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.
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,
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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).
Tags: ambiguous genitalia, Andrew Siegel MD, genetic sex, genital development, genital differentiation, genital sex, Guevedoces, testosterone
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