The Guevedoces: How An Intersex Genetic Defect Led To A Blockbuster Class Of Medicines

Blog #46   Andrew Siegel, M.D.

In the early 1970’s, a Cornell endocrinologist by the name of Julianne Imperato conducted an expedition to the Dominican Republic to investigate reports of a community where children who were thought to be “girls” at birth turned into “boys” at puberty.  In this remote area, these intersex children—biological males with a normal male chromosomal make-up (46 XY) who have female-appearing genitals—surprisingly develop male genital anatomy at the time of puberty. The very interesting tale of the guevedoces (literally, “penis at 12 years”) and how an understanding of their genetic defect led to the development of a commonly used medication is the subject of this week’s blog.

In Salinas, an isolated village of the southwestern Dominican Republic, 2% of the live births in the 1970’s were guevedoces.  These children who appeared to be girls at birth, developed a penis, testicles and all of the typical male physical characteristics at the time of puberty.  Most guevedoces were found to be descendants of a single common ancestor, Altagracia Carrusco.  Their underlying pathology was shown to be deficiency of an enzyme known as 5- alpha reductase (5AR).  This enzyme is responsible for converting the male hormone testosterone into dihydrotestosterone (DHT), the more potent, active form of testosterone.

During uterine gestation, DHT is essential for the development of normal male external genitals.  In the absence of DHT in utero, the external genitals develop as female.  However, internally the gonadal tissue is that of the male.  The guevedoces have feminized external genitals, a short “vagina,” undescended testicles and an absent uterus.  With the testosterone surge at puberty, the tiny penis– that was thought to be a clitoris–develops into a normal-size, functional penis; at the same time, the testicles, previously not within the scrotal sac, descend into the scrotum, and other usual male characteristics develop in terms of libido, musculature, voice change, etc.  For the duration of their lives, the guevedoces resemble other Dominican men in all respects except that they have scanty beard growth, never develop acne, their prostate glands remain small and they never develop baldness.

The discovery of this congenital 5-alpha reductase (5AR) deficiency in this small enclave of the Dominican Republic helped transform my field of urology from a largely surgical specialty into a discipline that became enabled to offer effective drug treatments and minimally invasive procedures for prostate and urinary conditions.  The clinical findings of the guevedoces led Merck researchers in the 1970’s to work on the development of a drug that would replicate the effects that the 5AR deficiency had on the adult guevedoces population. Pharmaceutical scientists reasoned that if 5AR could be inhibited after the external genitalia were fully formed and mature, then a medication to shrink the prostate, relieve urinary symptoms and treat baldness and acne might be developed.  The legacy of the guevedoces became a class of drugs known as 5 alpha-reductase inhibitors (5ARIs), the “prostate pills.”  Finasteride, the original 5ARI, was approved in 1992.  Dutasteride followed, and the treatment approach to prostatic obstruction was forevermore changed.  Aside from prostate shrinkage and symptomatic relief of urinary symptoms, this class of drugs is an effective treatment for male pattern baldness.

I do not believe in medications unless there is a compelling reason to use them and the benefits outweigh the potential side effects. The 5ARIs are genuine winners with a terrific reward/risk ratio and not only do I endorse them and prescribe them liberally, but I personally start my mornings with a dose of Finasteride.   The 5ARIs cause prostate atrophy and alter the natural history of benign prostate hyperplasia, BPH (prostate enlargement), improving the typical urinary symptoms that the aging male is prone to.  They help prevent a situation where a male cannot urinate (acute urinary retention) and requires emergency placement of a catheter and also help prevent the need for prostate surgery.  The 5ARIs are very useful to control blood in the urine that is of prostatic origin, a not uncommon manifestation of BPH.  Studies have shown that these medications confer a risk reduction for prostate cancer, so urologists often employ the 5ARIs for men at high risk: those with a family history; those with very elevated PSA levels; and those with prior prostate biopsies showing pre-malignant findings.   Men on 5ARIs will have a decrease in prostate specific antigen (PSA) to about 50% of baseline and this is factored into ongoing PSA testing.  Another utility is that if the PSA does not drop to 50% of baseline, it is suspicious that an underlying prostate cancer may be an issue.  Additionally, the shrinkage of the BPH as a result of these medications will make the digital rectal exam more sensitive to finding abnormalities that can help make an early diagnosis of prostate cancer.  Most recently, the 5ARIs have been shown to delay prostate cancer progression in men with low-risk, localized prostate cancer. Finally, the 5ARIs promote hair growth, particularly for men with hair loss at the crown of their heads.

The safety record of the 5ARIs deserves mention, as they are intended for long-term use. Aside from a relatively low incidence of sexual dysfunction—difficult to distinguish from the declining erectile capabilities that occur with aging—the 5ARIs are among the most benign treatments for any chronic condition.  Another rather inconsequential result of 5ARIs is that they cause a decrease in ejaculate volume as a result of the prostate atrophy.  5ARIs do not cause major side effects while still depriving the prostate of stimulation because inhibiting 5AR results only in lowering the concentration of DHT within the prostate gland, leaving serum testosterone levels normal or even slightly elevated.

My own tale:

A number of years ago, within a few day period of time, both my wife and father independently noticed and related to me that I had sunburn on the crown of my head.  This did not appeal to my sense of vanity!   I tried topical Minoxidil (Rogaine) but it was ineffective, so I started Propecia (Finasteride 1mg) every morning.  Lo and behold, about six months later, I was startled to find that my exposed scalp was not so exposed any more. It worked slowly, but within a couple of years after starting the Propecia, the vertex of my head had a full regrowth of hair.  No kidding!

When the Veterans Administration report came out demonstrating that the risk of prostate cancer diminished 25% with Finasteride use, this cinched it—particularly insofar as my father had been diagnosed with prostate cancer at age 65.  This is a drug that fixes my bald spot, shrinks my prostate, and helps prevent prostate cancer for which I have a positive family history. This was truly a win-win situation, a real no- brainer.  I will share with you a little insider information—a significant number of urologists and other physicians avail themselves of this class of medications for all of the reasons just stated.  It is truly a medication worth taking.

Andrew Siegel, M.D.

Author of Promiscuous Eating: Understanding and Ending Our Self-Destructive Relationship with Food

Now available on Amazon Kindle

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