Minoxidil Tests : Putting Hair Back Where It Belongs

When researchers tested the high blood pressure drug minoxidil in the 1970s, they were distressed to find that nearly all their patients suddenly grew more hair--all over their bodies. Some of the scientists even published papers describing ways to remove such hair, lest their patients quit taking the powerful drug.

But dermatologists around the country were intrigued. One of them was Virginia Fiedler-Weiss of the University of Illinois Medical Center in Chicago. She was treating patients who were made bald by severe allergies to their own hair follicles and who had failed to respond to all previous therapies.

Prepared Lotion

Fiedler-Weiss prepared a lotion from crushed minoxidil tablets and had three such patients apply a thin layer to their scalps twice a day. Within weeks, much to her amazement, two were growing normal hairs, including a 13-year-old girl who had been bald since age 8. The third grew no hair.

“The teen-ager ultimately had a cosmetically acceptable result as long as she kept using the medicine,” Fiedler-Weiss recalled in an interview. “It helped her adjustment in school and made her a much happier person.”

No one has figured out yet how minoxidil works, but the serendipitous discovery is being hailed by many dermatologists as one of the most important advances in the history of hair research.

“Minoxidil is the first (baldness) preparation that is not snake oil,” said Dr. Arthur P. Bertolino, a hair researcher at the New York University Medical Center. “It actually helps hair to grow.” But dermatologists caution that the minoxidil solution is unlikely to help most people with severe hair loss. Rather, many believe the drug’s greatest uses will be to help patients hold on to the hair they already have and to help reverse early baldness.

In addition, questions about the solution’s potential side effects remain unanswered.

Must Be Used Indefinitely

It seems to work only if a person uses it indefinitely. And minoxidil--in pill form, at least--can cause severe side effects, such as fluid retention. Thus, the safety of long-term use on the skin is still uncertain.

The solution, called Regaine and made by the Upjohn Co. of Kalamazoo, Mich., was given a large boost earlier this month when the Canadian government concluded that it was “safe and effective” and could be sold by prescription. Guatemala has also approved it.

In the United States, the drug is still considered experimental by the Food and Drug Administration, which is reviewing Upjohn’s test data. The firm has also applied to sell the drug in more than a dozen other countries.

Topical minoxidil has been tested against hereditary male-pattern baldness, which causes noticeable hair loss in about 50% of men by age 50, and severe cases of a lopecia areata, a puzzling allergic condition that affects both sexes and is the second most common cause of significant hair loss.

Alopecia areata is estimated to affect about 1% of the population at some point; some victims eventually regain their hair without treatment.

Most people, including some dermatologists, first learned about minoxidil’s effect on hair growth from a 1980 letter in the New England Journal of Medicine by Dr. Anthony R. Zappacosta of Bryn Mawr, Pa.

The kidney specialist noticed that a 38-year-old dialysis patient, who had been nearly bald since age 20, suddenly grew “extensive” hair on his scalp after taking minoxidil pills for high blood pressure. The hair growth was all the more surprising because the patient was receiving shots of a hormone that often causes scalp hair loss.

After Zappacosta’s two-paragraph letter was published, he was deluged with hundreds of letters and telephone calls from patients wanting his baldness “treatment.” He answered every letter and included Upjohn’s phone number and address.

‘Very Surprised’

“I was very surprised because I had not discovered some big secret,” Zappacosta recalled in a recent telephone interview. Indeed, he hesitated before writing the letter because he thought that it was “common knowledge” among doctors that minoxidil can cause hair growth.

Zappacosta’s letter and other case reports that surfaced at about the same time were catalysts for further research.

Dermatologists such as Fiedler-Weiss reasoned that minoxidil’s blood-pressure-lowering effects--and its side effects--could be avoided by applying the drug directly to the scalp.

“It was theoretically possible (that minoxidil would work), or I wouldn’t have tried it,” she recalled.

In 1981, after two of her first three patients had dramatic responses to minoxidil, Fiedler-Weiss called Upjohn and learned that the company had already started its own preliminary studies of the solution.

Fiedler-Weiss later collaborated with Upjohn on a larger study of a lopecia areata patients at the University of Illinois. Her results, published in 1984, showed that 25 of the 48 patients grew new hairs, but only 11 patients had what the researchers conservatively described as “cosmetically acceptable” results.

As word circulated about the favorable initial results of the hair-growth experiments, callers deluged Upjohn and dermatologists.

In mid-1983, Upjohn sponsored-trials, involving more than 3,000 relatively healthy patients with male-pattern baldness, started at 27 sites across the country. After Stanford University Medical Center asked for volunteers, the UCLA Medical Center also received hundreds of calls, even though UCLA was not part of the study.

Some of the volunteers were so motivated that they agreed to undergo scalp “biopsies,” a procedure in which small pieces of skin were removed to be examined under the microscope.

Each Hair Counted

In the trials, the dermatologists, who were kept unaware of which patients were using minoxidil and which a placebo solution, used magnifying glasses to painstakingly count each hair in small standardized circles on their patient’s scalps. They also took pictures of the scalps.

Teen-agers typically have 800 to 900 hair-growing follicles per square inch. Balding men often have only 200 to 300 hair-growing follicles, many of which produce only tiny fuzzy hairs. In male-pattern baldness, minoxidil appears to work by stimulating follicles that have shrunk with age to produce longer and thicker hairs.

For male-pattern baldness, the trials showed that minoxidil causes about three-quarters of the men who are already bald or significantly balding to grow new hairs that were more than fuzz after several months.

But, at most, only a third of the men, primarily the least severe cases, experienced enough new hair growth to be considered “cosmetically acceptable,” according to dermatologists who took part in the trials. Fewer still--dermatologist’s estimates varied from 2% to 15%--had dense hair growth.

“Many of my patients were happier after four months than after a year,” Dr. Harry Roth of the UC Medical Center, San Francisco, said in a telephone interview. “As time goes by, some realize that they are not going to get a heavy hair growth like a shaggy teen-age boy.”

Some researchers remained skeptical about the long-term benefits and the safety of minoxidil solution. Patients who take minoxidil pills for high blood pressure may have severe side effects, such as fluid retention, increased heart rate and fainting. Thus, most physicians reserve minoxidil, which has been sold in the United States as Loniten since 1979, for their most difficult-to-treat cases.

Concerns Allayed

Many of the researchers’ concerns about topical minoxidil have been allayed, however, by the Upjohn-sponsored studies, which show that, at most, only 4% of the dose of medicine applied to the skin was absorbed into the bloodstream. By comparison, at least 90% of the medicine is absorbed when taken by mouth.

Further tests using different strengths of the drug established that a 2% solution may be the best dose for treating male-pattern baldness--without stimulating hair growth on the face, arms and legs as well.

Upjohn said no major side effects from the solution were detected, such as those associated with the pills, although some patients had itching, blistering and scaling of their scalps. Even so, physicians have been reluctant to test the solution in patients with serious illnesses, such as heart failure or the chest pain called angina, according to Dr. Mark Houston of the Vanderbilt Medical Center in Nashville, Tenn.

(There have been 10 reported deaths as of April among people who have used topical minoxidil, but they are not believed to be related to the drug.)

As a result of the widespread favorable publicity, including articles in the major news weeklies and business publications, annual sales of minoxidil pills have increased sharply to about $5 million.

And already, at least several hundred thousand Americans are paying upward of $1,000 a year for bootlegged preparations, according to New York University’s Bertolino.

One San Francisco dermatologist estimated that more than half of his colleagues prescribe minoxidil solutions. In Los Angeles, one dermatologist put the number at 20% to 25%.

Physicians have the discretion to prescribe licensed drugs for unapproved uses, although both the FDA and Upjohn have issued warnings against prescribing such ad hoc minoxidil preparations. The bootlegged solutions are usually prepared by pharmacists following physicians’ directions, by dissolving minoxidil pills in a mixture of alcohol and propylene glycol. These solutions are of varying quality; some contain inadequate concentrations of the drug to grow hair.

One pharmaceutical analyst, Oleh Denysyk of Charles Kline & Co. in Fairfield, N.J., speculated that the eventual market for Regaine might rival the $500-million annual market for the anti-ulcer drug cimetidine, the current leader in prescription drug sales.

Partial Results Revealed

This spring, Upjohn fueled such speculations by revealing in a press release partial results of its studies involving topical minoxidil for male-pattern baldness after a meeting with the participating researchers.

The FDA was not pleased. It sharply criticized Upjohn for making “false and misleading” statements that implied that minoxidil solution was an “innocuous drug” that could cure baldness.

“The full safety and toxicity issues . . . have not yet been fully evaluated,” the agency said in a letter of reprimand to company officials. “Some of the 27 centers reported minoxidil treatment no better than placebo, and in some instances the ‘placebo effect’ (roughly 20%) was higher than the results of active drug.”

Upjohn disputed the FDA’s allegations, saying that the overall study results provided “statistically significant” evidence of minoxidil’s safety and effectiveness. The company said it had to make public the results at the same time that it told the researchers to comply with Securities and Exchange Commission regulations and avoid possible “leaks” of the information to some investors.

Nevertheless, Upjohn subsequently has stopped talking to the media about minoxidil.

But as word continues to spread about the initial results of the minoxidil tests, many dermatologists are having to counsel patients about the drug.

“The publicity has not been handled well,” Fiedler-Weiss said. “Initially, a great deal of hype was attached to it. More recently, the other extreme has been taken.

“It is reasonable to take a middle ground. (For some patients,) minoxidil has a place, but it is certainly no cure-all.”