RU58841 : Miracle Baldness Cure?
Androgenic alopecia, more commonly known as male-pattern baldness, affects millions of men and women worldwide. In androgenic alopecia, individuals inherit hair follicles that are particularly responsive to a hormone called dihydrotestosterone (DHT). DHT is a hormone derived from testosterone that plays an important role in maintaining male sexual charactestics. However, in individuals who inherit androgenic alopecia, DHT also causes hair follicles to undergo a process called miniaturization, during which they cease to produce normal hair. Eventually, baldness occurs.
A variety of treatments have been introduced for androgenic alopecia, but none can be said to be “the cure.” Several oral drugs that block the conversion of testosterone to DHT have been introduced (e.g., finasteride) that stop the progression of androgenic alopecia, but these drugs can have significant sexual and physiological side effects, such as impotence, headaches, and an elevated risk of a rare type of prostate cancer. In addition, do not seem to work on women with androgenic alopecia, nor do they stimulate hair regrowth. Topical minoxidil can help stimulate regrowth of hair, but it is only partially effective in most people.
Hair transplants are an option. In a hair transplant, hair follicles from the back of head, which are more resistant to balding than other scalp hair follicles, are moved to the top and front of the head. However, it is a painful, invasive, and very expensive procedure. It can cause scarring and numbness of the scalp. In addition, it does nothing to stop the remaining hair follicles on the front and top of the head from undergoing the balding process. A normal head of hair has over 100,000 follicles, and there are only 25,000 that can be transplanted from the back to the top and front of the head, and of these, around 10% of transplanted follicles never grow hair in their new location. Therefore, while a hair transplant may look good for a few years, it is not a balding cure.
RU58841 is applied topically, where it acts to block DHT from affecting the hair follicles. Because RU58841 only affects the scalp, it has practically no side effects. It is highly effective in stopping the progression of androgenic alopecia. It does not, however, significantly stimulate hair regrowth and is therefore most effective if applied very early in the balding process. If started early and used in combination with minoxidil to stimulate hair regrowth, it may actually be the first truly effective cure for balding.
Where Did RU58841 Come From?
RU58841 was first synthesized in France in the 1990s as part of experiments to identify anti-androgen drugs. It was found to be an effective anti-androgen useful for treating various hormone-related conditions such as acne, excess hair growth, and hair loss. Several studies in animal models demonstrated it was quite effective in treating androgenic alopecia (1, 2). For example, in one study, the stump tailed macaque, a kind of monkey, was studied. Macaques suffer from androgenic alopecia just like humans do. The macaques were treated topically with RU58841 and exhibited a dramatic increase in density, thickness, and length of their fur, without experiencing any side effects (1). In another study, human scalp samples taken from individuals with androgenic alopecia were grafted onto nude mice. If these mice were then given testosterone, the scalp samples begin to lose their hair. When the scalp samples were treated with topical RU58841, they did not respond to the testosterone and kept growing hair, and there was a statistically significant difference in the length of the hair between treated and untreated grafts, indicating that human hair follicles respond to RU58841 just like macaque hair follicles (2).
In 2008, the rights to RU58841 were purchased by Proskelia Pharmaceuticals, who re-named it PSK3841. However, for various reasons, such as the fact that the drug cannot be patented (the patent expired), no pharmaceutical company has invested the necessary money and time in getting the drug approved for sale to the general population to treat androgenic alopecia. A few small human clinical trials of the safety of the drug for topical use have been conducted, but none have yet been published (3). The last study published on RU58841 was published in 2008 (4). It was conducted in Brazil and was investigating the use of RU58841 as a topical treatment for acne. Because it has not received regulatory approval from any health agency in any country, it cannot be obtained from doctors or from pharmacies. However, it is legal to buy RU58841 for personal use.
Structure of RU58841
RU58841 is a non-steroidal anti-androgen drug. It is an arylhydantoin with a bicyclic-1H-isoindole-1,3-(2H)-dione structure that is similar to RU58642 and nilutamide. Nilutamide is approved for use in treating prostate cancer (4). It is an oral medication that blocks androgens from binding to and stimulating the growth of prostate cancer cells. RU58642 was synthesized as part of the same series of experiments that included synthesis of RU58841. At the time of its synthesis, RU58642 was thought to be one of the most potent anti-androgen drugs ever discovered (5). However, very little has been done with RU58642 since its discovery. It is occasionally used in laboratory studies of the androgen receptor.
The non-steroidal hydantoin anti-androgen drugs are considered preferable to the older steroidal anti-androgen drugs because the hydantoin drugs exhibit little to no cross-reactivity with other hormone receptors. Many of the steroidal anti-androgen drugs cross-react with estrogen or progesterone receptors, causing unwanted side effects. They also have poor bioavailability and tend to be toxic to the liver. Hydantoins in general have excellent bioavailability, being readily absorbed through either the skin or the digestive tract and exhibit little to no toxicity.
RU58841: How it Works ?
The androgen receptor is a protein that is expressed at high levels in prostate, skeletal muscle, liver, and the epididymis. It is also expressed in the dermal papilla at the base of hair follicles. The androgen receptor exists primarily inside the cytoplasm of the cell. When an androgen (testosterone or DHT) binds to the androgen receptor, it moves into the nucleus of the cell, where it affects the regulation of gene expression. Anti-androgen drugs act by binding to the androgen receptor (6). However, after these drugs bind to the receptor, it does not move into the nucleus. Instead, it remains in the cytoplasm, bound to the anti-androgen drug. Since the receptor is blocked by the drug, it cannot bind to any androgen molecules and it is therefore inactivated. The antagonist effect of RU58841 on androgen receptor can be summarized as below:
Testosterone is a steroid that is primarily synthesized in the testicles. It is also synthesized in small amounts in the ovaries and the adrenal glands. It is released into the bloodstream and taken up by cells throughout the body. In some cells, it is converted into DHT by the enzyme 5-alpha-reductase. DHT is a much more potent androgen than is testosterone, binding to the androgen receptor with much greater affinity. The androgens play important roles in maintaining secondary male sexual characteristics, sexual drive and function, bone health, and blood cell formation. When referring to their reproductive effects, the term “androgenic effects” is used; when referring to their effect on muscle and bone, the term “anabolic effect” is used.
Some hair follicles, such those on the face, chest, and top and sides of the head, express high levels of 5-alpha-reductase and androgen receptors. Others, such as the eyelashes, do not express them at all (7). DHT is an important regulator of hair growth. It is responsible for the characteristic pattern of growth of men’s body and facial hair. However, unlike most hair follicles, the hair follicles on the scalp do not respond to DHT by growing more vigorously. This is evident in the fact that men, women, and children all grow abundant scalp hair. The hair follicles on the scalp do still produce 5-alpha-reductase and androgen receptors, and in susceptible individuals, prolonged exposure to DHT causes the hair follicles to stop growing hair. The exact mechanism of this effect is still unclear. Practically all men will exhibit significant hair loss by age 80, but around 40% will begin losing significant amounts of hair before age 40. This early hair loss tendency is clearly inherited in a complex fashion.
Hair is a complex structure. The hair follicle is a tunnel-like structure that extends into the dermis. At the base is the papilla, which has a rich blood supply. The dermal papilla is the part of the hair follicle that expresses androgen receptors. Inside the papilla is the hair bulb, the only part of a hair that is alive. The cells of the hair bulb divide much more rapidly than any other cells in the body. Hair follicles normally actively grow hair for two to three years, a phase called anagen. Then the hair follicle goes into a transitional phase for a few months, a phase called catagen. The hair then falls out and the hair follicle rests in telogen for approximately three months. On a healthy head, around 90% of hair follicles are in anagen at any one time. In individuals experiencing androgenic alopecia, the follicles spend longer periods of time in telogen and have shorter periods of anagen.
DHT Accelerates Aging of Hair Stem Cells
Hair growth is stimulated by signals sent from the dermal papilla to stem cells in the bulb. This process is known to require activation of the Wnt/catenin pathway (8). In culture models, exposing scalp hair follicles from individuals affected by androgenic alopecia to DHT causes a down-regulation in the degree of Wnt/catenin activation. The DHT acts through the androgen receptor to down-regulate the signals sent from the dermal papilla to the hair stem cells, preventing them from proliferating and instead inducing differentiation.
During normal aging, everyone gradually loses hair follicles. At birth, there are around 5 million hair follicles present on a human baby, and over time, this number gradually diminishes. Even elderly individuals unaffected by balding have significantly thinner hair than teenagers. This process seems to be driven by loss of the hair stem cells (9). As mentioned above, these cells divide constantly, much faster than any other cell in the body. As such, they tend to accumulate DNA damage over time. Once a stem cell has accumulated a lot of damage, it terminally differentiates into an epidermal keratinocyte. When a hair follicle loses too many stem cells, it undergoes the same process of miniaturization that occurs in androgenic alopecia. Therefore, a decrease in Wnt/catenin activation due to DHT may be triggering stem cells to terminally differentiate years before their time, essentially accelerating the aging process of the hair follicle. Simply blocking the inhibitory effect of DHT through the use of RU58841 stops this accelerated aging.
RU58841: No Side Effects from Topical Application
When anti-androgen drugs such as nilutamide are taken orally, they block androgen receptors throughout the body, down-regulating both androgenic and anabolic effects of androgens. The side effects can be fairly significant. For example, nilutamide taken orally to treat prostate cancer, commonly causes decreased libido, impotence, and visual side effects. When RU58841 is applied to the scalp, it is able to penetrate the skin and enter the cells of the hair follicles (6). However, it does not enter the bloodstream and therefore has no systemic effects. The only cells that have their androgen receptors blocked are those in the local area, namely, the dermal papilla of the hair follicles. Clinical studies in monkeys, mice, and humans were unable to identify any systemic side effects after applying RU58841 to the skin (1-3). Volunteer users of RU58841 occasionally report minor scalp irritation after application, but no other side effects have been reported.
(1) Endocrine. 1998 Aug;9(1):39-43. Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stumptailed macaques.
(2) Br J Dermatol. 1997 Nov;137(5):699-702.
A controlled study of the effects of RU58841, a non-steroidal antiandrogen, on human hair production by balding scalp grafts maintained on testosterone-conditioned nude mice.
(3) ISRCTN49873657 DOI 10.1186/ISRCTN49873657 A double blind, randomised, vehicle-controlled, safety and tolerance study of topical PSK 3841 solution at 5% administered twice daily over four weeks to healthy Caucasian males with androgenetic alopecia
(4) J Steroid Biochem Mol Biol. 1998 Jan;64(1-2):103-11. Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders.
(5) J Steroid Biochem Mol Biol. 1998 Jan;64(1-2):103-11. Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders.
(6) Chem Rev. Author manuscript; available in PMC 2007 Nov 27. Chemistry and Structural Biology of Androgen Receptor
(7) Skin Pharmacol. 1997;10(5-6):288-97. Effects of topical antiandrogen and 5-alpha-reductase inhibitors on sebaceous glands in male fuzzy rats.
(8) Br J Dermatol. 2012 May;166(5):1035-42 doi: 10.1111/j.1365-2133.2012.10856.x. Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signaling in dermal papilla cells from patients with androgenetic alopecia.
(9) Science 2016;315(6273):aad4395 doi: 10.1126/science.aad4395. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis.