(Part 2): Next Generation AR Antagonists
The search for new drugs that target prostate diseases may once again lead to new treatments for androgenetic alopecia in the future.
Just as finasteride (Propecia®) was first developed as a treatment for benign prostatic hyperplasia, a new group of androgen receptor antagonists undergoing trials for prostate cancer may prove useful for treating hair loss in coming years.
Dihydrotestosterone (DHT), an androgenic hormone, is widely recognized as a key factor in the development of androgenetic alopecia. DHT's effects on hair follicles are mediated by the androgen receptor (AR). (For more information about DHT, androgen receptors, and AR antagonists, check out our previous post on the science behind anti-androgens.)
“Triple-acting” Androgen Receptor Antagonists
A collaboration between the laboratories of Charles Sawyers (Memorial Sloan-Kettering Cancer Center) and Michael Jung (UCLA) led to the discovery of two diarylthiohydantoin compounds, MDV3100 and RD162, which represent a new class of “triple-acting” AR antagonists.1
These two compounds are derivatives of RU59063, an AR antagonist originally synthesized by scientists at Roussel-UCLAF in the early 1990s.2
Out of 200 derivative compounds the Sawyers and Jung groups screened, MDV3100 and RD162 were two of the most effective inhibitors of AR activity.
MDV3100 and RD162 are unique compared to currently prescribed AR antagonists because they disrupt activity in three complementary ways:
First, they block binding of DHT to AR by occupying the ligand binding site where DHT usually binds. This first line of defense keeps the receptor from being activated by DHT that is normally produced in the body.
Second, the compounds impede movement of AR into the cell nucleus, where the receptor normally binds to DNA and regulates the expression of genes. By keeping AR in the cytoplasm, MDV3100 and RD162 physically isolate the receptor from its site of action.
Finally, they change the shape of AR and reduce its ability to interact with DNA. When the receptor binds to DNA sequences in the genome, it acts as a molecular "on/off switch" for genes that alter cellular behavior.
This third activity is critical for preventing any receptors that are already present in the nucleus from binding to DNA and regulating the expression of genes that are presumably responsible for hair loss.
MDV3100 has a higher affinity for AR and inhibits the receptor more effectively than other currently prescribed anti-androgens like bicalutamide. Initial observations in a Phase I/II clinical trial for advanced prostate cancer have shown promising results and Phase II/III trials are in progress. (Click on the image above to see a full-size version)
Proposed Use of MDV3100 for Hair Loss
The triple-acting AR antagonists MDV3100 and RD162 were first disclosed in US Patent Application No. 20070004753 as part of a series of RU59063 derivatives. While the primary focus appears to be treating prostate cancer, the patent application hints that the drug could also be used to treat androgenetic alopecia:
“Because these compounds are strong AR inhibitors, they can be used not only in treating prostate cancer, but also in treating other AR related diseases or conditions such as benign prostate hyperplasia, hair loss, and acne.”
The patent application goes on to describe how the compounds could be formulated for topical administration:
“The diarylhydantoin compounds of the invention can be formulated as pharmaceutical compositions and administered to a subject in need of treatment, for example a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue.”
“For topical administration, the diarylhydantoin compounds may be applied in pure form. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.”
Other Next-Generation Androgen Receptor Antagonists
Another androgen receptor antagonist to watch in the future is VN/124-1, discovered at the University of Maryland School of Medicine.3
VN/124-1 appears to work on AR by a different mechanism than MDV3100: reducing the expression of AR, i.e. the number of receptor molecules available to bind DHT.
“VN/124-1 was significantly more potent than the other compounds, with nearly complete reduction of AR expression at 15 µM in LNCaP cells, and 89% in LAPC4 cells.”
“The active ingredient, such as one or more CYP17 inhibitor(s) or compositions including any active ingredients may be administered by methods known to those skilled in the art including, but not limited to, intraperitoneally, intravenously, orally, subcutaneously, intradermally, intramuscularly, intravascularly, endotracheally, intraosseously, intra-arterially, intravesicularly, intrapleurally, topically, intraventricularly, or through a lumbar puncture (intrathecally).”
The next generation of AR antagonists are potent inhibitors of the androgen receptor that may hold promise for treating androgenetic alopecia in the future.
However, in order to realize this potential, several hurdles must be overcome, including tests on topical absorption and systemic toxicity, side effects, and efficacy in treating androgenetic alopecia. These studies will require a significant investment of time and money, so we will likely have to wait at least a few years before we know if any of these compounds will become available as a treatment for hair loss in the future.
Stay tuned in the coming weeks for another look into The Future of Hair Regrowth when the Avacor® Hair Regrowth Blog explores the promise of RNA interference technology for treating hair loss!
1. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. Link to Pubmed
2. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D. Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor. J Steroid Biochem Mol Biol. 1994 Jan;48(1):111-9. Link to Pubmed
3. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AM. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84. Link to Pubmed
During the second half of the 20th century, advances in surgical techniques have led to significant improvements in the cosmetic appearance of hair transplants. Still, it often takes several months for grafted follicles to begin growing new hair and some patients require multiple surgeries to reach their desired cosmetic outcome.
Over the last 20 years a growing number of physicians have begun suggesting the use of minoxidil to improve the results of these procedures.
Minoxidil as an Adjunct to Hair Transplantation
A roundtable group of 11 international hair transplant physicians in 2002 reached a consensus that using hair regrowth medications like minoxidil after surgery "can increase hair density, speed regrowth in transplanted follicles, and complement the surgical result by slowing down or stopping further hair loss."1
They also suggested that using minoxidil prior to surgery could make transplanting easier by enlarging miniaturized suboptimal follicles, although most recommended suspending treatment for a few days before and one to three weeks after the procedure to reduce the risk of bleeding and allow graft sites to heal.
These observations were based on the physicians’ own experiences with patients, but are also supported by at least three published clinical studies.
A pilot study in 1987 suggested that some patients who used minoxidil (3% topical solution) after hair transplant surgery demonstrated hair growth within several weeks (rather than the usual time of several months), without experiencing the shedding that occurred in untreated patients in the weeks following transplantation.2
Another study, in which patients applied 2% topical minoxidil solution to the balding area of their scalp for four weeks before surgery, discontinued use for 3 weeks after surgery, then resumed treatment for an additional 3 months, concluded that “minoxidil seems to be an adjunct for a better evolution of grafts after hair transplantation surgery.”3
Finally, a double-blind trial involving 12 patients with male pattern baldness found that using 2% minoxidil for 6 weeks before and 17 weeks after surgery significantly decreased the shedding of grafted hair in the weeks after surgery.4
A review in 2008 concluded that minoxidil is “highly effective at helping to maintain existing hair, thereby creating more perceived density from the procedure” and that continuing treatment “will often help increase the density of transplanted hair, slow down the rate of loss of existing hair, and increase the caliber of existing and transplanted hair.” 5
Hair transplantation can be a very effective method for dealing with hair loss resulting from androgenetic alopecia, but it carries a hefty price tag. Using current hair transplantation methods, several thousand grafts can be required to cover the affected areas, with costs ranging from $3-12 per graft.
After investing so much time and money, it would make a lot of sense to spend a little bit of time each day using minoxidil to improve the results of your hair transplant and protect your investment for the future. At Avacor®, we provide hair loss treatments to help you regrow hair. Visit our product page to learn more.
1. Avram MR, Cole JP, Gandelman M, Haber R, Knudsen R, Leavitt MT, Leonard RT Jr, Puig CJ, Rose PT, Vogel JE, Ziering CL; Roundtable Consensus Meeting of The 9th Annual Meeting of The International Society of Hair Restoration Surgery. The potential role of minoxidil in the hair transplantation setting. Dermatol Surg. 2002 Oct;28(10):894-900; discussion 900. Link to PubMed
2. Kassimir JJ. Use of topical minoxidil as a possible adjunct to hair transplant surgery. A pilot study. J Am Acad Dermatol. 1987 Mar;16(3 Pt 2):685-7. Link to PubMed
3. Bouhanna P. Topical minoxidil used before and after hair transplantation. J Dermatol Surg Oncol. 1989 Jan;15(1):50-3. Link to PubMed
4. Roenigk HH, Berman MD. Topical 2% minoxidil with hair transplantation. Face. 1993;4:213-6.
5. Avram MR, Rogers NE. Hair transplantation for men. J Cosmet Laser Ther. 2008 Sep;10(3):154-60. Link to PubMed
6. Sandoval A. Minoxidil 5% following hair transplantation for increased growth. Abstract of presentation at European Society of Hair Restoration Surgery, June 2002. London, England
So far, many of our posts here on the Avacor® Hair Regrowth Blog have focused on current and past options for treating hair loss. One of our last posts cataloged some outdated patent-medicine treatments for baldness that would raise eyebrows and FDA warning flags today.
Now in our new series, “The Future of Hair Regrowth,” the Avacor team will highlight some exciting possibilities for hair regeneration that are either currently in development or undergoing preliminary research.
New treatments can take twenty or thirty years (and hundreds of millions of dollars) to develop, so it is unlikely that any of these options will be on the market by next year. But if you are experiencing hair loss and are looking for the best way to grow and keep your hair, you will probably want to know about any promising technologies on the hair growth horizon.
One of the most exciting and anticipated potential treatments for hair loss comes from our own bodies: stem cells. We will give a basic review of what stem cells are, how they are important for hair regeneration, and how they might be employed in hair regrowth treatments.
RNA interference (RNAi) is a relatively new technology that can block the expression of a particular gene with great specificity. RNAi has yet to be used widely in the clinic, but many companies are developing targeted therapies to treat such wide ranging diseases as cancer, macular degeneration, and viral hepatitis.
Several research institutes and pharmaceutical companies are working on a new generation of androgen receptor antagonists. One of these drugs, currently known as MDV3100, is being developed for prostate cancer but is also considered a potential candidate for treating androgenetic alopecia.
In the final post of the series we will give a few glimpses of very early stage research programs and patent applications that may lead to promising hair loss treatments in coming years.
Hair loss has been an unwelcome fact of human existence for the duration of recorded history and probably much longer. Many ancient civilizations, from the Egyptians and Greeks to the Aborigines and Native Americans, developed their own remedies for baldness. While some treatments like grape seed extract (which contains resveratrol) and emu oil have made a comeback in recent years,1 other concoctions made from less palatable items like dog toes and bird dung may seem barbaric to us today.
Even as recently as the 20th century, options for treating hair loss were crude and often dangerous. Looking in the archives of U.S. patents during the late 19th and early 20th centuries, we found some particularly hair-raising (in a bad way) “inventions.” Tonics made from unpleasant ingredients and hazardous heavy metals seem to have dominated the field of hair regrowth treatments. Here are a few examples:
Michael J. Fleming of Portland, Oregon graced the public in 1897 with his invention of “a new and useful composition... for the restoration of hair upon the heads of persons who have become bald,” which he made from month-old rusty water, the best Jamaican rum, and pure hot melted bear’s grease. The ingredients were boiled together for six hours, cooled for two days, and left to set for a week before use.
In 1871, Sarah Amanda Reybert of New Jersey revealed a vegetable hair-tonic that she claimed was useful for “promoting the growth of the hair and preventing it from falling out,” as well as restoring gray hair to its original color, removing dandruff, and serving as a “beautiful hair-dressing.” The main ingredient, made by steeping Pukeweed (also known as Vomitwort, Asthma Weed, or Lobelia) in alcohol for about a week, was supplemented with castor oil and Spanish fly (tincture of cantharides).
A Texas hair-tonic from Annie and Jennie Newcom, patented in 1908, featured an aqueous extract of the quince seed, which is still used in the Middle East as a remedy for sore throat, cough, and pneumonia. Perfumed with oils of citronella and rose geranium, the tonic was likely fragrant and pleasant smelling, but it unfortunately also contained the highly toxic heavy metal salt mercuric chloride.
A “new and Improved Hair-Restorative” patented in 1872 by Phillip Trautwein of Brooklyn, NY, was made from gall nuts, abnormal plant growths caused by insect larvae. The creamy substance, which claimed to strengthen the nerves and materially increase the growth of hair, was probably sweet tasting due to a high content of sugar-of-lead (lead acetate). Users would likely have wanted to avoid ingestion though, since this lead compound has been blamed for the poisoning death of Pope Clement II and possibly also the composer Ludwig van Beethoven.2
Modern Treatments for Hair Regrowth
The last two decades of the 20th century brought two significant advancements in the treatment of hair loss: minoxidil, the first FDA-approved hair loss treatment for both men and women, and finasteride, an effective hormone-modulating treatment which is only approved for men.
These two medications have proven effective for thousands of men and women in slowing their hair loss and regrowing hair, but there is still no miracle cure for completely reversing or preventing hair loss. Recent discoveries like hair follicle stem cells and gene therapy have raised hopes for new treatments in the coming decades.
Keep an eye out in the coming weeks for the Avacor® Hair Regrowth Blog’s new series on the “Future of Hair Regrowth,” featuring several of the hottest prospects for hair regrowth in the 21st century.
1. Batchelder, T. “The anthropology of hair loss - Medical Anthropology.” Townsend Letter for Doctors and Patients. May, 2003. (accessed August 8, 2011)
2. Gensthaler, B. M. “Beethoven und Blei - Tödliches Zusammenspiel [Beethoven and Lead - Deadly combination].” Pharmazeutische Zeitung. July 23, 2001. (accessed August 9, 2011)
As we accumulate more and more information about hair loss and hair regrowth here on the Avacor® Hair Regrowth Blog, some of the newer posts are beginning to build on concepts introduced in previous entries.
If you are just visiting for the first time, it may be helpful to start with the earliest posts (at the end of the site) and read backwards from there.
For information on a particular subject, be sure to utilize the “Categories” and “Tags” on the right-hand side of the page to find all of the articles on that topic.
Here are a few pieces of suggested reading to get you started:
One of our first posts highlighted the importance of addressing hair loss as early as possible. Click here to read “Carpe Diem: Delaying Treatment Affects Results?”
The “Minoxidil Mini-Series” is a five part series that provides a comprehensive overview of minoxidil, the first FDA-approved treatment for male and female pattern hair loss and the active ingredient in Avacor Physicians Formulation®.
• Part 2 - Early History
• Part 3 - Clinical Trials
• Part 4 - FDA Approval
• Part 5 - Benefits, Limitations, and Side Effects
We welcome your questions and feedback on any subject related to hair loss, hair regrowth, or Avacor products, as well as any suggestions for future topics you'd like to hear about here on the Avacor Hair Regrowth Blog, so feel free to leave a comment or contact us privately and we'll respond as quickly as possible with more information to help you find the right approach to dealing with your hair loss.
Part 5 – Minoxidil Benefits, Limitations, and Side Effects
This post will conclude the Avacor® Hair Regrowth Blog's five part “mini-series” on minoxidil, the first FDA-approved treatment for hair loss. Earlier episodes of the mini-series covered the early history of minoxidil, clinical trials showing its efficacy in treating androgenetic alopecia, and its approval by the FDA as a hair regrowth treatment. In this final segment we will highlight the benefits, limitations, and side effects associated with minoxidil.
Benefits of Minoxidil Treatment
Several clinical trials have proven that minoxidil is able to prevent hair loss and regrow hair, with investigators observing hair growth in anywhere from 30-60% of patients (for details see our previous post on clinical trials). These studies also suggest that even if patients do not achieve noticeable hair regrowth with minoxidil treatment, they can at least stop losing hair and maintain their baseline hair count.
Minoxidil is the only hair regrowth medication that has been approved by the FDA for both men and women, unlike finasteride (Propecia®) which is only approved for use by men.
One of the other benefits of minoxidil is that it has not been associated with the sexual side effects experienced by some patients taking finasteride (Propecia®), such as decreased arousal and erectile dysfunction.1 For a description of the side effects that have been associated with minoxidil, keep reading for the section below on “Reported Side Effects of Minoxidil.”
There is no magic cure for hair loss, so it is important to begin any hair regrowth regimen with accurate information and reasonable expectations. Minoxidil will not work for everyone; its effectiveness is limited to certain types of hair loss and the degree of hair regrowth experienced by each person will differ. In addition, minoxidil requires a consistent, diligent program of use to achieve maximum results.
Only Works for Certain Types of Hair Loss
The only types of hair loss for which minoxidil has been approved by the FDA are male and female androgenetic alopecia. Some studies have reported positive results for a small number of patients with alopecia areata, but the benefits have not been consistent enough to recommend widespread use of minoxidil for this condition.
Men: Minoxidil 5% topical solution, (such as Avacor Physicians Formulation® for Men) is only recommended for men with male pattern hair loss, and is not intended for treating frontal baldness or a receding hairline. Despite a conference presentation by the lead investigator of several early minoxidil trials suggesting that it is also effective in the frontal hairline area,2 the supporting data do not appear to have been published in any peer-reviewed journals or evaluated by the FDA. Patients using minoxidil should not expect to regrow hair in any areas other than the top of the scalp.
Women: Minoxidil 2% topical solution, (such as Avacor Physicians Formulation® for Women) is only recommended for women with female pattern hair loss (general thinning of hair on the top of the scalp). Minoxidil products are not indicated for hair loss that is sudden, patchy, or associated with stress or childbirth.
Minoxidil may not work for patients whose hair loss is too advanced. A general visual guide that shows the degrees of thinning hair for which minoxidil is most effective can be found on Avacor's product packaging (pictured above).
Needs to be Used Consistently
In order to achieve the best possible results with minoxidil, it is essential to apply the topical solution regularly and consistently. The best way to do this is to commit to making it part of your daily routine, even if it's not your favorite part of the day. An analogy for this would be brushing your teeth: while no one particularly enjoys the act of brushing their teeth (at least that we are aware of), most people find the benefits are worth the little bit of time each day.
Like all good things, regrowing hair takes time. You may need to use minoxidil for at least 4 months before you see results, although you may begin to notice the effects as early as 2 months.
Continued use is necessary to prevent hair loss from progressing. One of the longest studies of minoxidil for male pattern hair loss (5 years) found that patients who continued to apply minoxidil twice per day were able to maintain nonvellus hair regrowth well beyond their baseline hair counts.3 Patients who stop using minoxidil will likely not maintain hair that has regrown during the course of treatment and will begin losing hair again.
Reported Side Effects of Minoxidil
More than 20 years after minoxidil was first approved for treating hair loss, the list of commonly reported side effects remains fairly limited. However, there are some rare side effects that should be watched for and taken very seriously.
Some of the most common side effects are:
• Localized scalp reactions or skin irritation (i.e., dryness, itching, redness and mild burning)
• GI discomforts (e.g., mild heartburn, nausea, constipation and diarrhea)
• Hair growth in other body areas (i.e., face, arms, back)
If you experience any of the following rare side effects, you should discontinue use immediately and consult your physician:
• Dizziness, light headedness, faintness, headaches
• Sudden unexplained weight gain, water retention
• Rapid heart beat or chest tightness/discomfort
• Swelling of the mouth, face, lips, or tongue
In addition to these side effects, some people have experienced changes in hair color and/or texture.
If you have heart disease you should talk to your doctor before using minoxidil. Minoxidil may be harmful if used when pregnant or breast-feeding, should not be used by children under the age of 18, and should be kept out of reach of children at all times.
Thanks again for checking out the “Minoxidil Mini-Series” here on the Avacor Hair Regrowth Blog. We hope the information we have collected here has given you a better understanding of the history, benefits, and limitations of minoxidil and that it will help you choose the best course of action for regrowing your hair.
If you have any questions or would like to see more information on a particular topic, please leave a comment below. We'd love to hear from you!
1. Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011 Jun;8(6):1747-53. Link to Pubmed
2. Olsen EA, Whiting DA, Miller JJ. Increased Frontal Scalp Coverage and Frontal Hair Regrowth with 5% and 2% Minoxidil Solution. Presented at the American Academy of Dermatology 61st Annual Meeting, March 2003.
3. Olsen EA, Weiner MS, Amara IA, DeLong ER. Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil. J Am Acad Dermatol. 1990 Apr;22(4):643-6. Link to Pubmed