Against armchair medicine: a retort to skeptical physicians

Playing up uncertainty about 5-alpha syndrome takes little effort and supports the interests of the medical profession

Nocebo effect. Ordinary depression. Social media illness. Not biologically plausible. These are just a few of the arguments that physicians have used to discredit 5-alpha syndrome. They have a veneer of authority, but on a closer look these arguments take a narrow view, overlooking social context, industry influence, the patient perspective, and bias in the evidence base (see Temperature check and ‘Safe and well-tolerated’). There is a hidden motivation: 5-alpha syndrome poses a threat to medicine because it is caused by a prescribed drug. Physicians have no interest in legitimizing a threat by investigating it, so instead they place it under a cloud of uncertainty.

This post gathers the most common arguments and provides rebuttals to each:

  • Finasteride is safe based on clinical trials and more than two decades of real-world experience – view rebuttal
  • The syndrome is a nocebo effect – view rebuttal
  • The syndrome was spurred by media coverage, online forums, advocacy and litigation – view rebuttal
  • Patients have pre-existing conditionsview rebuttal
  • Patients are experiencing depression, anxiety or another mental illness – view rebuttal
  • Patients lack expertise in reporting their adverse events – view rebuttal
  • Studies on the syndrome are of low quality – view rebuttal
  • A causal link to the drug has not been shown – view rebuttal
  • A controlled trial is needed – view rebuttal
  • Post-finasteride syndrome is ill-defined – view rebuttal
  • The syndrome is not biologically plausibleview rebuttal
  • The syndrome has a history of controversy – view rebuttal
  • I’ve never seen it in my practice – view rebuttal

REBUTTAL: Merck’s safety data cannot be verified. Social taboos and embarrassment have prevented reporting of sexual and mental problems in all settings.

In Merck’s Phase III extension trial, there was a case of post-finasteride sexual dysfunction which Merck did not disclose to FDA. Adverse outcomes in other trials were obfuscated, for example the PLESS trial where the finasteride group had double the rate of unrecovered sexual dysfunction compared to controls.

Neither individual participant data nor the safety methodology of the Propecia trials have been published, so it is impossible to assess the quality of safety data. The main article on Merck’s Phase III trial provided one sentence on the methodology: “Safety measurements included clinical and laboratory evaluations, adverse event reports, and patient body hair assessment via a self-administered questionnaire (US study only).”1 The Propecia label has been revised at least eight times since approval, suggesting that safety data initially submitted to FDA was inadequate.

Propecia was approved by FDA in 1997. By 2006 Merck had received at least 100 reports of unresolved sexual dysfunction after stopping the drug.

Physicians may not hear about problems that develop after stopping the drug because treatment has ended, and sexual dysfunction and psychological problems are embarrassing topics. Dermatologists do not specialize in these areas, so patients may feel it is inappropriate to report these concerns to the prescriber. Meanwhile, the dermatologist may discourage discussion of adverse drug events.

Patients may have overlooked finasteride as a cause of adverse events because they were not aware of the potential impact on sexuality and mental state, or because problems developed after discontinuing the drug.

Online hair loss communities have run polls on finasteride’s side effects. While these polls have limitations, their anonymity reduces concerns about reporting sexual dysfunction. In a pooled analysis of 7 informal polls, the rate of side effects was 44%, nearly 6 times higher than that of Merck’s Phase III trial.


REBUTTAL: No evidence for a post-drug nocebo effect has been found. A frequently cited study refers to on-drug side effects which are different from a post-drug syndrome.

Many authors have suggested post-finasteride syndrome is a nocebo effect, a phenomenon where side effects arise from patients’ negative expectations. They cite a 2007 study in which some patients were advised in advance that finasteride might have sexual side effects, while others were not. The group which received advance notice reported side effects at a higher rate.2 In fact, this study is not relevant to 5-alpha syndrome because the reports occurred while patients were using the drug. In a literature search, no evidence for a post-drug nocebo effect could be found regarding finasteride or any other drug.

Even if there were evidence for a post-drug nocebo effect, it could not explain certain cases. For example, the patient with lasting sexual dysfunction after leaving Merck’s Propecia trial extension would not have had access to websites, media coverage or warnings that would alert him to this possibility. A self-report of post-finasteride sexual dysfunction was posted online in the year 2000, before the rise of social media. Merck received 100 reports of unrecovered sexual dysfunction after stopping finasteride in the early 2000s when public information about risks was scarce.


REBUTTAL: Post-finasteride cases were observed and reported in the 1990s and early 2000s, before risks were publicized.

Elevated adverse event reports after a Propecia label change in 2012 raised eyebrows among physicians.3 It was interpreted as an externally driven change, termed stimulated reporting. There was no consideration that these experiences might have been disproportionately underreported prior to publicity, due to taboos and embarrassment over male sexual dysfunction. Online discussions, advisories, news and the like might be needed for men to attribute their sexual dysfunction to the drug and feel emboldened to report it. In this account, awareness unlocks experiences that were previously withheld. Likewise, publicity might spur physicians to correctly attribute patient reports to finasteride, whereas before they might have denied any link.

Moreover, the stimulated reporting argument could not explain cases of post-finasteride sexual dysfunction in clinical trials, nor postmarketing reports Merck received in the early 2000s. The first known online report of persistent sexual dysfunction linked to finasteride dates from September 2000. A Yahoo group called Propecia Side Effects was founded in 2003.


REBUTTAL: Cases without pre-existing conditions have been recorded, including one in Merck’s clinical trial and a postmarketing case disclosed by Merck.

A case in Merck’s Phase III extension trial casts doubt on this argument, because the company excluded men with “[a] history of any illness or condition that might have confounded the results of the study or posed additional risk.”4 Merck stated to the Swedish Medical Products Agency in 2006: “…one [patient] reported that the [sexual] adverse experience was still present 6 months after discontinuing finasteride therapy; however, no further follow-up information is available for this patient.”

Another case Merck disclosed to the Swedish drugs regulator in 2006 cannot be dismissed as a pre-existing condition (emphasis added):

[A] 22 year old male emotionally healthy male with no prior history of sexual dysfunction was placed on therapy with finasteride for the treatment of early male pattern balding. Three to four months later the patient began to experience complete loss of sexual drive, including loss of spontaneous erections… Therapy with finasteride was discontinued. Eight months later, the patient reported he continued to experience the same symptoms with no sign of any spontaneous resolution.”5

A urologist tweeted in 2020: “I have personally seen in my practice otherwise completely healthy young men who come in for ED and the only medication they had taken was Finasteride for hair loss.”


REBUTTAL: Genital alterations and numbness are not symptoms of depression or anxiety.

A common symptom of 5-alpha syndrome is genital numbness, which is not a symptom of depression, anxiety or panic disorder. A study found a signal of Peyronie’s disease or penile curvature in finasteride users. Other studies have linked finasteride and dutasteride to penile fibrosis, reduced size and other changes.

Moreover, even if a patient is depressed, anxious or suicidal, this does not automatically subsume other illnesses. For example, chronic pain, migraines and stroke have an association with depression, but most physicians do not claim that they are merely depression.

Finally, most physicians arguing that 5-alpha syndrome is depression do not have expertise in psychiatry, nor do they report seeking psychiatric evaluations of patients. Thus, they have not put their own ideas to the test, even while complaining about a lack of evidence for the syndrome.


REBUTTAL: Research has shown physicians underreport, discount and miss adverse events.

While physician decry patients’ lack of medical expertise, research has found that physicians underreport adverse events,6,7 underestimate their severity, and miss certain types of adverse events. Dr. Ethan Basch wrote that “a substantial body of evidence [shows that] clinicians systematically downgrade the severity of patients’ symptoms, that patients’ self-reports frequently capture side effects that clinicians miss, and that clinicians’ failure to note these symptoms results in the occurrence of preventable adverse events.”8

In a commentary entitled “Should we trust patient-reported outcomes?” Dr. Marie-Christine Nizzi wrote (emphasis added):

The expertise bias holds that physicians are best equipped to speak to patients’ quality of life because their medical knowledge grants them the relevant kind of expertise, which the patients lack. This one-sided view of what constitutes relevant expertise belongs to an outdated model of medicine. At its best, the healthcare relationship is not a tutelage but a partnership, where the physician’s expertise in biological processes is guided by the patient’s expertise in their own thoughts, feelings, and sensations.9

In an analysis of adverse events of finasteride, patient reports included more sexual adverse events while healthcare providers included more psychiatric adverse events. This reflects the deep divide between physicians and patients: patients have a direct experience of sexual adverse events while physicians are prone to interpret the patient’s report in psychological terms. Since sexuality arises from thoughts, feelings and sensations, patients would be a more reliable source than the physician who stands outside the patient’s experience.


REBUTTAL: Studies deemed “high-quality” were sponsored by Merck and co-authored by Merck researchers and affiliated physicians. Findings on the syndrome are preliminary because the condition is variable, funding is scarce, and the research community is small.

Merck reportedly spent $450 million on the development of Propecia.10 Clinical trials yielded dozens of publications, giving the impression of a massive and unassailable evidence base. Yet the safety methodology has been questioned.11 The Propecia label has been updated at least eight times since approval.

Meanwhile, funding to support research on drug harms is scarce. Early research on 5-alpha syndrome was funded by the Post-Finasteride Syndrome Foundation with contributions from patients and their relatives. Recruiting patients is challenging because the disease carries stigma. The patient population is heterogeneous, with a wide range in ages, time of drug exposure, time since stopping the drug, co-occurring conditions, and symptom profile. Baseline test results prior to disease onset are often unavailable.

Low-cost, exploratory studies are not necessarily low quality. They should be judged based on the research question and the state of the evidence, not a rigid hierarchy of evidence where multi-million dollar studies take precedence over all other forms of evidence. Case reports and case series may be the harbingers of an unrecognized disease—this is why they are published. If the evidence is inconclusive, that reflects the limits of medical knowledge, not the illegitimacy of a disease.


REBUTTAL: A causal link has not been adequately investigated.

Merck told Reuters, “the available evidence does not establish that finasteride…causes sexual dysfunction which persists after drug discontinuation.” A 2018 article, co-authored by an expert witness for Merck, stated: “In the absence of objective findings, it is impossible to attribute causality to use of [5-alpha reductase inhibitors, the drug class of finasteride].”

This does not rule out a causal role, but rather highlights a lack of attention to the problem. Physicians and regulators have not undertaken the research needed to assess a potential causal link. Treatment-related harms are threatening to medicine and industry, so traditional sources do not fund research on such topics. By avoiding investigation of these harms, medicine and industry can continue to deflect concerns about them.

Randomized, controlled trials are suited to assessing drug effects. Traditional trials are too costly, but a decentralized approach relying on mobile devices would be less expensive and afford greater anonymity for reporting sexual adverse effects.12

Even without a new controlled trial, a wide range of evidence is available to weigh: overlooked cases from clinical trials; more than two decades of adverse event data; case reports and series; and physician perspectives.


REBUTTAL: Physicians who call for a controlled trial express no intention of carrying one out or seeking funds to pay for it.

Articles on post-finasteride syndrome frequently call for prospective trials. Gray and Semla wrote: “We need placebo controlled trials using validated questionnaires and long term follow-up after treatment to examine persistence of symptoms.”13 Baas et al wrote: “[Post-finasteride syndrome] requires further research with placebo controlled, randomized trials with validated questionnaires and prior sexual and mental health histories followed for a sufficient length of time.”14

Yet researchers who make these calls do not seem to have any intention to carry out such trials or raise funds for them. On a realistic note, Leliefeld et al observed that a randomized, prospective trial is “unlikely to happen due to a lack of funding.”15 Given the lack of funding, researchers could suggest other types of studies such as a decentralized trial, perhaps in partnership with telehealth companies or health systems.


REBUTTAL: The condition is not well-defined because it has not been adequately studied. Other diseases which are now accepted were previously “ill-defined,” for example bacterial infections.

It is precisely the job of science and medicine to tackle problems which are not well-defined. The pathophysiology of long Covid is not well-defined,16 but most people consider it a legitimate disease. Post-finasteride syndrome is not well-defined because it has not been adequately studied. The onus is on researchers to investigate it, as the definition cannot be expected to reveal itself.

Investigating a complex and variable disease requires commitment of time and resources. It is much easier to dismiss the condition than to step into uncharted territory. The physicians who dismiss the syndrome as ill-defined merely signal that they have no interest in understanding it.


REBUTTAL: The disease has not been adequately studied. The burden is on researchers to investigate the biological basis rather than dismissing it out of hand.

Although the pathophysiology of 5-alpha syndrome has not been established, there are clues that 5-alpha reductase inhibitors (5-ARIs) could injure organs and result in impairments. Evidence has accumulated on ocular toxicity. Research has shown alterations to penile tissue associated with 5-ARI treatment. A 2023 systematic review found finasteride causes “oxidative stress and morphological changes mainly in the testis,” and was associated with “reproductive injuries, including damage to the epididymis, erectile dysfunction, decreased libido, and reduced semen volume” (Santana et al, 2023). In a clinical trial, three individuals who took finasteride (5 mg) had reduced sperm motility nearly six months after discontinuing the drug.

Finasteride is broadly disruptive to steroid metabolism. Numerous organs rely on steroid signaling including the brain, male reproductive system and eyes. It is plausible that such disruptions could interfere with the functions of these organs.

It is easier to express doubt based on one’s beliefs and limited knowledge, than to investigate an area that is not well-understood. If investigations were limited to theories viewed as “plausible,” science, technology and medicine would stall.


REBUTTAL: Many diseases and explanations have been “controversial” prior to recognition. Disagreement only means more research is needed.

Climate change and the germ theory of disease were once controversial, but today only extremists would deny them. The window of acceptability changes over time as knowledge progresses and social life evolves.

Physicians, pharmaceutical companies and regulators maintain an official view on which drugs are safe for prescription. When the consensus is challenged—for example, by a drug-induced disease like post-finasteride syndrome—it comes as a threat to their authority. They will likely meet it with denial, deflection and delay. The resulting “controversy” reflects power dynamics, but has little bearing on which view is correct.

As a tobacco industry executive wrote in a 1969 memo, “Doubt is our product… It is also the means of establishing a controversy… If we are successful in establishing a controversy at the public health level, then there is an opportunity to put across the real facts about smoking and health.”17 Evocations of the “controversy” surrounding post-finasteride syndrome are best understood as defenses of the status quo which add no new information.


REBUTTAL: Onset of problems after stopping the drug, as well as embarrassment over sexual and mental concerns, prevent reporting back to the doctor. Moreover, physicians may dismiss genuine reports.

The physician assumes she has a complete understanding of a treatment’s effects, while overlooking factors that might prevent patients from reporting problems back to her. If problems develops after the drug is discontinued, the patient may not attribute the problems to the drug, or think it is inappropriate to discuss post-treatment concerns with the doctor. He may not wish to reveal embarrassing symptoms such as erectile dysfunction, anxiety or panic to a doctor—especially a dermatologist. Some symptoms may be difficult to articulate, such as mental cloudiness, anhedonia or memory loss.

Even if the patient reports his concerns to the physician, she may deny they are due to finasteride. In this case, she has seen post-finasteride problems in her practice, but dismissed them as invalid. Finally, physicians may downplay or deny treatment-related harms because of concerns about liability. See also: From the depths: why finasteride harms took decades to emerge.


Notes
  1. Kaufman KD, Olsen EA, Whiting D, et al, and the Finasteride Male Pattern Hair Loss Study Group. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol. 1998. doi:10.1016/S0190-9622(98)70007-6 ↩︎
  2. Mondaini N, Gontero P, Giubilei G, et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon? J Sex Med. 2007. doi:10.1111/j.1743-6109.2007.00563.x ↩︎
  3. Harrell MB, Ho K, Te AE, Kaplan SA, Chughtai B. An evaluation of the federal adverse events reporting system data on adverse effects of 5-alpha reductase inhibitors. World J Urol. 2020. doi:10.1007/s00345-020-03314-9 ↩︎
  4. Merck Research Laboratories. Drug Approval Package: Propecia NDA #020788; Trial 087. Drugs@FDA. December 19, 1997. ↩︎
  5. Merck Research Laboratories Worldwide Product Safety. Periodic Safety Report for: Finasteride, 1 mg tablet and 0.2 mg tablet, MSD. November 30, 2006. View at pfsfoundation.org ↩︎
  6. Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006. doi:10.2165/00002018-200629050-00003 ↩︎
  7. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2009. doi:10.2165/00002018-200932010-00002 ↩︎
  8. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010. doi:10.1056/NEJMp0911494 ↩︎
  9. Nizzi MC. Should we trust patient-reported outcomes? AJOB Neurosci. 2021 Apr-Sep. doi:10.1080/21507740.2021.1904040 ↩︎
  10. Morrow DJ. New Baldness Drug Is Older Product at a Premium PriceNew York Times. January 20, 1998. ↩︎
  11. Belknap SM, Aslam I, Kiguradze T, et al. Adverse event reporting in clinical trials of finasteride for androgenic alopecia: a meta-analysis. JAMA Dermatol. 2015. doi:10.1001/jamadermatol.2015.36 ↩︎
  12. Harmon DM, Noseworthy PA, Yao X. The digitization and decentralization of clinical trials. Mayo Clin Proc. 2023. doi:10.1016/j.mayocp.2022.10.001 ↩︎
  13. Gray SL, Semla TP. Post-finasteride syndrome. BMJ. 2019. doi:10.1136/bmj.l5047 ↩︎
  14. Baas WR, Butcher MJ, Lwin A, et al. A review of the FAERS data on 5-alpha reductase inhibitors: implications for postfinasteride syndrome. Urology. 2018. doi:10.1016/j.urology.2018.06.022 ↩︎
  15. Leliefeld HHJ, Debruyne FMJ & Reisman Y. The post-finasteride syndrome: possible etiological mechanisms and symptoms. Int J Impot Res. 2023. doi:10.1038/s41443-023-00759-5 ↩︎
  16. Castanares-Zapatero D, Chalon P, Kohn L, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022. doi:10.1080/07853890.2022.2076901 • PubMed • PMC full text ↩︎
  17. Bero LA. Tobacco industry manipulation of research. Public Health Reports (1974-). 2005. http://www.jstor.org/stable/20056773 ↩︎