An on-ramp for researchers
This guide is intended to support hypothesis development and future investigations into the post-5-ARI disorder.
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:
- Deficits in multiple domains: sexual, neuropsychiatric, cognitive, energetic, musculoskeletal, ocular, vestibular and sleep-related.
- Acute and chronic phases after discontinuation. In the acute phase, there may be new symptoms, worsening symptoms and/or remitting symptoms.
- Significant variability in nature, severity and course of dysfunctions across individuals.
To anticipate a few common misconceptions:
- The disorder is not drug “side effects” in any sense.
- 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.
- A psychogenic account fails to explain penile abnormalities linked to use and discontinuation of 5-ARIs.
Disease experience and presentation
- Lasting dysfunctions after use of finasteride or dutasteride
- Firsthand reports: Volume IV • Volume V • Additional reports
- Analysis of adverse events from FDA FAERS database
- Research by system & function (scan main classification)
Historical & social context
- How was finasteride invented?
- Timeline (see key events)
- From the depths: why finasteride harms took decades to emerge
- What Merck knew in the 1990s
- A brief history of research on 5-alpha reductase inhibitors
- Bibliography: 5-alpha reductase deficiency
- Expression of enzyme 5-alpha reductase. See summary paragraph on distribution of SRD5A2. On 5-AR type 3, see Yamana, et al., 2010
- Epigenetics of adverse drug reactions: See Kacevska et al., 2011
- Propecia Prescribing Information (see section 12)
- Yamana et al., 2010: Human type 3 5α-reductase is expressed in peripheral tissues…
- Aggarwal et al., 2010: An overview on 5alpha-reductase inhibitors
- PubChem: Finasteride
- StatPearls: Finasteride • 5 Alpha Reductase Inhibitors
Signs & markers
|Penile alterations||Research review: Alterations to penile and prostatic tissue associated with finasteride and dutasteride treatment|
|Altered levels of neuroactive steroids||Melcangi et al., 2017|
Diviccaro et al., 2019
|Epigenetic modifications||Methylation of SRD5A2: see Melcangi et al., 2019|
Widespread epigenetic changes: Howell et al., 2022
|Pudendal nerve neuropathy||Melcangi et al., 2017|
|Gut inflammation||Diviccaro et al., 2022|
Disease analogues & references
|Disorders of sexual development||5-alpha reductase deficiency: Bibliography|
Androgen insensitivity syndrome: Cleveland Clinic
|Disorder of sexual function||Peyronie’s disease: Cleveland Clinic. See also related adverse events.|
|Neuroendocrine disorders||Disorders 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
Hypotheses / etiopathologies
|Epigenetic changes||Bibliography on altered expression of SRD5A2|
Bibliography on androgen receptor
Howell et al., 2022
|Altered expression of neuroactive steroids||Diviccaro et al., 2019|
|Additional findings & hypotheses from Melcangi & Giatti ||Melcangi lab bibliography|
|Vascular stress leading to injury, inflammation & fibrosis||Montaigne, 2022 (manuscript)|
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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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