How was finasteride invented?

by

Although finasteride came on the market in the 1990s, the underlying research 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 there have long known about children who follow an unusual developmental path: they are initially raised as girls, but around age 12 they develop male characteristics. 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, endocrinologist Julianne Imperato-McGinley, colleagues at Cornell, and a Dominican doctor traveled to Las Salinas to study people with this condition. They identified 24 people in 13 families who had been born with female or ambiguous genitalia, but developed male traits at puberty, a process they called virilization. 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.

Dr. Imperato-McGinley and colleagues 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). Today, the condition is called 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 male traits and tended to acquire a male psychosexual orientation. 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. 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 head of Merck’s research division, 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 reduced 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, Merck and other pharmaceutical companies undertook scientific work to develop a new class of drugs: 5-alpha reductase inhibitors.

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

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 (see: Since 1994, Merck has been aware of unresolved sexual dysfunction in men who stopped taking finasteride).

Reminiscent of genital abnormalities in the individuals in Dominican Republic, recent research has demonstrated an association of 5-ARI use with genital shrinkage and other penile abnormalities as described in this research review.

Note

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.

Further reading