Hair or manhood—choose one?

Early studies of atypical development hinted at effects of finasteride in healthy men

Since the 1940s, medicine has moved into new territory: the human scalp and hair. As we trace how balding became a medical subject, be advised that we’ll get into unfamiliar and sometimes disturbing topics. The history begins with eunuchs of ancient Greece, then moves to experiments on disabled people who had been forcibly sterilized, and finally a rare disorder of sexual development that sometimes involves a gender switch. Read on or abandon ship, depending on your interest and tolerance.

In ancient Greece, Hippocrates and Aristotle observed that eunuchs—males who had been castrated at a young age—did not go bald. Jumping ahead to the early 1940s, American anatomist James B. Hamilton studied the same link at an institution for the disabled in Winfield, Kansas. Under a program influenced by the eugenics movement, some residents had been castrated at different ages. Others had a testosterone deficiency for other reasons. Hamilton reviewed 104 men’s medical histories and found a pattern: the earlier the age of hormone deficiency, the less balding occurred. In an experiment, Hamilton selected 12 adult men who had a deficiency from a young age, and no hair loss. When they received injections of testosterone, four of the men began to lose hair. These four men had a family history of hair loss, while the others did not. Hamilton concluded that both male hormones and genetics had a role in balding.

In a 1951 article, Hamilton proposed a scheme for classifying different stages of baldness. The scheme was refined by dermatologist O’Tar Norwood in 1975. The resulting classification, the Norwood scale, remains in use today.

Dr. Norwood, in turn, had a prominent role in the rise of hair transplant surgery. In 1993, Norwood and another dermatologist, Dr. Dow Stough, took steps to form a professional society for hair surgeons. At this early stage, the specialty became entwined with the development of finasteride. Stough joined a “study group” on the drug, convened by Merck. Hair restoration doctors and the drug maker could both benefit from joining forces. The hair surgeons saw finasteride as a support for their transplant procedures, as the drug is intended to prevent further hair loss when follicles are transferred from another part of the scalp. Merck would also benefit, since the surgeons would be active prescribers of the drug.

Following approval by FDA in December 1997, Propecia brought in billions for Merck, and was frequently prescribed by hair restoration doctors.

There was another key precursor of the drug, this one concerning its mechanism. It came from study of another population where balding was absent, and once again the trait was linked to incomplete male sexual maturity.

In the early 1970s, Cornell endocrinologist Julianne Imperato-McGinley and colleagues traveled to a remote village in the Dominican Republic, to study individuals with an unusual pattern of sexual maturation. At birth they resembled girls, but developed some male characteristics at puberty. Locals called them guevedoces, while the researchers termed them male pseudohermaphrodites (today, the condition is called 5-alpha reductase deficiency). The researchers discovered that the lack of normal male traits at birth was due to a genetic mutation that prevented converting testosterone to another androgen. They also noted that these individuals had no recession of their hairline and small prostates.

These findings, first published in Science in 1974 and elaborated in later papers, caught the notice of Merck’s chief executive Roy Vagelos. The company saw an opportunity: if a drug could emulate the same androgen deficiency as found in male pseudohermaphrodites, it might stop growth of the prostate and hair loss. Merck engaged Imperato-McGinley to consult on drug development, as part of the study group on finasteride for hair loss. The group brought the scientific and clinical lineages of hair loss treatment together: as mentioned earlier, another member was Dr. Dow Stough, the hair transplant surgeon.

Looking across the populations studied—the eunuchs of ancient Greece, the castrated men of Kansas and the male pseudohermaphrodites of Las Salinas—the absence of hair loss has long been connected to altered sexual anatomy, impaired sexual function and infertility. The hormonal account nevertheless hinted at a “treatment”: if androgens cause baldness, then suppressing androgens might prevent going bald. This occurred to Hamilton, but he took a conservative stance: “No means of therapy is suggested for decreasing androgenic stimulation in sexually normal individuals,” he wrote in 1942. In the 1980s, pharma giant Merck set out to do exactly that: decrease androgenic stimulation. Its preferred drug candidate, finasteride, was designed to inhibit a potent androgen created from testosterone called dihydrotestosterone (DHT). (Merck claimed that the androgen was only needed up to puberty, and that male pseudohermaphrodites were healthy in adulthood.) Merck’s application for Propecia was ultimately approved by the U.S. Food and Drug Administration in 1997.

When Merck brought finasteride to market, the historical connection to the male pseudohermaphrodites of Las Salinas was obscure. This is no surprise, as these individuals often had underdeveloped or ambiguous genitalia and limited fertility as adults. Propecia was launched as a drug which was grounded in science, safe and well-tolerated. The first Propecia label acknowledged sexual side effects in less than 4% of men, adding that these effects stopped after discontinuing the medication in all men, and in “most” who continued taking the drug. Yet in real-world use of the drug, sexual dysfunction has been observed to continue after stopping the drug (an outcome observed in Merck’s own clinical trials). Recent research has linked finasteride and dutasteride to penile abnormalities. These outcomes call into question Merck’s claim that DHT is not necessary for adult men.

There is no harm in identifying a role of hormones in male baldness. But Merck and its collaborators in dermatology and endocrinology went much farther in pursuit of a blockbuster drug. They fashioned hair loss into a medical condition, and supplied a “treatment” which inhibits an androgen. Arguably this has opened Pandora’s box, as safety concerns have only increased since the drug’s introduction nearly 25 years ago. It is far from clear that inhibiting androgens is a good idea for healthy adult men who want to retain their male sexual characteristics and function.

Acknowledgment: Thanks to a social psychologist for providing historical context and valuable insights, making it possible to link Propecia to broader themes and developments.

Sources & further reading