POST-FINASTERIDE SYNDROME

The post-finasteride-syndrome is a direct effect of five-alpha reductase blockade.
This note is in response to a query regarding PFS (the post-finasteride syndrome) from Dr. Philip Roberts, the patient-support director of the post-finasteride syndrome foundation.
It is offered gratis and in humanitarian interest, as my personal opinion. It is based to some extent on my previous knowledge and experience and bolstered by current information available on the www.
Please bear in mind that I am to be regarded as a well-informed layman: I am not an academic, a recognised expert on functional medicine or any sort of pundit and now post-retirement, I am no longer a registered physician.
Therefore my musings amount to speculative suggestion only and should not be construed as instruction or advice to Dr. Roberts, or to PFS sufferers.

DEFINITION / BACKGROUND

Finasteride was patented in 1984 and approved for medical use in 1992. It is available as a generic.
Sold as Proscar, Propecia and other brand names, it was initially used to treat benign prostatic hyperplasia and subsequently hair loss, in men. It can also be used to reduce hair growth in women and as a part of hormone therapy for transgendered females. In 2018, it was the 87th most common medication in the United States, with over 8.9M prescriptions.
Adverse effects from finasteride are said to be rare, however some men experience sexual dysfunction, depression, breast enlargement and/or a host of other symptoms, reminiscent of chronic fatigue syndrome and intracellular hypothyroidism , which may persist after stopping the medication.
Clinical studies have revealed both high efficacy of treatment and a favorable safety profile, establishing the drug as first-line treatment for male pattern hair loss.
In 2012, Sato and Takeda [1] reported on efficacy and safety of 1 mg oral finasteride for treatment of male pattern hair loss in a very large population study (3,177 Japanese men). 87.1% reported increased hair: 11.1% “greatly”, 36.5% “moderately”, and 39.5% “slightly” increased. Further, the response rate improved with increasing duration of treatment and only 0.7% reported adverse reactions.
Sato and Takeda followed up in 2019 with a report on 532 Japanese men who were treated for androgenetic alopecia with finasteride, 1 mg/day, for 10 years. They reported that 91.5% of patients experienced improvement in their baldness, that in 99.1%, there was no disease progression and that during the 10 years, no serious adverse reaction was recognized. In the light of these and other reports on the use of finasteride in the treatment of baldness therefore, it is entirely reasonable to say that as medications go, finasteride is safe to prescribe for the treatment of male pattern baldness.

Nevertheless, approximately 0.8% of men for whom finasteride has been prescribed describe the early onset (within the first few months) of a constellation of psychologically devastating side effects, with the endpoint of suicide in a small number of cases. This has been dubbed “the post-finasteride syndrome”.

THE POST-FINASTERIDE SYNDROME:

PFS has been reported in men who have taken oral finasteride, for either hair loss or BPH (benign prostatic enlargement). [2,3]
Reported symptoms, including depression, cognitive impairment, loss of libido, erectile dysfunction, reduction in penis size, penile curvature or reduced sensation, gynecomastia, muscle atrophy and severely dry skin, continue despite quitting finasteride. [4] The condition allegedly may have a life-altering impact on sufferers and their families, such as job loss, the break-up of romantic relationships (or marriages) and suicides.

The Post-Finasteride Syndrome Foundation (www.pfsfoundation.org), a nonprofit organization, is dedicated to helping fund research on the characterization, underlying biologic mechanisms, and treatments of PFS and to improving public awareness of the condition.

The obstacles to finding a solution to the vexing situation in which sufferers find themselves is personified in two online articles, which I have dubbed “A DERMATOLOGIST’S VIEW” [5] and “A Comment on the Post-Finasteride Syndrome” [6], both from Dr Ralph Michel Trüeb, et al.
I have paraphrased “A DERMATOLOGIST’S VIEW”, below. Note that I do not agree with this paper, but it represents the attitude of some physicians to their patient’s complaints.

A DERMATOLOGIST’S VIEW (paraphrased, in the interest of brevity and simplicity).
“Finasteride represented a breakthrough, with high efficacy and safety.
PFS, characterized by sexual dysfunction, somatic symptoms, and psychological disorders, has been claimed to occur in men who have taken oral finasteride. In our opinion, PFS is a “mystery syndrome” like amalgam illness, chemical sensitivity, Morgellon’s disease, and Koro (fear of the genitals shrinking and retracting into the body): symptoms cannot be explained biologically and frequency of consultation parallels media coverage, indicating suggestibility. Finally, patients hold to their belief system despite rational argument, indicating a delusional aspect to their disorder. We report our first case, with evidence that PFS is delusional, due to histrionic personality.
In case of adverse effects, finasteride or dutasteride treatment should be stopped.
Patients are unlikely to benefit from any androgen and attention must focus on treatment of psychopathological disorders and sexual symptoms, with psychotherapy and psychotropic agents depending on the underlying depressive, delusional, or somatoform disorder”.

CONSTRUCTIVE ANALYSIS:

In my view, PFS is an unsurprising symptom complex which is only to be expected in view of the mode of action of finasteride.
My logic is as follows:
Finasteride is a 5α-reductase inhibitor and therefore an antiandrogen.
By blocking 5α-reductase, it reduces production of DHT (Di-HydroTestosterone) in the prostate and the scalp by about 70%, so it works very well to reduce and repair male pattern baldness.
Importantly however, 5α-reductase is the active enzyme in the synthesis of several anticonvulsant neurosteroids which the brain produces, including
allopregnanolone,
androstanediol ,
THDOC.

So let’s think about Allopregnanolone, Androstenediol and THDOC:

ALLOPREGNANOLONE is an antidepressant, anxiolytic, pro-social, anti-anger, pro-libido, sleep supportive and pro-cognitive hormone made in the brain as well as in the adrenal glands.
It is responsible for brain maintenance and repair, including myelin sheath maintenance, nerve connectivity, nurture of new brain cells and memory.
It is mood-enhancing.
It generates endorphins and is anticonvulsive.
It relieves depression, notably postpartum depression.
Deficiency of Allopregnanolone causes PMDD (PMS) (8), anxiety states, panic attacks and depression. Fluctuation of its blood level plays an important role in the pathophysiology of mood disorders, catamenial epilepsy, MS, Parkinson’s, Alzheimer’s and various other neuropsychiatric conditions.

ANDROSTENEDIOL is an intermediate in Testosterone synthesis from DHEA, so lessened availability reduces Testosterone levels.
This is not a major problem for many, but in those who are already “Testosteropenic”, it often leads to a loss of self-confidence (therefore increased anxiety), reduced muscle maintenance, increased fat storage and perhaps an increased tendency to breast enlargement (which some males already have): see the page on Testosterone.

THDOC (deoxycorticosterone), is a potent positive allosteric modulator of the GABAA receptor and has sedative, anxiolytic and anticonvulsant effects. Changes in the normal levels of this steroid may be involved in some types of epilepsy (catamenial epilepsy), PMS, stress, anxiety and depression.
As with Allopregnanolone, reducing production of THDOC increases any tendency to anxiety and depression in the short term: time will tell whether long-term effects will be observed.

Deficiency of Allopregnanolone, androstanediol and THDOC leads to depression and stress-related intracellular hypothyroidism, with all the symptoms of hypothyroidism.
Thus Finasteride, by reducing or eliminating production of those essential hormones, produces a PTSD/CFS/ME scenario with devastating depression, subjective helplessness and suicidal ideation: it is surprising that PFS does not occur more often.

MY OPINION, IN VERY BRIEF

  • Reported effects in affected persons are horrendous and although PFS is rare (relative risk 1.66), it warrants careful analysis and thoughtful consideration.
  • Clearly, since the mechanism of action of Finasteride is to inhibit 5α-reductase, which transmutes Progesterone to Allopregnanolone, DOC to THDOC and DHEA to Androstenediol, prescription of Finasteride carries the risk of deficiency of all three “downstream” Hormones.
  • Downregulation of Allopregnanolone lowers mood and reduces self-satisfaction and sense of tranquillity, setting the stage for anxiety and depression. Anxiety and depression are interpreted by the brain as stress and the stress increases cortisol output, which encourages preferential conversion of T4 into rT3 (see “the thyroid Hormone“).
    In this scenario Allopregnanolone deficiency produces mood swings and depression, the depression causes anxiety, the anxiety is interpreted by the brain as stress, the brain calls for a stress response, the stress response involves heightened Cortisol output, the tissues respond to increased Cortisol by converting T4 into rT3 instead of active T3 and an intracellular hypothyroid state ensues.
  • Intracellular Hypothyroidism tends to persist, because the increased anxiety which it causes is interpreted by the brain as stress and a vicious cycle ensues.
  • Regarding non-sexual symptoms of PFS: dry skin, hair loss, muscle aches, adiposity, skewing of the cholesterol balance, reduced cognition, chronic fatigue symptoms, low libido and anxiety with panic attacks are all symptoms of hypothyroidism .
  • SO: …… PFS is due to idiosyncratic sensitivity to the neurodebilitating effects of 5-alpha reductse blockade, with ALLOPREGNANOLONE, THDOC, ANDROSTENEDIONE (and possibly other) deficiency. The syndrome is compounded by deep intracellular hypothyroidism (akin to PTSD and CFS) which serves to increase the anxiety and further suppress Allopregnanolone, in a self-perpetuating spiral.
  • Impotence can also be a low-T3 effect, as can peripheral neuropathy, pretibial oedema, constipation, hair loss and innumerable other symptoms.
  • It is likely that DHEA deficiency is a contributing factor in the development of PFS, but no study has reported on DHEA levels, thus far.
  • NOTES:
    (1) regarding DHEA: DHEA production falls 1% per annum from age 25 in all humans and is therefore deficient by age 30. It should be recommended as a supplement, for all.
    (2) Progesterone supplementation supports Allopregnanolone production, so it improves sleep, memory, mood and self-satisfaction.
    (3) Penile curvature (Peyronie’s disease) must be a coincidental development unrelated to the other PFS effects: Peyronie’s disease is not, to my knowledge, a side effect of any hormone deficiency.
    (4) See https://cbhrt.ca/2021/08/28/thyroid-hormone-tests/ and https://cbhrt.ca/blog/ and https://cbhrt.ca/thyroid/

INVESTIGATION

Investigation of all cases of PFS should include, in addition to routine studies, free Testosterone, IGF
(a marker for growth hormone) DHEA, Oestradiol, Progesterone, fasting Homocysteine, HSCRP, TSH, free T4 & T3, rT3.

MANAGEMENT

PROGNOSIS and FOLLOW-UP

[1] Stop taking finasteride and contact a Metabolic Medicine or Functional Medicine MD, for an opinion re PFS: present a copy of this article.
[2] Correct Allopregnenolone deficiency with Pregnenolone and Progesterone (50 – 100 mg), at bedtime.
[3] Rx Melatonin, 10 mg at bedtime, it’s as an adjunct to Allopregnenolone, to improve sleep, mood and anxiety.
[4] Take DHEA (no more than 50mg /day, so as to avoid aromatisation to Oestrogen): >50mg may raise Oestrogen to female levels, producing gynecomastia and occasionally, painful breast cysts.
[5] Test for HS CRP, Homcysteine, IGF, Heavy Metals and other markers as necessary and treat ad hoc.
[6] Correct intracellular hypothyroidism with Triiodothyronine (AKA Liothyronine), titrated upward from 10mcg daily in 5mcg increments, to achieve a T3 level between 5.0 and 6.2 Picomoles/Litre: do not take desiccated thyroid, because 70% of D.T. is T4 (in intracellular hypothyroidism, T4 does not raise the serum T3: it is processed preferentially to rT3). DO NOT PRESCRIBE Eltroxin or Synthroid, for the same reason.
[7] Test for T3 weekly, at 4 hours post-dose (Ideal dose time 4AM) until the target T3 of 5.0 – 6.2 Pmol per litre is achieved. (Note that since T3’s half-life is only 2-3 hours, there is no need to wait six weeks for re-testing, as is done for T4, whose half-life is 5 – 7 days).
[8] Re-test for rT3 and other parameters later, when the serum T3 is > 5.0 Pm/L.
[9] Take Vit D, B12, MTHF, NAC, CoQ10, I3C, Zinc, Iron, Magnesium, Selenium, Iodine etc, ad hoc.
[10] Prescribe Zuranolone (synthetic Allopregnanolone) when it becomes available, as a short-term adjunct to relieve symptoms: do not depend on Zuranolone to supplant the entire protocol because it will not eliminate Functional Hypothyroidism, the perpetuator of the syndrome.

SIDE EFFECTS OF T3 OVERDOSE:
The classical side effects of T3 overdose are fast heartbeat, anxiety, hyper-reactivity/anger and “antsyness”, but they usually occur due to spiking of T3 when Cytomel is prescribed. They are rare when slow-release T3 is taken and do not occur if the dose is titrated slowly to a maximum FT3 of 6.2 Pm/L.
The main effect of mild overdose, with T3 over 6.2 (optimal is 5-6), is feeling “high” ….. a feeling of being “on top of the world”, sharp and optimistic, with sharpened vision, enhanced reds and greens and heightened perception.
The main symptom of insufficient T3 dose is afternoon fatigue, with recurrence of hypothyroidism symptoms late in the day.

I cannot estimate a time-frame for improvement in the patient’s symptoms, but the response to DHEA and Progesterone is usually rapid. Time to improvement in functional hypothyroidism will depend on the patient’s requirement for T3.
Follow-up will depend on the subject’s condition, so the time-frame should be discussed between practitioner and patient.

The bottom-line idea is that PFS, should respond well to treatment with: 
DHEA [low dose: 50mg] for general support and Testosterone enhancement.
PROGESTERONE [low dose – 50-100 mg HS] for Allopregnanolone support.
MELATONIN [10 mg HS], as a “promoter” of Allopregnanolone.
TRIIODOTHYRONINE, to eliminate Hypothyroidism [T4 makes intracellular hypothyroidism subjects, male or female, really sick].
MAGNESIUM (Threonate is best), MTHF, NAC, a good multivitamin and a probiotic regimen (including Lactobacillus and Bifidobacterium), for dietary support
PLEASE NOTE THAT A CURE CANNOT BE GUARANTEED.

REFERENCES

[1] LONG-TERM (10-YEAR) EFFCACY OF FINASTERIDE IN 523 JAPANESE MEN WITH ANDROGENETIC ALOPECIA, Masayuki Yanagisawa1-3, Hiroshi Fujimaki2,4, Akira Takeda1,2, Mitsuru Nemoto1, Takayuki Sugimoto1 and Akio Sato: January 2019 DOI:10.15761/CRT.1000273, https://www.researchgate.net/publication/337105943_Long-term_10-year_efficacy_of_finasteride_in_523_Japanese_men_with_androgenetic_alopecia

[2] Meta-Analysis: Adverse Sexual Effects of Treatment with Finasteride or Dutasteride for Male Androgenetic Alopecia: A Systematic Review and Meta-analysis
Solam Lee 1, Young Bin Lee, Sung Jay Choe, Won-Soo Lee https://pubmed.ncbi.nlm.nih.gov/30206635/

[3] Meta-analysis: Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials, Luhao Liu  1 Shankun Zhao  1 Futian Li  1 Ermao Li  1 Ran Kang  1 Lianmin Luo  1 Jintai Luo  1 Shawpong Wan  1 Zhigang Zhao  2: PMID: 27475241 DOI: 10.1016/j.jsxm.2016.07.006 From 493 articles, 17 trials / 17,494 patients were included. 9 trials evaluated 5ARIs in BPH. 8 trials reported 5ARIs in AGA. We included 10 trials (6,779 patients) on Finasteride, 4 trials (6,222 patients) on Dutasteride, and 3 (4,493 patients) on finasteride and dutasteride for AGA.
The relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in BPH and 1.21 (95% CI = 0.85-1.72) in AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in BPH and 0.66 (95% CI = 0.20-2.25) in AGA and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in BPH and 1.16 (95% CI = 0.50-2.72) in AGA. Conclusion: 5ARIs were associated with increased adverse effects on sexual function in BPH compared with placebo. However, the association was not statistically significant in men with AGA.

[4] Observational evaluation of 79 young men with adverse effects after finasteride: G Chiriacò  1 S Cauci  2 G Mazzon  1 C Trombetta  1, PMID: 26763726 DOI: 10.1111/andr.12147 https://pubmed.ncbi.nlm.nih.gov/26763726/ Of 79 participants, 40.5% declared erection difficult, and 3.8% never achieved. Orgasm was difficult in 16.5%, and never achieved by 2.5%. 75.9%) had anhedonia, 72.2% lacked mental concentration and 51.9% loss of muscle tone/mass. Most frequent sexual symptoms were low penis sensitivity (87.3%), low ejaculation force (82.3%), and cold penis (78.5%).

[5] https://www.karger.com/Article/Fulltext/497362 Post-Finasteride Syndrome: An Induced Delusional Disorder with the Potential of a Mass Psychogenic Illness? Trüeb R.M.a · Régnier A.a · Dutra Rezende H.a · Gavazzoni Dias M.F.R.b

[6] A Comment on the Post-Finasteride Syndrome, Int J Trichology. 2018 Nov-Dec; 10(6): 255–261.doi: 10.4103/ijt.ijt_61_18, PMCID: PMC6369643 PMID: 30783332Hudson Dutra Rezende, Maria Fernanda Reis Gavazzoni Dias,1 and Ralph Michel Trüeb https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369643/

[7] Neuroprotective and Antiapoptotic Effects of Allopregnanolone and Curcumin on Arsenic-Induced Toxicity in SH-SY5Y Dopaminergic Human Neuroblastoma Cells, Neurophysiology volume 52, pages 124–133 (2020): H. Khodadadi, G. P. Jahromi, G. Zaeinalifard, M. Fasihi-Ramandi, M. Esmaeili & A. Shahriary https://link.springer.com/article/10.1007/s11062-020-09861-6

[8] Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome: Gynecol Endocrinol. 2004 Feb;18(2):79-87, Lombardi I1, Luisi S, Quirici B, Monteleone P, Bernardi F, Liut M, Casarosa E, Palumbo M, Petraglia F, Genazzani AR. PMID: 15195499, DOI: 10.1080/09513590310001652955, https://www.researchgate.netpublication223979283_ACTH_and_Cortisol_Response_to_DexCRH_Testing_in_Women_with_and_without_Premenstrual_Dysphoria_during_GnRH_Agonist-induced_Hypogonadism_and_Ovarian_Steroid_Replacement

Published by Dr. Gervais Harry

I am a Toronto-trained Urologist. I practiced in downtown Toronto, from 1977 to 1997, when I went to Saudi Arabia as chief of Urology at the Armed Forces (teaching) hospital in Tabuk. Returning to Toronto in Y2000, I switched to family practice. In 2007, began to prescribe Hormone Restoration Therapy and in 2012, I became a member of the American Academy of Antiaging Medicine [A4M]. I successfully wrote the A4M's written examination in December, 2013 and In May, 2016 I passed the oral examination, for accreditation as a BHRT consultant. In 2014 I began BHRT practice in Collingwood, Ontario and in January, 2017, joined the Stone Tree Naturopathic Clinic. Now I am 82 and have retired, but it seems wasteful to jettison my learning and experience: the medical establishment knows nothing of BHRT / Functonal medicine and I feel obliged to offer my knowledge in the interest of those who are willing to think outside the box. MY QUALIFICATIONS: MB, BS, (from UWI), 1964. LMCC 1969. FRCSC (Urology), 1974. ECFMG 1984. Florida license 1998 [inactive], ABAARM Certification [A4M], 2016. I am a Member of CSAMM [the Canadian Society for Aging and Metabolic Medicine], the OMA&CMA, SUSO, CUA, RCP&S/C. PRACTICE TO DATE: Consultation in Functional Medicine, including assessment of Chronic Fatigue Syndrome, Fibromyalgia, Andropause, Menopause, Teenage and Postpartum Depression/Panic Attacks, Thyroid Hormone malfunction, Infertility, Sexual Dysfunction and “the Undiagnosable”. ALL ARE WELCOME to read, comment or question!

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