How was finasteride invented?

Although finasteride came on the market in the 1990s, the science that led to its development began two decades earlier. The rationale for the drug emerged from a study of a unique group of people in a remote village in the Dominican Republic called Las Salinas. Locals have long known about children who follow an unusual developmental path: they are initially raised as girls, but around age 12 they grow male genitalia and mature into boys. They are known locally as guabidós or guevedoces.1

The village of Las Salinas, where researchers investigated individuals with an intersex condition in the early 1970s, is in the southwestern part of Dominican Republic near the border with Haiti.

In 1972, a Dominican doctor teamed with an endocrinologist from Cornell University to investigate this condition. They identified 24 people in 13 families who had been born as females but matured into males at puberty. The researchers observed a few traits which were different from typical males: when mature, they had no enlargement of their prostate, no acne and no recession of their hairline.

Cornell researcher Dr. Julianne Imperato-McGinley and colleagues first reported their findings in a series of papers, the first of which appeared in Science in 1974. The studied individuals were found to have a deficiency of the enzyme 5-alpha reductase (5-AR) which is needed for the conversion of testosterone into another androgen called dihydrotestosterone (DHT). The condition was named 5-alpha reductase deficiency.

The enzyme 5-alpha reductase (5-AR) enables the conversion of testosterone to dihydrotestosterone (DHT). Individuals studied in Las Salinas had a congenital deficiency of 5-AR, and therefore low levels of DHT. In the 1980s, pharmaceutical companies developed compounds to recreate this deficiency in adults by inhibiting 5-AR, thereby lowering DHT levels. One of these was finasteride which would be approved by FDA in 1992 for the treatment of an enlarged prostate.

Because of the 5-AR deficiency, these individuals had low levels of DHT throughout their lives. Since DHT is required for male genitals to develop early in gestation, babies lacked male genitals at birth even though they had a male (XY) genotype. As mentioned earlier, around age 12 they developed penises and other male sexual characteristics. As they matured into adulthood, there were a few differences with typical male traits: people with 5-AR deficiency did not have enlarged prostates, acne or recession of their hairline. Because they lacked these traits, researchers deduced that normal levels of 5-AR—and therefore DHT—are associated with prostate growth, acne and hair loss in men.

A drug development opportunity is identified

The President of Merck, Roy Vagelos, came across this research and identified a drug development opportunity: if 5-AR could be inhibited in adult males, it might emulate the traits associated with 5-AR deficiency, such as lack of growth of the prostate. Slowing prostate growth could treat a condition in aging men which causes urinary symptoms. Other possible applications were treatment of acne or slowing of hair loss. During the 1980s, several pharmaceutical companies including Merck undertook scientific work to develop and test drugs inhibiting the action of the 5-AR enyzme (termed 5-AR inhibitors). They also filed patents for compounds they developed.

In 1992, FDA approved Merck’s application for a 5-AR inhibitor called Proscar (finasteride, 5 mg) to treat benign prostatic hyperplasia (BPH). In 1994, Merck decided to repurpose finasteride for the treatment male pattern baldness, to be taken by much younger men. This would be granted FDA approval as Propecia (finasteride, 1 mg) in 1997.

Implications of inducing 5-AR deficiency in adult males

Merck’s application for approval of Propecia acknowledged that finasteride induced a 5-AR deficiency. Merck claimed that while DHT was essential for normal early development, low DHT did not present significant risks to adult males. Nevertheless, Merck-sponsored clinical trials of finasteride have consistently indicated risks of sexual dysfunction. A 1992 paper in the New England Journal of Medicine reported significantly higher incidence of Decreased libido, Ejaculatory disorder and Impotence in groups taking finasteride compared to a placebo group. The Proscar drug label (as of 2003) noted:

Side effects due to PROSCAR may include impotence (an inability to have an erection) or less desire for sex.

Some men taking PROSCAR may have changes or problems with ejaculation, such as a decrease in the amount of semen released during sex. This decrease in the amount of semen does not appear to interfere with normal sexual function. In some cases these side effects went away while the patient continued to take PROSCAR.

Proscar drug label (2003)

In a 1994 clinical study of finasteride for hair loss, Merck recorded a case of Impotence which was not resolved several weeks after a patient discontinued the drug:

Excerpted results of Phase 2 clinical study (#047) of finasteride for male pattern baldness, 1992–1994. ‘Still present’ at bottom-right indicates that a patient who had taken finasteride 5 mg/day but discontinued due to Impotence, had not recovered from Impotence several weeks after stopping finasteride (source: Propecia Medical Review, Part 1).

Nearly three decades after this finding, doctors and researchers are divided as to whether finasteride may cause lasting sexual dysfunction after stopping the drug. Further developments in this saga may be found elsewhere on this website, including:

Notes

1. Sources for this post include Sarah Topol, Sons and Daughters: The village where girls turn into boys in Harper’s and Michael Mosley, The extraordinary case of the Guevedoces on BBC News. See also: Sources on the early history of finasteride.