"Wrinkles are a terrifying lesion for most people, and that's what this hullabaloo is all about," says Dr. Albert Kligman, professor of dermatology at the University of Pennsylvania and the discoverer of Retin-A. This prescription drug of the hour is suddenly on the lips of all fair-skinned people over 35, the aging baby boomers who want a sure-fire way to keep a youthful glow for the rest of their lives. They seem to have decided, en masse, that the way to look young forever is to get a prescription for this highly touted "miracle cream."

Retin-A, a vitamin A derivative delivered as a cream, lotion or gel, originally was approved for the treatment of acne. But its fame spread -- and its supplies all but disappeared -- within days of publication last month of a small study in Michigan that confirmed something dermatologists have suspected for 17 years. Retin-A seems to rejuvenate aging skin.

Why are so many people suddenly clamoring for Retin-A? Why the frenzy now, two years after Kligman's own study of its anti-aging effects was first published? And what does the Retin-A story tell us about Americans' reluctance, even in these days of health consciousness and feminist enlightenment, to simply look their age?

"Youth is what everyone is after," says Dr. Joseph Bark, a Lexington, Ky., dermatologist and author of "Skin Secrets" (McGraw-Hill, $18.95). "And that's what the reaction to Retin-A proves. It's incredible to get such a huge population of people willing to incur this much irritation" -- because Retin-A does have its adverse side effects -- and to wait patiently for the four to six months it usually takes for some visible improvement, all in the name of youth.

Incredible, maybe, but not so incredible that Bark and Kligman can't identify with the frenzy. Both men use Retin-A themselves to erase fine wrinkles and smooth out their skin. "It's working so well," says Bark, who started on Retin-A last spring, "that I wouldn't give it up."

Why Now?

The "hullabaloo" over Retin-A began with a Jan. 21 press conference sponsored by its manufacturer, Ortho Pharmaceuticals of Raritan, N.J. Ortho called the press conference to announce the results of a four-month study at the University of Michigan that found that Retin-A diminished wrinkles and other signs of age in 14 of 15 middle-aged subjects. Fifteen subjects in a control group who had used a placebo cream showed no such improvement.

By Jan. 22, when the study results were published in the Journal of the American Medical Association, news of the "miracle" anti-wrinkle cream was making headlines, and the price of stock in Johnson & Johnson, Ortho's parent company, had risen by $8 a share.

By early February, pharmacists up and down the East Coast had sold out of the prescription skin cream, which costs about $20 for a two-month supply. Reports were circulating that Americans were traveling to Mexico, where Retin-A is available without a prescription, to buy up supplies at one tenth the American price. That same week, Retin-A hit the comics pages, too; both "Doonesbury" and "Cathy" featured characters screaming for Retin-A to help them face their cartoon midlife crises.

Just how many physicians are prescribing Retin-A for cosmetic reasons is not known. The Food and Drug Administration approved the drug for the treatment of acne in 1971. The FDA, however, keeps no data on why a particular drug is prescribed. At the same time, agency officials have the impression that the drug is now often prescribed for wrinkles. "Our assumption is that there has been a great increase in interest in Retin-A generated by the JAMA article," says one FDA administrator, "not only in the media but also among patients who are interested in getting something for their wrinkles." Adds one FDA epidemiologist: "We've been hearing that supplies of Retin-A are running out, and that can't be because of a sudden need to treat acne."

The enthusiasm in the past weeks has let up only slightly. Kligman says he gets "hundreds" of calls a day about Retin-A, most from patients who got the drug from a general practitioner and need help dealing with the side effects they had not been warned about. Bark says that not once since late January has he mentioned the words "Retin-A" or "anti-aging cream" without a patient knowing just what he was talking about.

Dr. Jeffrey Schuldenfrei, acting chief of dermatology at the Kaiser Permanente Health Plan in Washington, estimates that "95 percent of the patients who have walked in {in the past month} have wanted to know, 'What's with this new drug?' "

Schuldenfrei says the only drug that ever came close to generating this level of interest was topical Minoxidil, which is used to treat male-pattern baldness, "and that pales in comparison to what has been going on with Retin-A."

Since the anti-aging properties of Retin-A have been known for years, the natural question is: Why now? Soon after the FDA approval in 1971, adult acne patients began telling their dermatologists that the cream seemed to make their skin smoother.

Based on these sporadic impressions, Kligman in the 1970s and early 1980s tested the effect of Retin-A on age-related skin changes in animals and found significant improvement in skin structure as detected under a microscope. He found similar microscopic benefits in humans who used Retin-A on their faces and forearms and in 1986 announced his results in the Journal of the American Academy of Dermatology.

The findings were reported in the medical press and in some special-interest lay publications like American Health, but knowledge about Retin-A's rejuvenating power did not spread far beyond the medical community. After all, Kligman's findings were based on tissue study, not appearance; the experimental design was not placebo controlled (that is, no comparison was made with skin changes in a group of subjects receiving an inert cream); and the journal was relatively obscure.

The JAMA article, however, received wide media play, encouraged in part by the press conference that Ortho sponsored the day before publication. Before-and-after photographs documenting the disappearance of fine wrinkles, published in many newspaper reports of the study, were all the baby boomers -- a group whose oldest members are now entering their forties -- needed to fuel their enthusiasm.

"To these people," says Kligman, "wrinkles are the harbinger of decline, decay, death -- everything."

A Wrinkle in Time

A wrinkle occurs when the deep layer of the skin, the dermis, loses moisture and elasticity. As the dermis shrinks, the skin's top layer, the epidermis, becomes too loose and begins to contract so that it fits better. The tiny creases and folds formed in this way are called wrinkles.

But most of the age-related changes of the skin, which include not only wrinkles but also "age spots," irregular pigmentation and rough texture, are the result of sun damage rather than of age itself -- what dermatologists call photo-aging.

"If you compare the skin of a nun and a sailor, by the age of 80 they'll both show signs of age," says Bark. "But the sailor will have worse sagging, and fine wrinkles that give the skin a leather-like appearance. That texture is the result of sun exposure."

Skin changes that occur primarily in regions that have been exposed to the sun -- on the face and hands, for instance, and almost never on the buttocks -- are those that dermatologists blame on "photo-aging."

These changes include wrinkling, yellowing, roughness, leatheriness and spotty pigmentation.

Under a microscope, photo-aging can be detected as an abnormal arrangement of cells that eventually can lead to the breakdown of collagen -- the network of connective tissue that gives skin its elasticity -- and, in extreme cases, precancerous growths (called actinic, or sun-caused, keratosis) and skin cancer.

Other age-related skin changes are thought to be caused by aging itself rather than exposure to the sun. "Intrinsic aging" of the skin leads to thinning of the skin epidermis and dermis, retraction of the blood vessel network and deepening of normal expression lines.

The deepest wrinkles and most evident sags result from the force of gravity working on the skin for many years -- and even Retin-A cannot reverse them.

What Retin-A Can, And Can't, Do

The wrinkles Retin-A works best against are the fine lines around the eyes and on the cheek that occur when fair, thin skin is damaged by the sun. It probably works best on people in their thirties, forties and fifties; beyond that age, enough intrinsic skin aging has taken place that visible improvement will be negligible.

"The real benefit of this cream," says Kligman, "will come when you start healthy people, without too much sun damage, on it early in life, and incorporate it into their routine hygiene, just like brushing their teeth."

But the medication does more than treat wrinkles. According to Kligman, Retin-A generates new blood vessels in the skin, stimulates the follicular bodies to produce more collagen, normalizes damaged epidermal cells and makes the skin rosier, smoother and firmer.

"I've been more impressed with the improvement in texture and blotchiness than with its action on wrinkles per se," says Schuldenfrei of Kaiser. "But it usually takes several months at a minimum, sometimes as long as six months, before a patient will mention to me that the skin texture has improved."

More important than its cosmetic benefits, though, is the possibility that Retin-A may actually prevent skin cancer. Kligman says the vitamin A acid interferes with the progression of an "incubating" tumor. The growth of all these precancers will be stopped, he says, "and the people who make a living out of treating skin cancer will go out of business."

Skin cancer results from a haphazard arrangement of epithelial cells, a derangement caused by ultraviolet light exposure. Retin-A seems to make the cells line up again as neatly as they did in youth. The result is that premalignant actinic keratoses are brought up to the surface of the skin as raised red bumps; within weeks, they are sloughed off entirely.

Schuldenfrei uses Retin-A in combination with more standard forms of treatment -- freezing and topical chemotherapy -- to remove the lesions of actinic keratosis and skin cancer. "Sometimes a lesion that is barely visible and is not treated at one session is, after using Retin-A, gone by the next session," he says.

The long experience of Retin-A with acne patients has turned up very few side effects. The most significant one is skin irritation. Especially when the medication is used daily, the skin can become inflamed, irritated, scaly and red. In the Michigan study, 92 percent of patients experienced some degree of skin irritation, leading three subjects to stop therapy altogether and 11 to use steroid creams. These problems usually ease up after the first few weeks and can be minimized by less frequent use of Retin-A, the application of a moisturizer and other methods.

Retin-A also makes the skin highly sun-sensitive, which requires the patient to wear a high-protection sunscreen every day. In one experiment on mice, Retin-A seemed to increase the incidence of sun-caused skin cancers, but this study has never been replicated in humans or other animals. Indeed, the thinking now is that Retin-A actually protects against, rather than causes, sun-induced skin cancers.

For the first few weeks of treatment, any underlying acne lesions will be brought to the surface, causing a flare-up of blackheads, whiteheads and pimples in many people who had acne in their teens.

"This isn't something you start on because you want to look good for your son's graduation this weekend," says Bark. "In fact, by the time this weekend comes along, you'll probably look worse."

Some dermatologists are withholding judgment about Retin-A's anti-aging powers. "So far I haven't seen any good data that Retin-A alters the morphology {cell structure} of the dermis," says Dr. Howard Baden, professor of dermatology at the Harvard Medical School. "The before-and-after pictures showed some difference in the skin, but even that is not dramatic." Baden says improved appearance need not be the result of deep changes in structure. For example, he says, wrinkles can disappear as a result of increased skin swelling, one of the side effects of Retin-A.

Into the Future

Retin-A is still hard to come by. According to Rich Salem, a spokesman for Ortho Pharmaceuticals, the "overwhelming reaction" after the JAMA article appeared led to a "significant" increase in orders for Retin-A. During the first week, Ortho filled orders no higher than 15 percent above a distributor's previous order.

By the second week, the company had added an extra shift devoted solely to Retin-A production.

"We're shipping it out now as fast as we can," Salem says, "but we'll still be back ordered for several weeks more."

Ortho is conducting several large-scale studies to establish Retin-A's efficacy in treating photo-aging, and within a year, Salem says, the company expects to apply to the Food and Drug Administration for approval of Retin-A for this condition. In the meantime, Retin-A is approved only to treat acne.

"But it's one of the strangenesses of our drug approval system," says Dr. Mervyn Elgart, chairman of dermatology at George Washington University, "that once a prescription drug is on the market, any doctor can write a prescription for the drug for any reason. That's considered the free practice of medicine."

But not all physicians are prescribing Retin-A for wrinkles at the behest of their patients. At Kaiser, where the majority of the health plan's 195,000 enrollees get their prescription drugs paid for, limits have been placed on the use of Retin-A for cosmetic purposes. According to Jane Galvin, director of contract administration and policy development, Kaiser physicians may write prescriptions for Retin-A only for acne or precancerous skin conditions.

"If the patient wants Retin-A purely for cosmetic purposes," she says, "we will not cover it." The health plan is currently evaluating how to handle cosmetic use of Retin-A: whether to dispense the drug out of its own pharmacies and require the patient to pay for it, or to have the patient go to an outside pharmacy -- possibly even an outside physician -- for a prescription.

"We feel we must protect our supply of Retin-A for those who really need it," she says. "If people want it for cosmetic purposes only, the feeling here is that we shouldn't pay for it." She says Kaiser administrators have not decided whether they should even condone its use for a non-medical condition, "because if the patients develop side effects, they'll be coming back to our physicians to have them take care of it."

Even some dermatologists in private practice are hesitant to prescribe Retin-A to just anyone. "This is still a prescription drug, and I feel I must use my clinical judgment about who would benefit from it," says Elgart of George Washington. "I try to turn down people who have wrinkles simply because they're old."

Baden of Harvard will not prescribe Retin-A for photo-aging at all. "Yes, you're allowed to prescribe a medication for something other than the approved purpose," he says, "but you do so at your own risk." He says he is not impressed enough with Retin-A's anti-aging properties to take that risk. According to Baden, creams containing lactic acid, available in both prescription and over-the-counter formulations, can be just as useful.

Kligman worries that non-dermatologists, without experience prescribing Retin-A as an acne treatment, will not provide patients with information about how to use the cream to minimize irritation.

"This is not a harmless treatment; it's a prescription drug," Kligman says. "As a prescription drug, it should come with good counseling."

If the irritation proves too great for people who could have benefited from Retin-A, he says, they will just throw out the tube and never give the cream a fair trial.

Still to be seen is the impact Retin-A will have on the $1.3 billion cosmetics industry. Many of the nation's leading skin care manufacturers have been developing anti-aging concoctions to capture the baby boom market as it swells into middle age.

The scientific consensus is that these preparations do not penetrate to the deep layers of the skin, where most age changes occur, but simply trap moisture on the skin's surface and appear to plump up lines and wrinkles. If Retin-A makes a more structural change in aging skin, it would offer some stiff competition to the wrinkle cream industry.

At the same time, because most physicians recommend that people use a moisturizer after putting Retin-A on their skin, Retin-A could help boost the demand for moisturizers.

Just what the long-term impact of Retin-A will be is hard to say. In the cosmetic world, beauty that is skin deep might truly be beauty enough.

"People have so much hope that this will suddenly transform them into beautiful creatures," says Kligman, who recently started a Center for Human Appearance at the University of Pennsylvania in Philadelphia to address cosmetic issues from a medical perspective.

Kligman says some of his patients are so enthusiastic about Retin-A that they come back to him just a few weeks after starting treatment and tell him they look much younger and prettier.

But as the saying goes, beauty is often in the eye of the beholder. "I'll be damned if I can see it," he says.

Robin Marantz Henig is a Washington free-lance writer and the author of several books, including "How a Woman Ages."

.................BOOM IN PLASTIC SURGERY....................




A "nose job," in which bone and cartilage are reconstructed,

parts are removed, to reshape the face

..........Number performed in 1981....................54,500

..........Number performed in 1986...................154,000



An "eye tuck," in which fat and skin around the eyes are re-

moved, eliminating bags and pouches.

..........Number performed in 1981....................56,500

..........Number performed in 1986...................101,900



Cartilage of protruding ears is reshaped, so ears no longer

stick out.

..........Number performed in 1981....................11,500

..........Number performed in 1986....................20,600


.............RHYTIDECTOMY OR RHYTIDOPLASTY..................

A "facelift," in which excess skin is removed from the face,

and the remaining skin is stretched and tightened.

..........Number performed in 1981....................39,000

..........Number performed in 1986....................74,500


............... HAIR TRANSPLANTATION........................

Plugs of skin with hair from the back and sides of head are

transplanted to bald areas.

..........Number performed in 1981.....................4,200

..........Number performed in 1986....................12,600

SOURCE: American Academy of Facial Plastic and Reconstructive Surgery