On the Tim Ferriss podcasts I heard a fascinating interview of Edward Thorp, an investor and author, but mostly a man who seems to have some answers on how to age well. While Mr. Thorp’s ideas on investing, statistics, and even gambling are interesting, two things struck me the most.

• One how young and vital Mr. Thorp sounds at the age of 89. (Anyone close to 90 crushing it like that, I am all ears.)
• Two, his use of the pharmaceutical drug Finasteride and how that positively affected his hair growth.

As a urology clinician, I have been against using 5-alpha-reductase-inhibitor (5ARI), the drug Finasteride category, as I’ve noticed significant adverse effects from the use of this drug. While there may be some moderate prostate benefits from using 5ARIs, the risk outweighs the benefits.

What are 5-alpha-reductase-inhibitor (5ARI) drugs, and how do they work

Let’s reverse engineer how 5 ARIs work and then discuss why it might be a problem.

• 5 ARIs inhibits the production of DHT, a byproduct of Testosterone (T), by suppressing the enzyme 5-alpha-reductase (5-AR)
  • Under normal circumstances, Testosterone uses the enzyme 5 AR to make Dihydrotestosterone (DHT)
  • By inhibiting this enzyme with a 5 ARI like Finasteride or Dutasteride, there is less DHT in the body.

Why Stop the Production of Dihydrotestosterone (DHT)?

• DHT seems to have two effects on the body that many men would want to avoid
  • One, it stimulates the muscle part of the prostate to grow.
    • The prostate is 70% glandular and 30% muscle.
  • Two, it promotes hair loss.

What does Dihydrotestosterone (DHT) do in the body?

• During fetal development, DHT is responsible for the formation of the penis, prostate, and scrotum.
• During fetal development, if you don’t make dihydrotestosterone (DHT) then what would be a penis becomes a clitoris.
  • This highlights the importance of DHT during fetal development in the masculinization of boys in the womb. (Walsh et al, 1974)
• While there is much less circulating DHT in adult males, it binds to androgen receptors stronger and longer than testosterone. (Gao et al, 2005)
• DHT is one of four principal androgens in humans and is synthesized primarily via the irreversible action of the 5-alpha-reductase enzyme (5-AR)
  • There are different types of 5-AR
    • In prostate tissue (type II)
    • skin (type I)
    • liver (types I and II)
    • hair follicles (primarily type I)
  • Conversion of T to DHT via the 5-AR activity in peripheral tissue is the main source of circulating DHT
    • little DHT synthesized in the prostate or liver enters the general circulation much metabolism of DHT in these tissues (Swerdloff RS, et al. 2017)

• Despite some false beliefs, there is no evidence that higher levels of DHT increase the risk of prostate cancer (Swerdloff RS, et al. 2017)

How about DHT and Hair growth?

• Do you ever wonder why most guys who have a full head of hair often have very little to no chest hair?
• Every strand of hair on your body grows from a hair follicle. Once it’s freely flowing through your bloodstream, DHT can then link to receptors on hair follicles in your scalp, causing them to shrink and become less capable of supporting a healthy head of hair.
• The progression of hair loss can be gradual, continuous or episodic.
• Paradoxically, DHT cant stimulate hair growth on the face, chest, and genital area, while inhibiting the growth of hair in the skin of the scalp. (Urysiak-Czubatka I et al. 2014)

What happens in a genetic disorder when DHT is not produced in the womb?

In the early 1970s, a rare genetic mutation was discovered in a group of boys from the Dominican Republic group of kids with a genetic mutation that inhibits the production of 5-alpha-reductase; therefore, (Guevodoces), male kids do not produce DHT. With no DHT, there is no development of the penis, prostate, and scrotum until roughly age 12.

Guevodoces

• The condition caused by the inability to produce the 5AR enzyme (by doing so suppress DHT production) is known as Guevodoces (Spanish for guevo – penis, doces- twelve or penis at twelve)
• Researchers observed that the affected males were born with unusual genitals – female-like labial folds with a scrotal appearance, ambiguous vagina, and a clitoral-like phallus
• These kids were initially raised as girls.
• So, despite having an XY chromosome, the boys appear female when they are born. After a T surge at about twelve years old, the form of their genitals, developed body muscle mass, deepening their voices, enlargement of their phallus into a functional penis, testicular descent, and absence of breast development.
• Researchers Imperato-McGinley and team observed that most Guevedoces males live their adult lives as men, though some go through an operation and remain female.
• Likely most interesting, almost all with Guevodoces maintain small prostates as adults. (Imperato-McGinley J et al. 1974)

The Development of 5-Alpha Reductase Inhibitors (5ARI’s), Finasteride (Proscar) and Dutasteride (Avodart)

• This observation, made in 1974, was picked up by Roy Vagelos, head of research at the multinational pharmaceutical giant Merck.
  • He thought this was extremely interesting and set in progress research, which led to the development of what has become a best-selling drug, finasteride, which blocks the action of 5-alpha-reductase, mimicking the lack of dihydro-testosterone seen in the Guevedoces.
• Finasteride (Proscar), a 5-AR1 inhibitor, was approved by the FDA in 1992 for the treatment of BPH(Leonard S Marks, 2014)
  • Proscar used at 5mg daily to is used reduce prostate size in an attempt to treat Lower Urinary Tract Symptoms (LUTS)
  • Propecia, the other tradename for Finasteride, is used at 1mg a day for male pattern baldness

Can Finasteride lower Prostate Cancer Risk, or Does it Increase Risk?

• DHT does not seem to cause significant prostate cancer
  • A study published in 2003 in the NEJM reported a 24.8% reduction in low-grade prostate cancer
  • However, researchers noticed a 27% increased risk of developing high-grade prostate cancer in the finasteride versus the placebo group (P<0.001).[i] (Ian M. Thompson et al, 2003)
• Finasteride can cross the blood-brain barrier and might induce a deficit in neurosteroid metabolism in the central nervous system. (B Rahimi-Ardabili et al, 2006)
• Dutasteride is the other popular 5ARI and goes by the trade name Avodart
  • Dutasteride, a 5-AR1, and 5-AR2 inhibitor, was found to reduce the risk of low-grade prostate cancer in a study involving over 6,000 men.
  • In this trial using dutasteride, the incidence of high-grade prostate cancer during the 4 years of the study was not significantly increased
  • it is important to note; however, the number of men diagnosed with high-grade prostate cancer using dutasteride numbered 29, versus only one in the placebo group. (Gerald L. Andriole et al. 2010)

Do 5-Alpha Reductase Inhibitors (5ARI’s) help lower prostate size and Lower Urinary Tract Symptoms (LUTS)

• 5-ARIs therapy was shown to effectively reduce prostate volume by approximately 20% in many patients.
• However, about 25%-30% of patients do not experience any improvement in their urinary symptoms, and another 5%-7% developed worsening symptoms and may ultimately require surgery (Bechis SK et al, 2014)

What is Post-finasteride syndrome (PFS)?

Post-finasteride syndrome (PFS) is a controversial and ill-defined spectrum of symptoms in 3 categories: sexual, physical, and psychological that putatively arise and persist despite finasteride exposure and cessation.  The FDA mandated a label change on finasteride advising a risk of libido loss, erectile dysfunction (ED), ejaculatory disorders, gynecomastia, and other adverse experiences based on low level evidence reports lacking validated questionnaires. (CA Ganzer et al. 2015)

The Food and Drug Administration Adverse Event Reporting System (FAERS)

• From April 1, 2011, to October 27, 2014 looking at over 3200 cases spanning a 43-month period shows the following:
  • A monotherapy dose observed in the data: finasteride 1mg or Propecia (1581 cases); finasteride 5mg or Proscar (240 cases); dutasteride or Avodart (1 case); finasteride unreported dose (226 cases)
  • The age of the 5mg finasteride users was significantly older, of course, at a mean of 59 years old, give or take, compared to those who used finasteride 1mg, a mean age of 35.
  • Significantly higher frequencies for the 1mg dose were found for sexual dysfunction, libido decrease, ejaculation disorder, erectile dysfunction, testicular atrophy, orgasmic disorder, hypogonadism, skin rash, metabolism abnormalities, self-harm, slow cognition, psychological pathology, change in emotional affect, and sleep disturbances.
  • Breast enlargement (gynecomastia) was the only symptom reported as more prevalent for 5mg versus 1mg.
  • No differences between the 1mg and 5mg doses were found for loss of penis size, curvature of the penis, infertility, prostatitis,fatigue, muscle weakness, hearing defect, and memory impairment.
  • Interestingly, no PFS symptoms were reported for dutasteride in the 1 monotherapy case in the FAERS database. (Source link)

Closing Thoughts on Finasteride and Prostate Health

The discussion on Finasteride in Tim Ferris’ interview came up when Tim asked, “how does an eighty-nine-year-old grow and grow their hair?” Mr. Thorp answers by admitting he “stumbled” upon the Finasteride drug to prevent his prostate from getting larger, preventing urinary symptoms. As a side effect to presumably the prostate benefits, Mr. Thorp attributes to having so much hair from consuming the drug at his age. When I heard Mr. Thorp speak on Finasteride with such enthusiasm, I was reminded of my bias against 5-alpha-reductase inhibitors and how chemicals in the body work differ for different people. There is some chance, of course, that some people can benefit from a 5-ARI with minimal to no negative effects. Lastly, when listening to Mr. Thorp’s robust and vital voice at almost ninety, you can easily say, “I’ll take what he’s having.”

The likelihood of clinically recommending 5-ARI’s is minimal and some of the reasons might be that:

• I tend to see people who do poorly from 5ARI’s (Post-Finasteride Syndrome), so the homogeneity of my practice dictates to rarely see the positive effects of such drugs.
  • Patients clinically see me for natural medicine to improve their prostate health.
• Despite being an integrative practitioner and recommending pharmaceuticals when necessary, I find natural, nutritional, and lifestyle methods, when properly prescribed, work well for all prostate diseases, including prostate cancer.

The bottom line is the management of prostate-related urinary problems can be effectively managed through meditation, physical exercise, botanicals, and nutrition. If a pharmaceutical drug is required, I find alpha-blockers like Tamsulosin to work well with minimal side effects–mostly no ejaculate after orgasm and, in small cases, sinus pain and discomfort. Some surgical procedures may benefit if a big prostate contributes to urinary problems (sometimes the bladder is the primary problem). When I have a patient like Mr. Thorp in my office – healthy, engaged with life, and energetic – I have them keep doing what works for them. Who am I to question a healthy 89-year-old?

Podcast Resource:

Let’s talk about an Enlarged Prostate (BPH)

How Sleep Can Improve your Urological Health

Sources and Citations:

• Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944–949.
• Gao et al, 2005)W, Bohl CE, Dalton JT.Chemistry and structural biology of androgen receptor. Chem Rev. 2005;105(9):3352–3370.
• Swerdloff RS, Dudley RE, Page ST, Wang C, Salameh WA. Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr Rev. 2017;38(3):220-254. doi:10.1210/er.2016-1067
• Urysiak-Czubatka I et al. 2014)Kmieć ML, Broniarczyk-Dyła G. Assessment of the usefulness of dihydrotestosterone in the diagnostics of patients with androgenetic alopecia. Postepy Dermatol Alergol. 2014 Aug;31(4):207-15. doi: 10.5114/pdia.2014.40925. Epub 2014 Sep 8. PMID: 25254005; PMCID: PMC4171668.
• Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974 Dec 27;186(4170):1213-5. doi: 10.1126/science.186.4170.1213. PMID: 4432067.
• Leonard S Marks. 5α-Reductase: History and Clinical Importance. Rev Urol. 2004; 6(Suppl 9): S11–S21.
• Ian M. Thompson, M.D., Phyllis J. Goodman, M.S., Catherine M. Tangen, Dr.P.H., M. Scott Lucia, M.D., Gary J. Miller, M.D., Ph.D., Leslie G. Ford, M.D., Michael M. Lieber, M.D., R. Duane Cespedes, M.D., James N. Atkins, M.D., Scott M. Lippman, M.D., Susie M. Carlin, B.A., Anne Ryan, R.N., et al. The Influence of Finasteride on the Development of Prostate Cancer. N Engl J Med 2003; 349:215-224
• B Rahimi-Ardabili, R Pourandarjani, P Habibollahi, A MualekiFinasteride induced depression: a prospective study; BMC Clin Pharmacol, 6 (2006), p. 7
• Gerald L. Andriole, M.D., David G. Bostwick, M.D., Otis W. Brawley, M.D., Leonard G. Gomella, M.D., Michael Marberger, M.D., Francesco Montorsi, M.D., Curtis A. Pettaway, M.D., Teuvo L. Tammela, M.D., Claudio Teloken, M.D., Ph.D., Donald J. Tindall, Ph.D., Matthew C. Somerville, M.S., Timothy H. Wilson, M.S., et al., for the REDUCE Study Group. Effect of Dutasteride on the Risk of Prostate Cancer. N Engl J Med 2010; 362:1192-1202.
• Bechis SK, Otsetov AG, Ge R, Olumi AF. Personalized medicine for the management of benign prostatic hyperplasia. J Urol. 2014 Jul;192(1):16-23. doi: 10.1016/j.juro.2014.01.114. Epub 2014 Feb 25. PMID: 24582540; PMCID: PMC4143483.
• CA Ganzer, AR Jacobs, F IqbalPersistent sexual, emotional, and cognitive impairment post-finasteride: a survey of men reporting symptoms;Am J Men Health, 9 (2015), pp. 222-228