Temperature check on recent literature

5-alpha syndrome (post-finasteride syndrome) is appearing more regularly in the medical literature. Recent articles show slightly more openness to the syndrome as legitimate, especially in the fields of andrology and sexual medicine. But they continue to recycle old arguments that pin the problem on the patient, such as pre-existing psychological and sexual disorders, a nocebo effect, false reports due to media coverage, the influence of Internet forums, “low-quality studies,” lack of a biological explanation and a history of “controversy.”

This post surveys articles published from 2022–2023 which include a discussion of post-finasteride syndrome (see also a full bibliography). For each article, a denial score is assigned. A score of 1 means the post-finasteride syndrome is taken seriously and there is no denial or patient-blaming. A score of 10 means that the disease is deemed illegitimate, often by reference to mental disorders, nocebo effect and other arguments mentioned above.

This is not a comprehensive review of these articles. See original articles for the full context. In excerpts, emphasis has been added.

Chislett et al, 2023

Chislett B, Chen D, Perera ML, Chung E, Bolton D, Qu LG. 5-alpha reductase inhibitors use in prostatic disease and beyond. Transl Androl Urol. 2023. doi:10.21037/tau-22-690PubMedPMC full text

This article is noncommittal, but hints at skepticism with the phrases “a growing chorus of consumers” and “persistent symptoms have been labelled…” It says the “existence, incidence and mechanism of [post-finasteride syndrome] remain debated.” Like other articles, it calls for controlled prospective trials, but it is unclear whether this research group has any interest or funding to carry out such trials.

A growing chorus of consumers have reported persistent adverse side effects from 5-ARIs, despite its discontinuation of the medication. These persistent symptoms have been labelled post-finasteride syndrome (PFS), embodying a constellation of sexual, physical, and neuropsychiatric symptoms that developed during or after the use of 5-ARIs. Consequently, several countries, including the US FDA, have amended warnings to include the possibility of persistent side effects. The pathological mechanism of PFS is unclear, though it is theorised 5-ARIs inhibit the synthesis of neurosteroids known to affect mood, cognition and libido. Current literature is conflicting regarding the existence of PFS, along with the dosing and duration required to be at risk. The PLESS study showed 15% of patients taking finasteride experienced sexual side effects within the first 12 months, compared to 7% in the placebo group. During the remaining 3 years of follow-up, there was no difference in reported sexual side effects between groups. However, only 50% of people taking finasteride reported resolution of their adverse sexual side effects following discontinuation, compared to 41% in the placebo group. Recent meta-analysis on adverse side effects of 5-ARIs did not assess persistent symptoms. Current evidence in support of PFS consists of case reports, surveys or low volume observation data. It is, for this reason, that the existence, incidence and mechanism of PFS remain debated. To establish the existence of PFS, quality prospective data, including placebo trials, is required.

Fierro et al, 2022

Fierro MC, Yafi FA, Reisman Y. Post-Finasteride Syndrome. In: Reisman Y, Lowenstein L, Tripodi F, eds. Textbook of Rare Sexual Medicine Conditions. Cham: Springer; 2022: 65–79. doi:10.1007/978-3-030-98263-8_6

The authors of this textbook chapter are unconvinced, calling for “demystification” of the “rare condition.” Pre-existing sexual and psychological disorders, including personality disorders, are mentioned. The authors suggest a biopsychosocial approach to treatment, implying that psychological and social changes could improve the patient’s condition. Calling post-finasteride syndrome “enigmatic,” the authors maintain a skeptical position until an association with finasteride is “confirmed or denied…”

The establishment of post-finasteride syndrome began with the use of limited, low-quality evidence such as post-marketing reports, targeted case series, and inconsistent surveys of selected patient populations. Since then, attempts to fill the knowledge gap have still not provided definitive conclusions on PFS validity, and most studies focusing on specific adverse effects have found varying levels of statistical support.

Bearing the above elements in mind, the primary aim of this chapter is to provide a succinct and concise overview of current knowledge of PFS and aid in the understanding and demystification of this rare condition. 

Again, finasteride used for the treatment of AGA is historically well tolerated and considered safe for long-term use; however, the conflicting and limited data regarding persistent adverse events continue to create hesitation and influence medication compliance. 

At this time, there are no predictive factors for the development of PFS. However, it would seem appropriate to be mindful of pre-existing sexual dysfunction or mental health disorders prior to finasteride treatment consideration 

Of note, personality disorders in patients with AGA were significantly more common than in the general population. 

Like many other sexual medicine conditions, PFS with its reported symptoms is favorably evaluated and managed using the biopsychosocial approach, as these three domains of distinction encompass PFS symptoms as a whole. 

The BPS model expanded past the biomedical model of understanding illness that exclusively analyzed physiological or biological elements, an augmentation that would also include psychological or mental health components as well as social and cultural components.

[T]reatment with phosphodiesterase type 5 inhibitors such as sildenafil and tadalafil, in addition to cognitive therapy, can be considered. In addition to antidepressant and anxiolytic medication, psychotherapy, sex therapy, cognitive behavioral therapy, and healthy lifestyle changes may also be beneficial for those suffering from psychological adverse effects.

Patients with a history of sexual dysfunction, psychiatric disorders, or fertility issues should especially be informed of current literature prior to finasteride prescription as they may be at higher risk of developing adverse effects. 

As of now, PFS remains enigmatic, and until the association is confirmed or denied, it is recommended to reflect on possible undesirable outcomes…

Gül et al, 2023

Gül M, Fode M, Urkmez A, et al. A clinical guide to rare male sexual disorders. Nat Rev Urol. 2023. doi:10.1038/s41585-023-00803-5 • PubMed

This article uses many of the common arguments to deny the syndrome legitimacy: “controversy,” a biological basis that is “not yet convincing,” “unexplained” symptoms, media coverage, patient suggestibility, unreliable adverse event data from patients, selection bias in studies, nocebo effect, “psychological reactions,” previous psychiatric and sexual disorders and family history of the same.

Thus, numerous controversies surround this syndrome, as studies have failed to shed light on the onset of male sexual dysfunctions in the short and long term after the suspension of 5-ARI treatment. Notably, the biological basis of the relationship between these disorders and 5-ARI therapy is not yet convincing and some patients report symptoms that cannot be adequately explained biologically, with the frequency of consultations for the conditions paralleling the respective media coverage, indicating a high degree of suggestibility.

Furthermore, reports from drug control agencies are also affected by selection bias, artefact and sometimes even confusion regarding the objectivity of the symptoms reported. When considering these studies, one must keep in mind that voluntary reporting of these disturbances considerably distorts the scientific data as the participants were a self-selected population.

Treatment of PFS

Contrasting evidence in the literature means that the treatment of PFS is still under discussion… Unfortunately, specific risk factors for PFS are not yet identified and no specific recommendations to treat this syndrome are available, owing to the combined influence of psychological effects, nocebo reactions, comorbidities and other factors. 

In terms of practical recommendations, the presence of previous psychiatric or sexual disorders, family history of psychiatric illnesses and the presence of previous sexual dysfunction should all be considered in patients receiving finasteride treatment who report relevant PFS symptoms. After ruling out these aspects, patients referred with PFS should be offered support for their sexual symptoms, through both psychological and pharmaceutical approaches.

Hui et al, 2022

Hui EX, Huang X, Oon HH. Review of dermatologic medications and impact on male fertility, sexual dysfunction and teratogenicity. Andrology. 2022 Oct. doi:10.1111/andr.13236 • PubMed

This short passage in an extensive review of dermatological medications hints at openness to the syndrome’s legitimacy, noting that “compelling reports…in clinical literature” have led to labelling updates. The reference to men who are trying to conceive is puzzling, as fertility risks are present in men who are currently taking finasteride.

The condition of persistent sexual (low libido, erectile dysfunction and orgasmic dysfunction) and psychological (depression, anxiety and suicidal ideation) symptoms that persist despite discontinuation of finasteride is termed post-finasteride syndrome. An increasing number of compelling reports of the post-finasteride syndrome in clinical literature has resulted in the update of the labelling of finasteride to include the risk of depression and persistent sexual dysfunction, by regulatory agencies such as the Swedish Medical Products Agency, Medicine Health Care Products Regulatory Agency and the US FDA. Males who are trying to conceive should be counselled on the post-finasteride syndrome.

Leliefeld et al, 2023

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 • PubMed

One of the authors of this article was also an author of Fierro et al, 2022 (denial score: 9), but this article takes the syndrome more seriously. The authors note that a nocebo effect is insufficient to explain the condition. They thoughtfully call for a collaboration of clinicians and researchers from different disciplines. There is a discussion of potential biological mechanisms.

Nevertheless, the article goes on to recycle patient-blaming arguments such as past psychiatric disorders, sexual dysfunction or infertility.

The article acknowledges a lack of funding for research, a reality that few physicians seem to recognize when they call for more research. The authors note the urgency of the situation, suggesting they take the condition seriously.

The adverse effects of finasteride like depression and suicidal thoughts got public awareness in 2012. This could have led to stimulated reporting and a nocebo effect as well, the so-called Weber effect.

The sexual side effects are common and transient, but in a small subgroup of patients these side effects can persist even years after discontinuation of the drug. This so-called PFS has serious implications for the quality of life and unfortunately till now no effective therapy exists.

Physiological mechanisms of PED and genital anesthesia are yet to be understood; is there an endocrinological, psychological or neurological cause (central or peripheral)? The above mentioned etiological mechanisms like the change in neurochemistry and neurogenesis, the novel state of androgen deficiency and the nocebo-effect are steps further but by far insufficient to explain why there are subgroups of patients with side effects during and after use of 5ARIs and to reach in the end a concrete therapy. For a better understanding of the existing relations between hormonal and cerebral symptoms a consistent cross-consultation is needed between urologists/sexologist/endocrinologist/dermatologists on one end and psychiatrists/neurologists/researchers on the other hand. In general it is sometimes difficult for patients and professionals to recognize the link between symptoms and the 5ARIs because symptoms exist or appear (long time) after discontinuation of the drug. A very interesting and promising development is the identification of genetically influenced metabotypes, so called GIMS, that represent the genetic basis of chemical individuality, which gave new biological insights. With the help of these GIMS it was possible to prove a consistent genetic association between greater 5α-reductase activity and the risk of male-pattern hair loss… [C]hemical individuality might be the way to identify subgroups of patients at risk for side effects due to 5ARIs. 

The lack of quality studies is a major problem in assessing the presence and frequency of the side effects. Further research is warranted with PCRCT including validated questionnaires at baseline with detailed history regarding past psychiatric disorders, the use of medications or drugs and relevant comorbidities, and with a follow up for several years. But this is unlikely to happen due to a lack of funding. Until then it is utmost important to identify individuals with a previous history of depression, sexual dysfunction or infertility who may be more susceptible for the various side effects. The possible risks should than be discussed with the patient and weighed out against the benefits of the use of 5ARIs as mentioned in the introduction. Men under the age of 40 who use finasteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia. Physicians need more awareness regarding the decrease of PSA due to 5ARIs of 50% after 6 to 12 months use which can mask high-grade prostate cancer. They should restrict the 5ARIs to patients with a prostate volume of >40 ml according the EAU guideline 2023. Therapeutic innovation is urgently needed that might cure or relieve this wide range of health risks.

Michel & Madersbacher, 2022

Michel MC, Madersbacher S. Medikamentöse Behandlung des benignen Prostatasyndroms: Was gibt’s Neues? [Medical treatment of male lower urinary tract symptoms: What’s new?]. Akt Urol. 2022;53:240–245. German. doi:10.1055/a-1749-4556

This article is unusual in pointing out that another 5-alpha reductase inhibitor, dutasteride, can also cause the syndrome. They suggest the broader term post-ARI syndrome. They point out low-quality studies, ask whether the syndrome exists and say that its definition is “controversial.” But the final sentence of the passage refers to drug effects on the central nervous system, implying a biomedical basis of psychiatric adverse events.

New safety concerns have also emerged for the use of ARIs. After first hints 20 years ago, various studies in recent years have shown that the so-called post-finasteride syndrome can occur after the use of these drugs; since the risk seems to be similar when using dutasteride, it should probably be called post-ARI syndrome. It includes changes in sexual function, psyche and cognition. Interestingly, the post-ARI syndrome is mainly described in younger men who took 1 mg finasteride for the alopecia indication. However, many clinical studies on post-ARI syndrome are of low scientific quality. Whether it actually exists as a clinical syndrome and how to define it exactly remains controversial. However, various findings indicate a connection between the intake of ARIs and symptoms of the central nervous system such as depression or dementia.

Trüeb et al, 2022

Trüeb RM, Luu NC, Gavazzoni Dias MFR, Dutra Rezende H. How to deal with the issues of fertility, malignancies, and the postfinasteride syndrome while prescribing finasteride for male pattern hair loss. Skin Appendage Disord. 2022 May. doi:10.1159/000520493• PubMed

Three of the authors published an earlier case report proposing that the syndrome is an “induced delusional disorder” emerging from a histrionic personality disorder and a nocebo effect. Here, similar arguments are repackaged as guidance for clinicians. This article recaps the earlier article, mentioning the delusional disorder and histrionic personality disorder, “mystery syndromes,” lack of a biological explanation, influence of media coverage, and the suggestibility of patients.

The authors argue that mental health disorders put patients at a greater risk of a nocebo effect, so the patient should be assessed for these disorders before finasteride is prescribed. To this end, they provide a diagnostic checklist for histrionic personality disorders.

In summary, this article repeats bizarre ideas from the earlier case report, but has a slightly less dismissive tone, so it is rated with a denial score of 9.

And yet, particularly fertility issues and postfinasteride syndrome (PFS) have become concerns of both users and prescribers of the drug, sensitized by social media coverage following the respective reports on decreased fertility and persistent sexual side effects after cessation of finasteride therapy…

…The condition allegedly may have a life-altering impact on sufferers, while also being linked to depression and suicidality.

The condition is not recognized by the scientific community. And yet, individuals who suffer from the syndrome do present with very distinctive and relatively homogenous symptoms that cannot be simply dismissed as nonexistent. Ultimately, it is not sufficient to only discuss the plausibility of PFS, not alone to ridicule its proponents. Rather, there is a need for a pragmatic approach to PFS to include such important issues as listed in Table 1.

In fact, after a 20-year history of successful prescription of finasteride for treatment of MPHL, we eventually reported our first case of PFS with circumstantial evidence that the condition may rather have represented a delusional disorder of the somatic type than an endocrinological disorder, possibly on the background of a histrionic personality disorder. Besides, the PFS demonstrates some striking analogies to other mystery syndromes, such as amalgam illness, multiple chemical sensitivity, Morgellons disease, and Koro, in which the alleged symptoms cannot be explained biologically and the frequency of consultations for the respective condition strikingly parallels the media coverage, which points to a high degree of suggestibility.

Consequently, we devised a system for patient selection and risk assessment, including fertility issues, regular prostate-specific antigen determinations, and specific mental health assessment. Pre-existing mental health disorder may put patients at an increased risk of nocebo, while the prevalence of personality disorders in subjects with MPHL is known to be significantly higher than in the general population, specifically the histrionic personality disorder.

…To diagnose histrionic personality disorder, people must persistently exaggerate their emotions and seek attention, as shown by at least 5 of the symptoms listed in Table 2.

Table 2. Diagnostic criteria for histrionic personality disorder
They feel uncomfortable when they are not the center of attention
They interact with others in inappropriately sexually seductive or provocative ways Their emotions shift rapidly, making them seem shallow
They consistently use their physical appearance to call attention to themselves Their speech is extremely vague, lacking detail
They express their emotions in a dramatic, theatrical, and extravagant way
They are easily influenced by others or situations
They view relationships as more intimate than the relationships are

[…] To finish, with regard to management of PFS, attention must be focused on the treatment of depression and sexual symptoms…