Guide for researchers

The post-5-ARI disorder is variable in presentation, but often includes sexual dysfunction and neuropsychiatric disturbances. Within sexual dysfunction, common symptoms are genital numbness and loss of libido. In the neuropsychiatric domain, common symptoms are depression, anxiety, panic attacks and suicidality. There may also be deficits in cognitive, musculoskeletal, energetic and sensory functions as well as sleep.

An etiology must explain:

  1. Deficits in multiple domains: sexual, neuropsychiatric, cognitive, energetic, musculoskeletal, ocular, vestibular and sleep-related.
  2. Acute and chronic phases after discontinuation. In the acute phase, there may be new symptoms, worsening symptoms and/or remitting symptoms.
  3. Significant variability in nature, severity and course of dysfunctions across individuals.

To anticipate a few common misconceptions:

  1. The disorder is not drug “side effects” in any sense.
  2. No clear pattern of sex hormone abnormalities has emerged. The disorder cannot be explained away as male hypogonadism (low testosterone). Anecdotally, hormone therapies such as testosterone and human chorionic gonadotropin have led to mixed and generally unremarkable results.
  3. A psychogenic account fails to explain penile abnormalities linked to use and discontinuation of 5-ARIs.

Disease experience and presentation

Historical & social context

Research context

Pharmacology

Clinical research

Signs & markers
CategoryReferences
Penile alterationsResearch review: Alterations to penile and prostatic tissue associated with finasteride and dutasteride treatment
Altered levels of neuroactive steroidsMelcangi et al., 2017
Diviccaro et al., 2019
Epigenetic modificationsMethylation of SRD5A2: see Melcangi et al., 2019
Widespread epigenetic changes: Howell et al., 2022
Pudendal nerve neuropathyMelcangi et al., 2017
Gut inflammationDiviccaro et al., 2022
Disease analogues & references
Disorders of sexual development5-alpha reductase deficiency: Bibliography
Androgen insensitivity syndrome: Cleveland Clinic
Disorder of sexual functionPeyronie’s disease: Cleveland Clinic. See also related adverse events.
Neuroendocrine disordersDisorders of the hypothalamic-pituitary-gonadal (HPG) axis: Handbook of Neuroendocrinology, Chapter 30
Disorders of the hypothalamic-pituitary-adrenal (HPA) axis: Oyola & Handa, 2017
Hyperprolactinemia: Johns Hopkins Medicine

Proposed etiologies

HypothesisReferences
Epigenetic changesBibliography on altered expression of SRD5A2
Bibliography on androgen receptor
Howell et al., 2022
Altered expression of neuroactive steroidsDiviccaro et al., 2019
Additional findings & hypotheses from Melcangi & Giatti [1]Melcangi lab bibliography
Vascular stress leading to injury, inflammation & fibrosisMontaigne, 2022 (manuscript)
Note 1: Neuroinflammation; altered expression of GABA receptor subunits; altered gut microbiota composition; off-target effect on PNMT; reduced epinephrine

Potential treatments

There is no known effective treatment. For penile alterations resembling Peyronie’s disease, regenerative therapies would be of interest. Israeli et al., 2022 discusses platelet-rich plasma injections and stem cell therapy for penile rejuvenation.

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Selected references

Diviccaro S, Melcangi RC, Giatti S. Post-finasteride syndrome: an emerging clinical problem. Neurobiol Stress. 2019. doi:10.1016/j.ynstr.2019.100209 • PubMed

Ganzer CA, Jacobs AR, Iqbal F. Persistent sexual, emotional, and cognitive impairment post-finasteride: a survey of men reporting symptoms. Am J Mens Health. 2015. doi:10.1177/1557988314538445 | PubMed

Howell S, et al. Differential gene expression in post-finasteride syndrome patients. J Sex Med. 2021. doi:10.1016/j.jsxm.2021.05.009

Kacevska M, Ivanov M, Ingelman-Sundberg M. Perspectives on epigenetics and its relevance to adverse drug reactions. Clin Pharmacol Ther. 2011. doi:10.1038/clpt.2011.21 • PubMed

Khera M, Than JK, Anaissie J, et al. Penile vascular abnormalities in young men with persistent side effects after finasteride use for the treatment of androgenic alopecia. Transl Androl Urol. 2020. doi:10.21037/tau.2020.03.21 • PubMed • PMC full text

Melcangi RC, Casarini L, Marino M, et al. Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study. Endocr Connect. 2019. doi:10.1530/EC-19-0199 • PubMed

Melcangi RC, Santi D, Spezzano R, et al. Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. J Steroid Biochem Mol Biol. 2017. doi:10.1016/j.jsbmb.2017.04.003 • PubMed

Montaigne M. A proposed etiopathology of persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors: sequelae of drug-mediated microvasculopathy. Manuscript at OSF. 2022 Feb 11. doi:10.31219/osf.io/86cnm