As Published in TG Forum and the Pinnacle

We all have had our time in the closet secreted from our closest relatives. But what if you had just discovered that your present state of gender expression has been a secret understood by your parents, grandparents and preceding generations, but never understood by you until their pasts were revealed. Would you then go out and tell the world?  Well, such is the story of "Middlesex", a 2003 Pulitzer Prize winning novel, written by Jeffrey Eugenides. This wonderfully written sensitive tale is a fictional epiphany as told by a male pseudo-hermaphrodite. That is someone born as a male with normal XY chromosomes and undescended testes, but appearing at birth to have female or ambiguous genitalia and therefore raised as a female only to emerge as a male at puberty. Other male pseudo-hermaphrodites may have different developmental scenarios depending on their etiology. The story is beautifully narrated describing the thoughts of the protagonist's confusion about where She came from, her differences in sexual development, and where He will end up. Using the author's knowledge of the Greek-American community and some Greek mythology, we learn that this creative masterpiece is based on one true scientific fact. That a rare form of hermaphroditism has existed for centuries on the Turkish-Greek border due to a genetic failure to produce the enzyme, 5-alpha reductase Type 2, which converts Testosterone (T) to the more powerful and useful Dihydrotestosterone (DHT). Its expression as this rare form of intersex is guaranteed when intermarriage between cousins occurs because it is a recessive gene requiring both parents to possess it. Also because it is recessive, the birth of pseudo-hermaphrodites may skip generations, but the gene marches on.

While hermaphroditism has existed for millennia, it was only in 1974 that this particular form of pseudo-hermaphroditism was first described in detail by Dr. Walsh of Johns Hopkins in the New England Journal of Medicine (NEJM). Since then families from Lebanon, Mexico, Brazil, Cyprus, New Guinea and the Dominican Republic have been found to possess this gene (SRD5A2) mutation on Chromosome 2.  Thankfully the author had misplaced it on Chromosome 5, the home of the 5-AR Type 1 gene, which suggests that this wonderful work of fiction cannot be used to justify any ideological position taken on the subject of intersex and future gender identity.  What is more remarkable are the scientific discoveries based on this original discovery that have lead to the development of the drugs Proscar, Propecia, Finasteride and Dutasteride. Since this is a Medical Column and not a book review, a little basic science is in order as the drugs and hormones mentioned above will affect your life no matter what form your gender expression takes.

Before 1974 it was recognized that Testosterone was converted to DHT by the enzyme 5-alpha reductase, (5-AR), and later it was noted that there were 2 different 5-AR enzymes, Type 1 and Type 2 acting on different end organs. Type 1 acts on the scalp and predominates through adult life.  While Type 2 appears at puberty in smaller amounts and influences hair on the face, chest, and genitalia.  While androgens are not required for normal scalp hair growth, DHT appears briefly at birth, and is required for the expression of beard, chest and abdominal hair after puberty. There is evidence to suggest an interaction between Type 1 and Type 2 in developing baldness. It also appears that increased DHT sensitivity is required for the development of familial balding late in life. Testosterone by itself can be sufficient for pubic, scant upper lip, and axillary hair growth as seen in these individuals at puberty. It now appeared that this deficient enzyme (5-AR Type 2) was also necessary for the full development of the male genitalia and prostate growth in the developing fetus.

In the early 1970�s, Dr. Imperato, a Cornell endocrinologist, studied an isolated village in the Dominican Republic, where children raised as girls would turn into men at puberty. In the village they were known as "guevedoces" translated as "penis at 12" or "machihembra" or "half man / half woman." While these children appeared to have female genitalia at birth, at puberty they would develop a small penis, an enlarged scrotum with occasional testicular descent and pubic hair. As the male phenotype develops with the pubertal surge of Testosterone, they experience a deepening of the voice, increased musculature and a male psychosexual orientation. For the rest of their lives they live as men doing what men do in the village. With the absence of DHT, they are absent a beard with no loss of scalp hair, have decreased ejaculations and no prostate growth.

And then some brilliant chemists at Merck Pharmaceuticals, realized that if they knew what the enzyme was that produced prostate growth and caused balding, "Why could't they develop a drug that inhibited the natural enzyme, 5-alpha reductase type 2 ?" and so the drug, Finasteride, a 5-AR Type 2 inhibitor, was born. After long testing it was noted to be safe in men while causing a 30% reduction in benign prostatic growth and was marketed as Proscar. Then in further testing it was noted to decrease hair loss and was marketed as Propecia. But its greatest accomplishment has just been published in the NEJM as the first preventive drug proven to reduce the risk of developing a specific cancer, Prostate Cancer.  Much work has to be done to improve the promise of this drug, but already a new drug, Dutasteride, known as Avodart,  has been developed which inhibits 5 AR Type 1 and Type 2.  As an aside, only 4% of men 18 to 40 years of age taking Finasteride reported a decrease in libido and increased erectile dysfunction.

With a little vision I can see this family of drugs being of great value to the TG community. Its safety profile is much better than the androgen receptor blockers, such as Flutamide, which women have used to reduce unwanted hair. For MTF's in transition, it can block that receding hairline and balding, decrease the regrowth of facial hair after you have spent all that money on laser treatments and may become your anti-androgen of choice for the earlier stated benefits. It is certainly more effective than Spironolactone which only blocks 2-5% of all Testosterone. It can also be easily obtained with a prescription for any of the above indications, but the book can be purchased without a prescription and is highly recommended for sheer enjoyment.

Best of Luck in Your New Future,

Cerise Richards, M.D.