Part 1: Propecia and persistent sexual side effects
I recently had a patient, let’s call him Ed, come to me because he was experiencing erectile dysfunction that began while taking finasteride (Propecia) for male pattern baldness. When his sexual symptoms began, he immediately stopped the finasteride. Six months (and many Google searches!) later and he still had ED, which he was convinced was due to his previous use of finasteride. He told me that he didn’t just have ED, he had also lost sensitivity in his penis and was experiencing anxiety and low libido. Oh, and he had become incredibly depressed, sometimes even suicidal.
According to the Post-Finasteride Syndrome Foundation (www.pfsfoundation.org), my patient Ed is not unique. The PFS website notes that more than 16,000 finasteride-associated adverse drug reactions have been reported worldwide. Most alarming, their website claims 63 known suicides have been directly caused by finasteride. “Men under the age of 40 who use finesteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia,” says Dr Michael Irwig, MD, Attending endocrinologist at Beth Israel Deaconess Medical Center.
In 2012 more than 1100 men brought a lawsuit against Merck, the makers of Propecia (trade name for finasteride 1 mg tabs), stating that Merck failed to adequately warn of the potential for Propecia to cause persistent sexual problems. Side effects named in the Propecia lawsuits include erectile dysfunction, decreased libido, reduced ejaculation volume, genital shrinking, infertility, cognitive impairment and depression. Although Merck noted that 3.8% of men taking Propecia experienced sexual side effects during their clinical trials, their original label said that the symptoms resolved in “all men” once they stopped taking the drug. In 2018, Merck agreed to pay a (measly!) lump sum of $4.3 million to be divided among 500+ of the plaintiffs, but several lawsuits are still ongoing. One such lawsuit, discussed in a Reuters investigation, was brought by a Park City, Utah woman (Pfaff) who blames her husbadn’s suicide (secondary to insomnia, sexual dysfunction and depression) on Propecia.
“We do crazy things for vanity. But if we are going to do that, we should know what the risks are,” Pfaff said. “I’m pretty sure if John knew he would poison his body, he would be bald.”
This all sounds rather damning and ominous, but, as with many medical dramas that play out in the media and online, one has to examine what parts of this story are real, supported by solid scientific evidence and what parts are the theories of a few frustrated people that have bounced around the echo chamber of the internet for so long they now have an air of legitimacy to them?
I’ll go through some of the science and literature that supports the possibility of persistent side effects after finasteride use. And, for the record, the possibility of Post Finasteride Syndrome is being acknowledged by more and more clinicians and scientists. But, the clinical studies that support the possibility of persistent side effects are of low to medium quality and many of the studies are observations, based on self-reporting of the symptomatology by the patients, which can be misleading. Also, several good clinical studies have shown no evidence that finasteride causes persistent side effects.
And, then there are some bizarre studies, such as the FAERS Data review, which quantified reports made to the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding post-finasteride syndrome complaints. In their review, they noted that more adverse events were reported at the 1 mg dose (taken for male pattern baldness, generally in younger men) than at the 5 mg dose (taken for prostate disease, generally in older men), including higher numbers of dermatologic, metabolic, sexual, psychological and neurological complaints at the lower dose. Why on Earth would the young, healthy guys on lower doses be more prone to having side effects than older guys who are taking higher doses of the medication? One thought – maybe the young, male-pattern-baldness guys are spending more time online reading about all of the side effects they’re supposed to have?
The idea of a “nocebo” effect shouldn’t be dismissed here. The opposite of placebo, nocebo is when a patient develops side effects from a medication because those side effects were suggested to him as a possibility. In one study on finasteride, for example, 9.6% of patients who were not counseled by their physician about the potential for side effects ended up with erectile dysfunction, whereas 30% of the patients who were counseled by their physician about the potential for side effects ended up with ED. That’s the nocebo effect and it’s as real with drugs affecting erectile function as anything else – maybe more so because there is such a strong psychological component to getting and maintaining a stellar erection. “It’s all in your head” is referring to BOTH heads, in this case. They’re both important.
We’ll talk more about this “post-finasteride syndrome” but first, what is finasteride? Finasteride is a medication that was originally approved for men with symptoms of enlarged prostate, but was later approved, in smaller doses, to treat androgenic alopecia (male pattern baldness). Propecia is the trade name for 1 mg finasteride tabs (while Proscar is the 5 mg version, approved for benign prostatic hypertrophy, BPH). Prior to Propecia becoming generic, it was really expensive so many men would buy the 5 mg tabs and cut them into fourths, taking 1.25 mg daily for hair loss.
Finasteride is an inhibitor of an enzyme called 5-alpha-reductase (aka: 5aRI), which blocks the conversion of testosterone to dihydrotestosterone (DHT). Male pattern baldness is known to be caused by a sensitivity of the hair follicles to DHT, so if this hormone can be blocked, it can help the hair follicles stay healthy and intact. And, when it comes to hair, finasteride really does work. More than 80% of men who take finasteride will see preservation of their current hair and about 66% will see significant regrowth within 2 years. Compare that to Minoxidil 5% (Rogaine), which is applied topically and only helps about 50% of men, and you’ll see why Propecia is currently being prescribed for more than 9 million men in the U.S. each year.
Finasteride reduces systemic DHT production by about 70% once it reaches steady state. A newer drug called dutasteride (Avodart) blocks both type 1 and type 2 5-alpha-reductase inhibitors, meaning a 90% reduction in DHT production. Dutasteride, approved for prostate disease, has been used off-label for male pattern baldness (apparently with even better results than finasteride), but, as we’ll see below, this turbo-blocking of DHT might not be the best idea for the average Joe.
Before we get too deep into the science weeds (because we will – we have to!) let me tell you that I’ve generally been a friend of finasteride. In fact, until recently, I’d recommended oral finasteride for most of my male pattern baldness patients as one of the tools in their proverbial toolkit. Yes, I understood that about 2-4% of men experience sexual side effects with finasteride, but most of my patients accepted that low level of risk and most of them have never had any problems. My own husband has been taking finasteride for over five years and has never had an issue. I know hair transplant surgeons and dermatologists who hand finasteride out like candy and they generally say the same thing.
And yet…. There are patients like Ed. Young, healthy men who seem normal and not prone to hyperbole who SWEAR that their symptoms started after taking finasteride. AND NEVER WENT AWAY. This is the part I have a hard time wrapping my head around – why would there be side effects from this medication that continue for months (or years) after the medication was stopped? It doesn’t make sense, right? Finasteride has a half-life of 5-8 hours. Even if you account for the slow accumulation that can happen after multiple doses, we know that finasteride only suppresses DHT production for about 4 days. Logically, this means that whatever side effects you were having due to low serum DHT levels should be resolved within a week or two after stopping the medication, right?
A study by Kiguradze in 2017 looked at electronic medical records of more than 11,000 men who had taken 5-alpha-reductase inhibitors (such as finasteride) to see how many (if any) of them developed persistent erectile dysfunction (PED), defined as erectile dysfunction that persisted for at least 90 days after stopping the medication. They found that while only 4.4% of men developed erectile dysfunction, 31% of the symptomatic men still had ED 90 days after they’d stopped the medication. Factors that seemed to increase the likelihood of developing persistent ED (PED) were advanced age, prostate disease, longer duration of 5aRI use (more than 205 days) and NSAID use. Higher doses (ex 5 mg finasteride) was not a significant risk factor for PED when compared to lower doses (ex 1 mg finasteride).
Another study, which questioned symptomatic men who were more than 3 months out from stopping finasteride, note that the most common symptoms reported were decreased libido (in 94%), ED (92%), decreased arousal (92%) and difficulty achieving orgasm (69%). Other common symptoms mentioned by these men included fatigue, skin changes, breast enlargement, decreased memory and attention, anxiety and depression. Interestingly, many of these men didn’t have symptoms while taking the medication, but noted problems after they stopped taking it.
Let’s start with the sexual side effects because these are the ones that are the most supported by the literature. Testosterone is produced by the Leydig cells in the testes then released into the circulation, where it gets taken up by different tissues. If 5-alpha reductase is present, a portion of testosterone gets turned into DHT. Both DHT and testosterone are androgens, but DHT is the more potent of the two. We know from many preclinical (animal) studies as well as human studies that testosterone and DHT are both involved in the creation (if you will) of an erection. Not only are these androgens necessary for the signalling of an erection, they are also needed to keep the penis structurally sound over time. If a man has very little testosterone and very little DHT, he will likely experience metabolic and structural imbalances in the corpora cavernosa of the penis (which are the tubes that fill with blood during an erection) that results in venous leakage and erectile dysfunction. This is not disputed.
The question is, what happens if you have testosterone, but not much DHT? Does that affect the quality of one’s erection? There’s very little human data on this, but there are some rather compelling rat studies that looked specifically at what happens when rats are given 5aRI’s such as finasteride (thus blocking DHT, but not testosterone). In one study by Zhang (2013) rats were given 5aRI for 16 weeks then compared to untreated rats. In the drugged-up group, their little rat penis’ cavernosal nerves didn’t respond as well to electrical stimulation, meaning that those rats suffered in the erection-having-department. When they looked inside said penises, they found that the rats given the 5aRI’s had a 22% decrease in the weight of their corpus cavernosum (the tubes that fill with blood during an erection actually lost volume!) and that the smooth muscle cells of the corpora cavernosa had been replaced by collagen (not a good thing because it’s not as elastic and expansive as the normal smooth muscle cells). They also noted less autophagy and more apoptosis in the drugged rats as well as increased injury to mitochondria in the cavernosal smooth muscle cells. All of this means that the 5aRI drug, which blocked DHT, resulted in structural changes that lead to erectile dysfunction in these rats after just 16 weeks.
In another study, rats who had their DHT production blocked were noted to have more disorganization of the collagenous fibers of the tunica albuginea compared to normal rats. The tunica albuginea is the white membrane that surrounds the spongy corpora cavernosa. A strong, supportive tunica albuginea is required to trap blood in the penis, thereby allowing for sustained erections. As you might imagine, a structurally-unsound tunica albuginea is a recipe for erection disaster because the blood doesn’t stay trapped and instead leaks right out before anybody is ready for it to do so.
Another similar study (Oztekin et al) looked at giving dutasteride (the stronger of the 5aRI’s) to rats. Rats were fed the drug for 6 weeks and then there was a 2 week wash-out period before they were evaluated. Just like in the Zhang study, the drugged rats had seriously weak erections (lower intracavernosal pressure after stimulated) compared to the placebo group. They were also noted to have the same changes in the corpora cavernosa, as well as decreased neuronal nitric oxide synthase production, “suggesting that dutasteride induces altered gene expression in the corpus cavernosum”. These effects were still seen after being off of the drug for 2 weeks.
In a study on human men by Di Loreto et al samples of foreskins from men complaining of post-finasteride sensory changes (such as numbness) were compared with the foreskins of men without prior finasteride exposure. Despite being off the finasteride for at least 6 months, the foreskin dermal cells of the finasteride-treated group contained significantly higher concentrations of androgen receptors than the untreated men’s foreskins. How the androgen receptors are related to things like penile skin numbness is unclear, but the fact that the foreskin of these men was notably different histologically compared to other men’s supports the idea that perhaps this drug is affecting the skin itself in a way that we don’t understand. The authors discussed their findings by saying, “Since finasteride inhibits T conversion into DHT, which is responsible for most androgen activity, it is plausible that prolonged finasteride use in predisposed individuals could stimulate the effects of aging in young men.”
Perhaps these studies are giving us a clue as to why some men have persistent erectile dysfunction after finasteride. Yes, the DHT levels in the body will return to normal after a man has been off finasteride for several weeks, but if the drug caused structural damage to the nerves, smooth muscle cells, skin and tunica albuginea of the penis, that damage may take time to resolve. Or, as Di Loreto went on to say in his study, “...it is tempting to speculate that patients could still suffer from adverse sexual effects several months or even permanently after finasteride discontinuation because of aging effects caused prematurely by androgens deprivation, namely by artificially reduced DHT concentrations.”
The difficulty of all of this, of course, is that most men don’t experience ANY side effects at all. About 97% of men pop their daily Propecia and go about their lives without ever thinking about how it’s affecting their penis (and, presumably, it’s not). Unfortunately, at this time there are no known predictive factors for the risk of developing of PFS. Well, unless you consider some of the more strange ideas put forth in the last few years. Motofei et al, for example, suggested that right-hand dominant homosexual men were at the highest risk for developing persistent sexual side effects after finasteride based on the rationale that sex hormones, sexual orientation, handedness and cognition might all be related and have to do with specific lateralization (sides) of the brain. Another theory involves measuring the ratio of a man’s 2nd to 4th finger (2D: 4D ratio – this is a real thing) to determine whether he was exposed to higher androgens before birth. How this relates to finasteride use later in life is unclear. But this is something that has literally been discussed as a way to predict which men might be more susceptible to post-finasteride syndrome. WTF? How have we come to this?
Although the sexual side effects of finasteride are the most widely discussed (and debated), gynecomastia and prostate concerns top the list of widely-acknowledged-by-the-medical-community adverse effects of 5-alpha-reductase inhibitor use.
Gynecomastia (enlarged breasts) is a relatively common side effect of 5aRI’s, especially in older men. Even the large meta-analyses that readily disregard the persistent sexual and psychiatric side effects admit that a few quality studies support the idea that gynecomastia is a legitimate concern in some men. The reason is likely because more testosterone is being turned into estrogen through aromatization pathways (since it’s not being turned into DHT via 5-alpha reductase). Along the same lines, there is some evidence (not as good) that higher doses of finasteride and dutasteride can increase the risk of breast cancer in older men.
Another frequently-touted concern with finasteride involves prostate cancer. It is known that finasteride artificially decreases serum levels of PSA (prostate specific antigen) by about half. So, in a man taking finasteride (even if just for hair growth), the PSA level obtained by his doctor through blood tests needs to be doubled to give a more correct representation of prostate cancer risk. Most doctors know this, but men taking finasteride should still remind their physician that they’re taking finasteride because if the PSA is not treated appropriately, physicians could miss a key early warning sign of prostate cancer. There have been numerous studies looking at finasteride and prostate cancer risk and most of them do not support that finasteride increases such risk but it is known that men taking finasteride may develop higher grade prostate cancer (diagnosed later) than men not taking finasteride, at least partially due to the sneaky effects finasteride has on PSA.
Finally, I will leave you with the idea that 5-alpha reductase inhibitors are not only found in the genitalia of men, they are also found in the brain (Wait, what?!). There is fascinating research that has come out in the past few years about how drugs like finasteride might be leading to a variety of neuro-psychiatric illnesses and problems. In Part II of The Finasteride Story we’ll learn about neurosteroids and how 5-alpha-reductase inhibitors affect their production, potentially explaining the myriad of complaints in many post-finasteride syndrome patients that have been thus far swept under the rug.
Then, in Part III – Alternatives to oral finasteride that may work just as well for hair growth. And, potential under-explored treatments for persistent sexual side effects in post-finesteride syndrome patients. Woo hoo!
by Dr Amy Killen