulty achieving an erection. They’re supposed to go away when men stop taking the drug.

Not for Randy, he told his parents when he stopped taking PROPECIA the impotence continued along with deepening depression.

“He hated all the things that the drug had done to him. He hoped his family and friends would understand why he didn’t want to live anymore,” said Rosemary.

Randy and scores of other men have shared their devastating discoveries on propeciahelp.com. But they’re too embarrassed to show their faces.

One man told us, “It basically destroyed my life. It’s devastating. It’s terrible.

Another says, “It’s not worth it, if you can’t have a sex life. I feel like my twenties have been taken away from me, and it’s not fair.”

New research from Dr. Michael Irwig at George Washington University shows some men can have persistent sexual side effects lasting five years after they stop taking PROPECIA.

“The presence of persistent sexual side effects in young men who were previously completely healthy can really take a big toll on their life,” said Dr. Irwig.

PROPECIA works by altering hormones. Dr. Irwig suspects, in a small percentage of men, that can cause sexual dysfunction.

Merck, the maker of PROPECIA, says that study is flawed.

“They feel less than human because of it,” said Alan Milstein, a New Jersey lawyer. He is suing Merck, on behalf of several men who claim the drug ruined their lives.

“When something as essential as sexual pleasure is taken from you, it has a profound affect,” said Milstein. He says Merck was not adequately warning men taking PROPECIA about the potential for long term impotence.

“Whether that was done intentionally so they could make a lot of money and not scare people away, that’s going to remain to be seen as this lawsuit progresses,” said Milstein.

Randy’s parents say he tried therapy and different medications, but nothing worked.

“This is really the closest thing we have to a suicide note,” said Randy’s father. He saved his sons postings from the PropeciaHelp website.

“I’m really hoping that this drug kills me so I don’t have to do it myself. I don’t think my family and friends would ever understand suicide. But if they really knew what the meaningless ghostly hell I’ve descended into, then they would understand,” read Randy’s father.

Merck says it will vigorously defend the lawsuits.

Just two weeks ago, since we started working on this story, warning labels for PROPECIA in the United States were revised to include complaints about persistent sexual side effects.

But Merck stands by its studies saying once the drug is stopped the dysfunction goes away.

If you have any questions, be sure to contact your doctor.

 

[visionquest99]

Randy's story is heartbreaking. The effects of this drug are devastating.

RIP buddy.

 

[Mens Rea]

Anyone on these boards seeing improvements on there finasteride nightmare?

I have been off a year and a month now, and no improvement.

Same as you. I quit 17th March 2010 after using it for one year. Things steadily declined until December. Now things are just generally pretty shit (sexually) but i do get fluctuations.

I'm currently on arimidex. It helped at the start but things tailed off. I've got high hormones in just about everything: Testosterone, Estrogen and DHT. All either top range or above.

There's no way i should be having the sexual sides i have, with the hormonal levels i present. I just don't know. I'll continue to try and tweak but my best bet is a natural recovery.

So i've cut down on alcohol, fixed my diet and started more exercising. It's a long term plan that will hopefully garner some results.

That said im just back from a urologist yesterday. He checked me for prostatitus and candida and other infections. Negative. He just said id get better over time. How reassuring.

As i said, for now im still working on things and still pushing my endo for certain bloods (3adiolG and Reverse T3) but i've pretty much gave up on any treatment that will recover me over a short period of time.

In the interim, whilst i "recover over time" I've got cialis which i can take when i want. I'll take it maybe 2 days a week to give me modest boosting in my erections. That way i can atleast "get by".

At 25 this is all bullshit though but im trying to stay positive, because what's the alternative.


As for pregnenolone. It helped me for a few weeks too and then i stopped it (ran out). I was only using the 1% stuff. Im from the UK and don't have easy access to the stronger stuff but i do believe the 10% stuff with better vehicles (potentially along with T3) could be a potential valid treatment. I'll maybe look into that in the future.

I'm also still working with arimidex and considering proviron whcih i have at my disposal.

 

[Propeciahell]

Mens rea can u contact me re proviron for post finasteride syndrome (impotence).
Many Thanks,
PropeciaHell

 

[Madlib]

Proviron hasn't helped anyone. I have tried it.

 

[Deadballs]

If you have PFS all proviron will do is maybe give you a boost but then you will crash again. That is what happened to me anyway!

 

[sade]

Wouldn't supraphysiological doses of T work? This is what I have to do and I never took fin!

 

[Deadballs]

That's the avenue I may be going down if this next clomid run doesn't work!

 

[Madlib]

Are you doing the clomid with a doctor? taking clomid alone?

 

[Deadballs]

I am taking clomid alone. 25mg daily for 1 month! I primed myself for 2 weeks with very low doseage of arimidex (1mg per week) before hand as I took clomid for 4 days a while back and my balls shrank and I felt week and tired and irritable and libido dropped even further than it currently is.

I am seeing an endo though but it's like 3 months between sessions and I know as much as he does about treatments, probably more. I have waited nearly 2 years now so I decided, fuck it!

 

[Michael Scally MD]

Goldstein I. An Old Problem with a New Cause—5 Alpha Reductase Inhibitors and Persistent Sexual Dysfunction. The Journal of Sexual Medicine 2011;8(7):1829-31. An Old Problem with a New Cause—5 Alpha Reductase Inhibitors and Persistent Sexual Dysfunction - GOLDSTEIN - 2011 - The Journal of Sexual Medicine - Wiley Online Library

To the readers of your leading sexual medicine journal, please be aware of one more iatrogenic threat to men’s sexual health. We are becoming more and more aware of persistent sexual health problems occurring as a result of the use of 5 alpha reductase inhibitors, finasteride, and dutasteride, in a subset of patients. What is even more alarming is that in addition to persistent sexual issues, there are persistent central cognitive issues and concerns of persistent depression.

The 5 alpha reductase enzyme ALSO metabolizes progesterone to 5 alpha-dihydroprogesterone and deoxycorticosterone to 5 alpha-dihydrodeoxycorticosterone. And in the brain, the products of 5 alpha reductase inhibitors are transformed by another group of specific enzymes known as 3 alpha-hydroxysteroid dehydrogenases, which reduces 5 alpha-dihydrotestosterone to 3 alpha, 5 alpha-androstane 17b-diol (3a-diol), and 5 alpha-dihydroprogesterone to 3 alpha, 5 alpha-tetrahydroprogesterone (allopregnanolone). Similarly, 5 alpha-dihydrodeoxycorticosterone is further reduced to 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone. Theoretically, these important neurosteroid derivatives are UNNECESSARILY LOWERED (collateral damage) by 5 alpha reductase inhibitors for hair loss. These reduced important neurosteroid derivatives are thought to function in the central nervous system with important physiological functions including modulation of gamma aminobutyric acid type A receptor, sigma receptor function, nicotinic acetylcholine receptor, voltage gated calcium channels, and synaptic and brain plasticity. To translate into clinical terms, these physiological functions may impact mood, rhythm, stress, sleep, memory, anxiety, and sexual function.

 

[quenca333]

finasteride and brain

CNS Drug Rev. 2006 Spring;12(1):53-76.
A new look at the 5alpha-reductase inhibitor finasteride.
Finn DA, Beadles-Bohling AS, Beckley EH, Ford MM, Gililland KR, Gorin-Meyer RE, Wiren KM.
Source

Department of Veterans Affairs Medical Research, Portland Alcohol Research Center, 97239, USA. finnd@ohsu.edu
Abstract

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme 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.

PMID:
16834758
[PubMed - indexed for MEDLINE]

 

[1erCru]

Im not sure if I read the above study correctly but is it saying finasteride enhances GABA transmission?

 

[quenca333]

that's what I read

 

[Michael Scally MD]

M Duskova sent me a series of his publications on finasteride, which look very interesting. The studies focus on the effects on neurosteroid formation. Email me for the full-text articles.


Duskova M, Hill M, Staka L. The influence of low dose finasteride, a type II 5?-reductase inhibitor, on circulating neuroactive steroids. Hormone Molecular Biology and Clinical Investigation 2009;1(2):95-102. http://www.reference-global.com/doi/abs/10.1515/HMBCI.2010.010 (de Gruyter Reference Global - Hormone Molecular Biology and Clinical Investigation)

Background: Finasteride is a 5?-reductase inhibitor that has received clinical approval for the treatment of human benign prostatic hyperplasia and androgenetic alopecia. The treatment is practically without side effects, although some occasional cases of depression syndrome have been reported. 5?-Reductase is an enzyme responsible for the reduction of testosterone, progesterone or deoxycorticosterone to their 5?-reduced derivatives possessing anticonvulsant, antidepressant, and anxiolytic activity. Therefore, the formation of GABAergic neuroactive steroids is likely to be impacted by finasteride.

Objective: The objective of the study was to show how the treatment of premature androgenetic alopecia with low doses (1 mg/day) of finasteride influences the broad spectrum of steroids with potential neuroactivity.

Methods: A group of 12 men with premature androgenetic alopecia participated in the present study. The steroid hormone profile was determined for all individuals. Finasteride was administered for 4 months at a daily dose of 1 mg. After the treatment, the same hormonal profile was determined again.

Results: 5?-Reduced steroids, e.g., 5?-dihydrotestosterone, androsterone, epiandrosterone, 5?-androstene-3?,17?-diol, allopregnanolone, isopregnaolone, and some 5-ene steroids, such as dehydroepiandrosterone and pregnenolone, decreased gradually during treatment.

Conclusions: The decrease of 5?-reduced steroids, especially of allopregnanediol, dihydrotestosterone, and pregnenolone, is probably one of the factors responsible for the increased occurrence of depression in men treated with finasteride, even at low doses.


Duskova M, Pospisilova H. The role of non-aromatizable testosterone metabolite in metabolic pathways. Physiol Res 2010;60(2):253-61. The role of non-aromatizable testosterone metabo... [Physiol Res. 2011] - PubMed - NCBI

Dihydrotestosterone (DHT) originates via irreversible reduction of testosterone by catalytic activity of 5alpha-reductase enzyme and it is demonstratively the most effective androgen. Androgens influence adipose tissue in men either directly by stimulation of the androgen receptor or indirectly, after aromatization, by acting at the estrogen receptor. DHT as a non-aromatizable androgen could be responsible for a male type fat distribution. The theory of non-aromatizable androgens as a potential cause of a male type obesity development has been studied intensively. However, physiological levels of DHT inhibit growth of mature adipocytes. In animal models, substitution of DHT in males after gonadectomy has a positive effect on body composition as a testosterone therapy. Thus, DHT within physiological range positively influences body composition. However, there are pathological conditions with an abundance of DHT, e.g. androgenic alopecia and benign prostatic hyperplasia. These diseases are considered as risk factors for development of metabolic syndrome or atherosclerosis. In obese people, DHT metabolism in adipose tissue is altered. Local abundance of non-aromatizable androgen has a negative effect on adipose tissue and it could be involved in pathogenesis of metabolic and cardiovascular diseases. Increased DHT levels, compared to physiological levels, have negative effect on development of cardiovascular diseases. Difference between the effect of physiological and increased level brings about certain paradox.


Duskova M, Hill M, Hanus M, Matouskova M, Starka L. Finasteride treatment and neuroactive steroid formation. Prague Med Rep 2009;110(3):222-30. Finasteride treatment and neuroactive steroid... [Prague Med Rep. 2009] - PubMed - NCBI

Finasteride is the 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostate hyperplasia and androgenetic alopecia. The 5alpha-reductase is enzyme responsible for the reduction of testosterone to dihydrostestosterone, progesterone to dihydroprogesterone and deoxycorticosterone to dihydrodeoxycorticosterone, steroids modulating the action of gamma-aminobutyric acid on GABA receptors. These neuroactive steroids possess anticonvulsant, antidepressant and anxiolytic effects. The objective of the study was to determine the effect of finasteride therapy on a broad steroid spectrum in men with benign prostate hyperplasia. A group of 20 men with benign prostate hyperplasia was involved in the present study. Finasteride in the daily dose of 5 mg/day was administrated for 4 months. In all individuals, their hormonal profile of steroid hormones was determined before and after 4 months lasting finasteride treatment. Finasteride treatment resulted in a significant decrease all alpha-reduced and increase of most 5beta-reduced metabolites of testosterone and progesterone as well as in an increase of 7alpha-hydoxyderivatives, which are known as neuroactive steroids acting by modulation of GABAA and NMAD receptors in the brain. In the course of finasteride treatment the decrease of the concentration of circulating steroids with known inhibitory activity on GABA-ergic excitation in the brain is very probably an important factors contributing to the development of the symptoms of depression seen in some isolated cases of finasteride administration.

 

[quenca333]

So, does finasteride increase or decrease GABA?

 

[Michael Scally MD]

5?-Reduced Glucocorticoids - A Story Of Natural Selection

Glucocorticoids are steroid hormones synthesized in the adrenal cortex, which exert a plethora of effects in the body, ranging from modulation of metabolism and suppression of inflammation, to regulation of stress responses and neuronal function. These hormones are vital to health, most vividly demonstrated in disorders characterized by glucocorticoid deficiency or excess. Diminished glucocorticoid production, Addison’s disease, leads to critical illness and is life threatening if inadequately treated. The converse is seen in Cushing’s Syndrome, where excess glucocorticoid production manifests as insulin resistance, obesity, dyslipidemia, altered immune responses (e.g. impaired wound healing) and disturbed central nervous system activity (e.g. depression).

While endogenous glucocorticoids play a key role in many aspects of health and disease, synthetic exogenous glucocorticoids have become widely used therapeutically, predominantly as anti-inflammatory agents. Many synthetic glucocorticoid variants have been developed, aiming to maximize clinical utility through optimization of pharmacological properties. Despite their success in treating inflammatory conditions, synthetic glucocorticoids remain plagued by side effects wrought through widespread activation of the ubiquitous glucocorticoid receptors. Receiving glucocorticoids therapeutically incurs a dose-dependent rise in the relative risk of cardiovascular morbidity, with an increase of up to 3 fold amongst current users of high-dose glucocorticoids. The relative risk for any fracture in those using glucocorticoids is 1.33, and this increase in risk is particularly marked for vertebral fractures with a relative risk of 2.60.

5?-Reduced glucocorticoids have received little attention in terms of their biological activity, despite other 5?-reduced steroids being well recognized as active hormones. They are formed in many tissues where Glucocorticoid receptor (GR) is expressed and revisiting recent and previous literature allows one to propose a distinct profile of actions in comparison to the parent glucocorticoid. They appear weak regulators of metabolism but retain other biological actions of pharmaceutical interest.

A further avenue of interest in 5? reduced glucocorticoids relates to the common pharmacological inhibition of 5?Rs in clinical practice. 5?-Reductase inhibitors are used to treat benign prostate hyperplasia, a disease afflicting over half of elderly men. Although unlicensed, these drugs are also used to treat women with PCOS. It is possible these patients will develop an imbalance of parent and 5?-reduced metabolites, leaving them susceptible to adverse metabolic effects and inflammatory changes and effect more marked with dutasteride, a new dual 5?R inhibitor.

To date, there have not been any comprehensive metabolic studies in patients on these drugs. Greater understanding of the role of 5?-reduced glucocorticoids in health, disease and therapeutics will provide important insights into effects in patients on 5?-reductase inhibitors, as well as providing an exciting focus of research in the quest for novel selective glucocorticoid receptor modulators.

While 5?-reduced glucocorticoids present a potential prototype for drug design, a question remains about their role in vivo. In the many tissues where 5?-reductases are expressed, this enzyme will regulate the proportions of the parent steroid and the metabolite, potentially modulating the balance of metabolic and anti-inflammatory actions. Given the high expression of the isozymes in liver and rapid inactivation of 5?-reduced glucocorticoid by hepatic conjugation, circulating concentrations will be low, predicting paracrine rather than endocrine signaling. Therefore understanding the factors regulating the balance between parent and metabolite is crucial.


Nixon M, Upreti R, Andrew R. 5Alpha-Reduced Glucocorticoids - A Story Of Natural Selection. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2011/09/08/JOE-11-0318.abstract

5?-Reduced glucocorticoids are formed when one of the two isozymes of 5?-reductase reduce the ?4-5 double bond in the A-ring of glucocorticoids. These steroids are largely viewed inert, despite acceptance that other 5?-dihydro steroids, eg 5?-dihydrotestosterone, retain or have increased activity at their cognate receptors. However recent findings suggest that 5?-reduced metabolites of corticosterone have dissociated actions at glucocorticoid receptors in vivo and in vitro and thus are potential candidates for safer anti-inflammatory steroids.

5?-Dihydro- and 5?-tetrahydro-corticosterone can bind with glucocorticoid receptors but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the glucocorticoid receptor and recently the abilities of 5?-reduced glucocorticoids to suppress inflammation have been demonstrated in vitro and in vivo.

Thus the balance of parent glucocorticoid and its 5?-reduced metabolite may critically affect the profile of glucocorticoid receptor signalling. 5?-Reduction of glucocorticoids is up-regulated in liver in metabolic disease and may represent a pathway which both protects from glucocorticoid induced fuel dyshomeostasis and the concomitant inflammatory insult. Therefore 5?-reduced steroids provide hope for drug development, but also may act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5?-reductase inhibitors, drugs which are commonly administered long-term for the treatment of benign prostatic hyperplasia.

 

[D12]

In reading some of the recent clinical info posted on the effects of propecia, such as:


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.



it got me wondering about other drugs that affect GABA and if they can pose the same danger of permanent sexual side effects. Specifically, I was curious if anyone new if Gabapentin (neurontin) which is an anti convulsant and pain drug that is basically GABA, could cause something similar?

Lyrica (pregabalin) is another of these GABA related drugs.. Does anyone know of any clinical evidence that shows these affect the neurosteroids in the same way as propecia, or are they working so differently as to be irrelevant to this conversation?

 

[Madlib]

Nothing will fuck you up sexually like propecia and finasteride.

 

[D12]

I went and read some of that website propeciahelp.com and thats some scary shit. It makes me really wonder about all prescription meds they give us and how little do they really know and how much do they not tell us..

I've had libido problems ever since I got off Dilantin. I assumed it was from the new drugs I took Neurontin and now Keppra, but it makes me wonder if the dilantin or the other drugs could have done something that the docs just don't know about.

I've had the same experience of bringing up a problem to a doctor and having them question me like I am being paranoid or don't know what I am talking about.