POST-FINASTERIDE SYNDROME

The post-finasteride-syndrome (PFS) is a direct effect of
five-alpha reductase blockade.

By blocking this all-important enzyme, 5 alpha reductase, finasteride prevents production of Allopregnanolone. Allopregnanolone deficiency causes depression, which is the main cause of the post-finasteride syndrome.

I present this paper, based on my previous knowledge and experience and bolstered by current information available on the www, gratis and in humanitarian interest, as my personal opinion.
Please bear in mind that I am not an academic, a recognised expert on functional medicine or any sort of pundit.Also, Since I have retired, I am no longer a registered physician.
Therefore my musings amount to educated speculation and should not be construed as instruction or advice 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 (“BPH”) 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.

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.
Adverse effects from finasteride are said to be rare, however some men experience sexual dysfunction, depression (often, with suicidal ideation), breast enlargement and/or a host of other symptoms, reminiscent of chronic fatigue syndrome (“CFS“)and intracellular hypothyroidism. These side effects may persist for years, after stopping the medication.

A good reputation, among doctors

In 2012, Sato and Takeda [1] reported on the efficacy and safety of 1 mg oral finasteride for treatment of male pattern hair loss in a very large Japanese study (3,177 men).
By their account, 87.1% reported increased hair: 11.1% were “greatly”, 36.5% “moderately”, and 39.5% “slightly” increased. Further, the response rate improved with increasing duration of treatment and only 0.7% of the men 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 and that in 99.1%, there was no disease progression.
Further, Sato and Takeda stated that during the 10 years, no serious adverse reaction was recognized.

While working as a urologist (1974 – 2001), I occasionally prescribed Finasteride, for prostatic enlargement (never for baldness) , with no reports of side effects, .

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 percentage of cases. This has been dubbed “the post-finasteride syndrome”.

THE POST-FINASTERIDE SYNDROME (PFS):

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 (and/or marriages) and suicides.

THE POST-FINASTERIDE SYNDROME FOUNDATION

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, 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.
The post-finasteride syndrome (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”.

However having said this, Dr. Trueb subsequently wrote (again, paraphrased):  
“In any case, the PFS is a problem that has to be dealt with. It is as inappropriate to dismiss the condition, as it would be to demonize finasteride. The best way to alleviate the emotional distress related to hair loss is to effectively treat the condition causing the problem. It is not sufficient to only discuss the plausibility of PFS.”

How finasteride causes PFS: unsurprising, in view of how finasteride works.

My logic is as follows: Finasteride is a 5α-reductase inhibitor and therefore an antiandrogen.
By blocking 5α-reductase, it reduces DHT (Di-HydroTestosterone) production 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 , and THDOC.

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

ALLOPREGNANOLONE

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. As such, it is indispensable and without it, much can go wrong.

• It is mood-enhancing.
• It generates endorphins (the body’s painkillers) and it is anticonvulsive.
• It relieves depression, notably postpartum depression.
• Deficiency of Allopregnanolone causes PMDD (PMS) (8), anxiety states, panic attacks and depression.
• Fluctuation of its availability in the brain plays an important role in the pathophysiology of mood disorders, catamenial epilepsy, MS, Parkinson’s, Alzheimer’s and other neuropsychiatric conditions.
• The beneficial effects of antidepressant drugs are due to the fact that they increase the brain’s production of Allopregnanolone: it is the Allopregnanolone, not the drug, which reduces the patient’s depression.

ANDROSTENEDIOL

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 already have “low T”, it may lead to a loss of self-confidence (therefore increased anxiety), reduced muscle maintenance, increased fat storage and a tendency to breast enlargement (which some males already have): see my page on Testosterone.

THDOC

THDOC (deoxycorticosterone), is a potent positive allosteric modulator of the GABA_A receptor and has sedative, anxiolytic and anticonvulsant effects, similar to Allopregnanolone. Changes in the 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 brain maintenance hormones

Deficiency of Allopregnanolone, Androstanediol and THDOC leads to depression, by the following sequence:
Depression causes perceived stress.
Stress increases cortisol production.
Cortisol (A) blocks conversion of T4 to T3, (B) encourages conversion of T4 to reverse T3 and (C) causes destruction of T3, inside the cells: the result is very low serum T3 and intracellular hypothyroidism.

Intracellular Hypothyroidism

Intracellular hypothyroidism produces the symptoms of true hypothyroidism, varying from person to person.
Thus on the one hand, in a small percentage of patients, Finasteride causes depression both by eliminating production of essential brain hormones. On the other hand, It causes intracellular hypothyroidism.

MY OPINION, IN BRIEF

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 essential Hormones.

The effect on affected individuals is a PTSD/CFS/ME scenario with devastating depression, subjective helplessness and suicidal ideation. In my view, it is surprising that PFS does not occur more often. Reported effects in affected persons are horrendous and although PFS is rare (relative risk 1.66), it warrants careful analysis and thoughtful consideration.

Summary

In a small percentage of patients, finasteride causes Allopregnanolone, THDOC, and Androstanediol deficiency. In this scenario, Allopregnanolone deficiency produces mood swings, anxiety and depression.
Anxiety and depression are interpreted by the brain as stress and the stress increases cortisol output. In the peripheral tissues, including the brain, Cortisol encourages conversion of T4 into rT3 instead of active T3 and conversion of T3 to (inactive) T2, so intracellular T3 falls almost to zero in the cells can’t function.

Intracellular Hypothyroidism tends to persist long-term, 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, such as dry skin, hair loss, muscle aches, adiposity, skewing of the cholesterol balance, reduced cognition, chronic fatigue symptoms, low libido, impotence and anxiety with panic attacks: all of these are hypothyroid symptoms.

SO: PFS is due to idiosyncratic sensitivity to the debilitating effects of 5-alpha reductse blockade, with ALLOPREGNANOLONE, THDOC, ANDROSTENEDIONE (and possibly other) deficiency.
Deep intracellular hypothyroidism (IH) makes the syndrome much worse, mimicking PTSD and CFS, thus increasing the anxiety and further suppressing Allopregnanolone, in a self-perpetuating spiral.

It is likely that DHEA deficiency is a contributing factor in the development of PFS and it is fair to say that all subjects over the age of 45 years are DHEA deficient, by definition; however that aspect of PFS has not been studied so far.

Regarding DHEA, progesterone and Peyronie’s disease

(1) DHEA production falls 1% per annum from age 25 in all humans and is deficient by age 30. It should be recommended as a supplement for all, after age 30.
(2) PEA, Progesterone and/or Pregnenolone supplementation improves Allopregnanolone production, improving sleep, memory, mood and self-satisfaction. Males produce both pregnenolone and progesterone, so supplementing them in males does no harm.
(3) Peyronie’s disease in PFS must be coincidental: Peyronie’s disease is not caused by hormone deficiency.
(4) See https://cbhrt.ca/2021/08/28/thyroid-hormone-tests/ , 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 and HSCRP. A thyroid profile,including TSH, free T4 & T3, rT3 should also be obtained, so as to see whether the patient also has intracellular hypothyroidism..

Suggested Management, side effects, Prognosis and Follow-up

Management: Stop taking Finasteride and contact a Metabolic Medicine or Functional Medicine MD – present a copy of this article and discuss these suggestions:
[1] Correct Allopregnenolone deficiency with Pregnenolone and Progesterone (100 – 200mg), at bedtime.
[2] Take Melatonin, 10 mg at bedtime: it helps Allopregnenolone, to improve sleep, mood and anxiety and is an antioxidant.
[3] Take DHEA, 50 mg, daily (no more than 50mg /day, so as to avoid increasing Oestrogen): >50mg may raise Oestrogen to female levels, producing breast swelling and occasionally, painful breast cysts.
[4] Test HS CRP, Homcysteine, IGF, Heavy Metals and other markers and treat as necessary.
[5] Correct intracellular hypothyroidism with slow-release Triiodothyronine (AKA Liothyronine), starting with 10 µg daily and titrating upward in 5mcg increments, to achieve a T3 level between 5.0 and 6.2 Pmoles/Litre. T3 can be tested weekly because its half-life is only one day (vs. the 5-7day half-life of FT4).
Do not take desiccated thyroid (DT), Eltroxin, or Synthroid). The T4 will be processed to reverse T3.
[6] Test for T3 weekly, at 4 hours post-dose, until the serum FreeT3 is 5.0 – 6.2 Pmol /L.
[7] Re-test for rT3, T4 and TSH when the serum T3 is > 5.0 Pm/L.
[8] Take Vit D, B12, MTHF, NAC, CoQ10, I-3C, Zinc, Iron, Magnesium, Selenium, Iodine etc, as necessary.
[9] Request Zuranolone (synthetic Allopregnanolone) when it becomes available, as a short-term adjunct to relieve depression, but do not depend on Zuranolone to supplant the entire protocol because it will not eliminate Functional Hypothyroidism.

SIDE EFFECTS OF T3 OVERDOSE and UNDER-DOSE

The classical side effects of T3 overdose are fast heartbeat, anxiety, hyper-reactivity, anger and “antsyness”.

When IH is treated with Cytomel these symptoms are common, due to spiking of T3. They are rare when slow-release T3 is taken and they will not occur if the dose is titrated slowly to a maximum FT3 of 5.0 – 6.2 Pm/L.
The side effect of a mild overdose, with T3 over 6.1, is feeling “high”. It is not unpleasant:p patients report feeling “on top of the world”, alert, optimistic, with augmented 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.

Prognosis

The response to DHEA and Progesterone is usually rapid. However the time to improvement in IH depends on how long it takes to achieve the desired T3 level.
Most often, the Triiodothyronine prescription must be maintained. However if the patient improves to the point at which he or she is stress free, weaning and discontinuation may be successful.

Follow-up

Follow-up will depend on the subject’s condition, so the time-frame should be discussed between practitioner and patient. However thyroid profile observations should be scheduled at one month, 3 months, 6 months, and thereafter, yearly.

The bottom line

PFS, should respond well to treatment with: 
DHEA [50mg or more, daily] for general support and Testosterone enhancement.
PROGESTERONE [50-200 mg or more, HS], or Pregnenolone, for Allopregnanolone support.
MELATONIN [10 mg HS], as a “promoter” of Allopregnanolone.
TRIIODOTHYRONINE, if necessary, for Intracellular Hypothyroidism: T4 should be avoided.
MAGNESIUM (Threonate is best), MTHF, NAC, a good multivitamin and a probiotic regimen (including Lactobacillus and Bifidobacterium), for dietary support.
Vitamin D3.
Follow-up surveillance should include CBC, HbA1c, creatinine, liver function tests, T3, rT3, HS CRP, homocysteine, DHEA, testosterone, estradiol, progesterone, vitamin B-12, vitamin D, calcium, magnesium, IGF, and such other tests as seem necessary.

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 From493 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

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