Posts Tagged ‘Guevedoces’

“Girl” At Birth, “Boy” At Puberty… and A Blockbuster Drug

December 17, 2016

Andrew Siegel MD 12/17/16

Last weeks’ entry discussed the similarities and common embryological origin of male and female genitals.  Today’s entry segues into a fascinating genetic defect that causes “ambiguous” genitalia and how Big Pharma capitalized on the positive aspects of this genetic defect and created a billion dollar industry with a type of medication in common usage and, in fact, one that yours truly takes on a daily basis.

Whether one develops a penis or a vagina is determined instantly the moment the father’s sperm penetrates the mother’s egg. The egg contains only an X chromosome and the sperm either an X or Y chromosome. The blueprint for female genital development is when the coupling results in an XX; the blueprint for male genital development when the coupling results in an XY.

Bottom Line: Genetic (chromosomal) sex determines genital sex. The father determines the sex of the child.

Skip ahead to a few weeks later, when the fertilized egg has turned into an embryo. At this time the external genitals are identical…somewhat surprising considering how very different the genitals are in appearance at birth and beyond.

Female genitals are the “default” model, which will remain female, absent the presence of the male hormone testosterone (T). When T is present it is converted into an activated form–dihydrotestosterone (DHT) –which causes conversion of what would be a vulva and vagina into a penis and scrotum. Biochemical magic!

In the young embryo there are three key genital structures: the “tubercle,” the “folds” and the “swellings.”

In the absence of T/DHT, the genital tubercle (a midline swelling) develops into a clitoris. The urogenital folds (two vertically-oriented folds of tissue below the genital tubercle) become  labia minora (inner lips). The labio-scrotal swellings (two vertically-oriented bulges outside the urogenital folds) fuse to become labia majora (outer lips).

In the presence of T/DHT the genital tubercle morphs into a penis, the urogenital folds become the urethra and part of the penile shaft and the labio-scrotal swellings fuse to become a scrotum.

Bottom Line: Female external genitals are the default model. The developing embryo will remain female unless T/DHT are available to masculinize the external genitals. 

“Ambiguous” genitalia

XY chromosomes determine male genital development and XX chromosomes determine female genital development and the vast majority of the time, the external genitals develop as per genetic blueprint with no ambiguity—a penis vs. a clitoris, scrotum vs. labia, etc.

However, the developmental process that causes genital tissue to become “male” or “female” can be disrupted and may lead to “ambiguous” genitals. These disruptions can cause the external genitals to not have a typical male or female appearance, making it difficult to identify an infant as male or female. Rarely, the appearance may be the complete opposite of the genetic sex (XX or XY).

The ambiguous genitals of a genetic female have the following characteristics: a clitoris that is substantially enlarged and can look like a small penis; the urethral opening in an abnormal location; and fused labia that appear like a scrotum. The situation can be so extreme that the infant is thought to be a newborn male with undescended testicles.

By far, the most common cause of XX appearing males is a condition of the adrenal gland that affects the production of hormones ultimately resulting in a genetic female having high levels of T.  These high levels “masculinize” the female default model.

The ambiguous genitals of a genetic male have the following characteristics: a small penis resembling an enlarged clitoris; an abnormal location for the urethral opening, sometimes opening on the perineum and not the penis; a small scrotum that may be separated in the midline appearing as labia; and undescended testicles.

XY appearing females can occur because of lack of production of T, lack of T receptors such that the body cannot respond to T, or the presence of T but lack of the enzyme that converts T to DHT (more on this below).

The Guevedoces

In the early 1970s, a Cornell endocrinologist (hormone specialist) conducted an expedition to the Dominican Republic to investigate reports of children who were thought to be “girls” at birth who turned into “boys” at puberty.  These biological males with normal male chromosomal make-up (XY) are born with female-appearing genitals and shockingly develop male genital anatomy at the time of puberty. These children were called guevedoces (“penis at 12 years”).

In this isolated village, 2% of births in the 1970s were guevedoces.  These children who appeared to be girls at birth developed a penis, testicles and typical male physical characteristics at the time of puberty. Most guevedoces were found to be descendants of a single common ancestor. The problem was shown to be deficiency of an enzyme known as 5-alpha reductase (5AR), responsible for converting T into  DHT, the more potent activated form of T. During embryonic development, DHT is essential for the development of normal male external genitals.  In the absence of DHT, the external genitals develop as female.

Internally the guevedoces have male gonadal tissue (testes and not ovaries). The external genitals are feminized, with 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 typical male characteristics develop including sex drive, body 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 and never develop acne, prostate gland enlargement or baldness.

guevedoces-bbc-republica-dominicana

A male with 5AR deficiency at age 12, 19 and 42

The discovery of this congenital 5-alpha reductase (5AR) deficiency in this small enclave of the Dominican Republic enabled an effective drug treatment for prostate enlargement. In the 1970s a drug was developed that replicated the effects that the 5AR deficiency had on the adult guevedoces population. 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 5AR inhibitors (5ARIs), the “prostate pills.”  Finasteride (Proscar for the prostate; Propecia for male pattern baldness), the original 5ARI, was approved in 1992. Dutasteride (Avodart) 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.

Wishing you the best of health,

2014-04-23 20:16:29

www.AndrewSiegelMD.com

A new blog is posted every week. To receive the blogs in the in box of your email go to the following link and click on “email subscription”:  www.HealthDoc13.WordPress.com

Andrew Siegel MD practices in Maywood, NJ.  He is board-certified in both urology and female pelvic medicine/reconstructive surgery and is Assistant Clinical Professor of Surgery at the Rutgers-New Jersey Medical School and attending urologist at Hackensack University Medical Center. He is a Castle Connolly Top Doctor New York Metro area and Top Doctor New Jersey.

Dr. Siegel is the author ofTHE KEGEL FIX: Recharging Female Pelvic, Sexual and Urinary Health (www.TheKegelFix.com) and MALE PELVIC FITNESS: Optimizing Sexual & Urinary Health (www.MalePelvicFitness.com). 

 

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

February 18, 2012


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

www.PromiscuousEating.com