Treating Hair Loss

There are currently only 2 FDA approved drugs for the treatment of male pattern baldness, minoxidil (Rogaine) finasteride (Propecia).

Provided Courtesy of: Richard Lee, MD

Minoxidil (Rogaine)

The treatment of MPB was greatly expanded in the late 1980’s. These newer approaches to therapy include attempts to interrupt the miniaturization of the follicle by (1) using biological response modifiers, (2) blocking androgen receptor sites, (3) inhibiting the target organ conversion of androgens to the most potent androgen, DHT, and (4) enhancing the conversion of androgens to estrogens.

Minoxidil is a biological response modifier, although we still don’t understand the exact mechanism by which minoxidil stimulates hair to grow. Biologic response modifiers may include cell mitogens, vasodilators, promoters of angiogenesis, epidermal growth factors, and regulators of cellular differentiation. A biologic response modifier, such as minoxidil, may have several of the physiological effects.

The initial research leading to the registration application of topically applied minoxidil for MPB was conducted at The Upjohn Company in 1960. Filing of the topical minoxidil IND (Investigational New Drug) was delayed until late 1977 and an FDA approval for a prescription 2% solution was granted in 1988. In 1997, 5% topical minoxidil solution was FDA approved for over-the-counter use in men.

Minoxidil sulfate appears to be the active metabolite responsible for hair growth stimulation. Vasodilation does not appear to play a key role in minoxidil’s hair growth-promoting effects. In fact, hair cultures are enhanced by minoxidil without the presence of a blood supply.

Initial clinical studies measured efficacy on minoxidil on vertex thinning and subsequent studies confirmed that minoxidil works also on frontal scalp thinning.

During the 96 weeks of treatment, the 5% and 2% minoxidil groups showed a substantially greater hair mass from baseline compared to the placebo and untreated groups. The 5% minoxidil group showed the greatest increase in percent change in mean weight, the 2% minoxidil group also showed an increase, but it was smaller than the 5% minoxidil group. On the other hand, the placebo and untreated groups seemed much alike in their response, showing a steady decrease in hair mass from baseline over the 120 weeks. After treatment was stopped at week 96, the 5% and 2% minoxidil groups showed a rapid loss of hair mass. By 21 weeks, after stopping treatment the hair mass was similar among the minoxidil-treated groups and the placebo and untreated groups. The percent change in mean number generally paralleled the percent change in weights. The weights tend to greater accuracy since the somewhat uncertain number of very small hairs affect the number count, but have little effect on the weight.

The major increase in hair weight was observed within the first twenty weeks following initiation of therapy. Minoxidil application then stabilized the hair loss over the two years, while both placebo treated men and untreated men had approximately a 7% decrease in hair mass per year.

In addition to the total hair count, hairs with pointed tips were separately counted from those with blunt or cut ends. A large increase in the number of pointed hairs in the treated samples was noted, especially during the early treatment intervals. A surge in hair weight was similarly observed in the first 20 weeks after initiating treatment. These increases were most prominent in the 5% group and are due to the known effect of minoxidil initiating anagen growth. The initial surge was followed by a period of shedding, by a smaller surge, and so on, with eventual diminishing of these periodic responses.

These observations demonstrate that 5% and 2% topical minoxidil solutions promote hair growth and retard the hair loss process over 96 weeks, with the 5% topical minoxidil solution having the greater efficacy. Although a slight decrease in hair mass was seen over a long period, minoxidil maintained weight production at a high level compared to the placebo and untreated groups, which had about a 7% to 8% decrease in hair loss. Every hair growth promoter is effective only while it is being used because the underlying genetic signals are still present.

This graph (unavailable) provides some indication of the safety profile for topical minoxidil. There is an approximate 15-20 fold safety margin with the use of 5% topical minoxidil before there would be any systemic hemodynamic effects. However, that doesn’t mean that there aren’t any side effects with the use of topical minoxidil. ~6% of patients will have local scalp problems due to the use of 5% minoxidil, because of the large amount of propylene glycol in the base. The manufacturers use 50% propylene glycol in the base for stability and an enhanced shelf life. Since I can formulate minoxidil solutions on based on demand rather than shelf-life, I chose to make 5% minoxidil solutions that contain only 30% propylene glycol.

Finasteride (Propecia)

The only other FDA approved medication for the treatment of MPB utilizes the hormonal approach of decreasing the amount of DHT that’s available to combine with the androgen receptor proteins. Finasteride at a dose of 1mg/day was approved for use in men with MPB in the U.S. by the FDA in late 1997. Merck chose the proprietary name of Propecia.

Finasteride is not a new medication. The 5 mg tablets of finasteride (Proscar) was approved by the FDA for treating men with enlarged prostates in 1992. On a previous slide, the conversion of testosterone to DHT was shown. This reaction utilizes the enzyme 5-alpha reductase, of which there are two types. Type 1 5-alpha reductase if found primarily in the skin and type 2 5-alpha reductase is found primarily in the prostate with small quantities also in the root sheaths of the hair follicles.

Propecia will cause an approximate 65% suppression of DHT in the bloodstream. Previous studies with 5mg daily doses of finasteride showed that there is 38% (about half the amount) suppression of DHT in the scalp. Finasteride has no affinity for the androgen receptor.

This graph plots the number of hairs at the vertex against time. The study is carried out to three years. As compared to the previous graph derived from topical minoxidil use, this study used crossover data, i.e. some patients on Propecia were switched to placebo after the first year, while patients on placebo were switched to Propecia. At the end of year two, they were again switched back. There are two inarguable conclusions: (1) the best results were obtained by continuous treatment and (2) the earlier the treatment began, the better the results. Propecia maintained or increased hair count from baseline in the majority (74%) of men at year three.

I have had a continuous disagreement with Merck in regards to the incidence of the adverse effects, but there is no doubt that finasteride does have a high safety margin.

Shampoos containing ketoconazole have been proven to be beneficial in treating MPB. Ketoconazole is a broad-spectrum antifungal agent. It impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. This same pharmacological action inhibits the synthesis of DHT in the scalp, which is why ketoconazole shampoo is beneficial in the treatment of MPB.

Spironolactone has been used for many years for treating women with FPB, utilizing its anti-androgen properties. In men, spironolactone can be applied topically to avoid its feminizing effect. It has three pharmacological actions that are helpful. (1) It inhibits the synthesis of DHT. (2) It blocks the androgen receptor sites. And (3) it converts the existing testosterone to estrogen.

As for ‘any herb or natural product for MPB’, we have a Catch-22 situation. In fact, there may be some very beneficial herbs and natural products. It costs in the hundreds of millions of dollars to obtain an FDA approval for a new drug. The FDA will not grant an exclusive patent for ‘herbs and natural products’. The pharmaceutical company cannot recapture the cost of its research and development. As a result, we have no well-designed studies to prove the value of or to establish the optimal doses for “any herb or natural product for MPB”.

Some potentially dangerous situations have arisen due to the popular use of herbals, e.g. St. John’s wort has been found to interfere with certain types of chemotherapy, kava kava has been the cause of liver damage, etc. Some products, like garlic, ginkgo, kava, vitamin E, fish oil, and some Chinese herbs can interfere with blood clotting. Others, such as black cohosh and St. John’s wort, can affect blood pressure. Still others-kava, valerian-can interfere with anesthesia.

So, although I have heard or read of studies that demonstrate benefits of substances such as capsaicin or sophora root extract, there isn’t enough scientific work done to prove their safety and efficacy. I would be particularly suspect of products that contain multiple herbs.

New Approach – Molecular Signaling

We’ve probably gone as far as can or should in reducing the DHT in the scalp to combat DHT. What new direction can we take in developing alternative medications for treating MPB? Well, you recall that during embryological development of the hair follicles, there was communication between the ectoderm (top layers of the skin) and the underlying mesoderm. The cells in the mesoderm signal the overlying ectoderm to make an appendage. In response, the ectoderm cells organize, proliferate and invade the mesoderm, becoming an elongated structure called a hair germ, which eventually forms the hair follicle and produces hair. Alone among all the organs of the body, the hair follicle recreates itself 10 to 20 times during your lifetime. What if we could understand how the communication, i.e. the molecular signaling, took place between the layers of the skin? There is a lot of ongoing work to isolate and identify the molecules involved in molecular signaling. The implications are wonderful. What if we had control of telling the stem cells to begin anagen or to stay in anagen or even to produce a new follicle?

Here’s a simplified version of a type of molecular signaling: often a cell will initiate a behavior, such as making new proteins, after a molecule from the outside binds to a receptor on the cell surface and triggers a cascade of molecular interactions within the cell. These signaling cascades frequently lead to the activation of specific genes in the nucleus, resulting in the production of new proteins.

Within the past few years, Elaine Fuchs and her colleagues at the University of Chicago have discovered that the dermal papilla’s signals probably convey their directives largely by activating still other signaling molecules—members of the Wnt family of proteins.

Subsequent experiments confirmed that Wnt is the mesodermal signal that instructs the overlying ectoderm to begin forming an appendage and is likewise the ectodermal signal that tells the underlying mesoderm to form the dermal papilla. After development of the hair follicle, Wnt appears to be the message that directs matrix cells above the dermal papilla to differentiate into hair cells.

Perhaps the most dramatic evidence for the central importance of Wnts was the creation of mice that, after birth, could not degrade beta-catenin in their epidermal cells. The inability to destroy beta-catenin made the cells behave as if they were constantly receiving a Wnt signal. These mice grew an unusually lush furry coat by forming new hair follicles between the ones that were formed during embryonic development.

That’s really “WOW!” So, why don’t we rub our scalps with Wnt? As these furry mice aged, they grew benign lumps in their skin that resembled a common human scalp tumor called pilotricoma. But, if we learn to deliver Wnt in a pattern that mimics nature or if we can manipulate other steps in the Wnt signaling cascade, we may have a way to correct disorders of the hair, including MPB.

In 1995 Elaine Fuchs’ group discovered that a regulatory protein called lymphocyte enhancer factor 1 (LEF1) participated in activating the hair keratin genes. This lymphocyte enhancer factor 1 was also found to be present during hair follicle formation in the embryo. Presumably on orders from some outside signal, LEF1 became active and helped to turn on genes needed for follicle formation or hair growth. And when Fuch’s team engineered mice that produced excess LEF1 in the skin, the animals produced more hair follicles than normal. Rudy Grosshedl at the University of California at San Francisco, which showed that without LEF1, mice fail to make a furry coat at all.

Other proteins have been identified in the molecular signaling scheme. One by the name of ‘sonic hedgehog’ could be particularly crucial for hair growth. Although sonic hedgehog is not necessary for formation of the hair germ, it is necessary for subsequent conversion of the germ to a full-fledged follicle. Two years ago, Ronald Crystal at Cornell University found that when hair follicles in adult mice are induced to make the protein during the telogen phase, the follicles shift prematurely into the anagen phase. Thus, sonic hedgehog can stimulate dormant follicles to begin producing hair.

But another caution: Too much signaling by the sonic hedgehog molecule results in basal cell carcinomas in humans.

Obviously, there is a lot of work to be done before signaling proteins can be used as a treatment for MPB. But the information is exciting and the future is very promising in this field of research.

New Treatments

Because of the structure of the FDA and the huge amounts of capital involved in the development of new drugs, much research done by companies is kept secret until drug candidates reach clinical trials. Several companies have developed molecules that inhibit the 5 alpha reductase enzyme. Hoechst has done some laboratory testing of a drug that would be applied to the scalp to block DHT from binding to hair follicle cells. And Bristol-Myers Squibb has a drug in early clinical studies that is thought to function similarly to minoxidil. Johnson & Johnson has recently spun off a complete company named Juvenir Biosciences to focus predominantly on hair research. The chief scientific officer, Kurt Stenn, is quoted as saying, “This is a wonderful time to be working in hair biology. So many breakthroughs are coming.”

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