MINOXIDIL
Topical Minoxidil : Effectiveness & Limitations
Background: The discovery of minoxidil as a hair loss therapy was serendipitous, since it was first developed in the late 1960’s as an oral treatment for high blood pressure based on its function as a blood vessel dilator (vaso-dilator). However, it was quickly reported by some patients to have a side effect of hypertrichosis (hair growth stimulant) causing increased hair growth. This side effect lead researchers to formulate a topical solution for targeted treatment of scalp hair loss, in order to avoid the systemic effects on blood pressure and possible unwanted hair growth in other areas of the body. (1,2)
In 1988 the FDA approved 2% topical minoxidil as an effective treatment to combat hair loss caused by androgenetic alopecia (male pattern baldness) in men. The solution was known by the brand name, Rogaine. Then, in 1992, the FDA also approved its use in women for treatment of female pattern hair loss. Since then, further renditions of the topical solution have been created, including a 5% solution as well as a 5% foam.(3) Despite its impressive ability to stabilize and improve the appearance of hair density in some patients, the response to topical minoxidil therapy has not been universal, with variable response rates reported in the 50-80% range. Even though responders did better with higher concentrations of topical minoxidil , there were still some patients who did not respond at all. (4) Researchers determined that minoxidil is a ”pro-drug”, and in order to stimulate hair growth, it must undergo a chemical reaction in the body to produce the active ingredient minoxidil sulfate . The presence of the enzyme minoxidil sulfortransferase is key to this reaction. (5) All people have many types of sulfotransferase enzymes in various body tissues which function to attach a sulfate molecule when needed for various physiologic needs . At least one study has shown that varying levels of the sulfotransferase enzyme in human scalp correlate with the effectiveness of minoxidil as a hair growth stimulant. (6) The amount of the sulfotransferase enzymes appears to be under genetic control and it is postulated that genetic differences in sulfation capacity determine a patients response to minoxidil (7) Non-responders appear to have little available enzyme to convert the minoxidil into the active ingredient, minoxidil sulfate.
One may question why the therapy isn’t just administered in its active form to begin with. Unfortunately, outside of the body’s physiologic environment, minoxidil sulfate is highly unstable The only known mechanism for activation to safely occur, is by physiologic sulfation inside the body or inside the hair follicle during topical absorption.
Available topical formulations
Minoxidil is offered in 2% and 5% concentrations, applied to the scalp as a liquid or foam. Both concentrations are FDA approved for men and women. All topical forms are sold over-the-counter (OTC) and do not require a doctors prescription. Many expensive “hair growth therapies” actually rely on topical minoxidil combined with other ingredients that are not FDA approved as hair loss treatments.
The foam preparation does not use propylene glycol as a solvent. Propylene glycol has a greasy feeling and is a common skin irritant, which makes the foam an attractive alternative to the solution for some patients. At present the foam preparations are a 5% concentration- for both men and women.
Administration
Topical: applied to the scalp as a liquid or foam, ideally right after bathing so it is not washed away. Maximum efficacy requires application 2 times daily to the affected area for men; 1 time daily for women. The original minoxidil study results used to gain FDA approval were only performed on the vertex area, so they were only approved for this claim. However, minoxidil can stimulate hair growth wherever the active medication can reach. Most hair restoration doctors advise patients to use minoxidil on all thinning areas, both the vertex and frontal scalp. However, patients must be consistent and apply this therapy daily or risk causing shedding. If patients decide to discontinue topical minoxidil it is advisable to wean the dosing over several weeks rather than abrupt discontinuation, as the latter is more likely to provoke shedding in patients who are responders.
Oral minoxidil: Some doctors around the world are beginning to use low dose minoxidil orally (5mg or less per day) combined with spirinolactone with reported success.(8) Patients irritated by minoxidil topically usually do well with the oral route. This also allows physiologic activation of the drug to occur internally, which likely increases the response rate. However, oral minoxidil has not been FDA approved for hair loss treatment. Off label users must take care to maintain low doses to avoid potentially serious systemic effects.
Mode of Action
How minoxidil acts to slow hair loss and stimulate hair regrowth is not well understood. It is believed that minoxidil sulfate acts by prolonging the anagen phase (growth phase) of the hair follicle, and increasing the size of the follicle. (9)
Effectiveness
Studies have shown that minoxidil slows or halts hair loss and promotes hair regrowth in both men and women, at both 2% and 5% formulations. The 5% formulation is generally more effective. Positive response to minoxidil therapy (reduced hair loss and/or hair regrowth) has been reported in various studies as less than 50% to more than 80%–possibly owing to genetic variation in study recipients. Any positive response is lost if minoxidil therapy is discontinued.
Side Effects
The most common reported side effects are scalp redness, Itchy scalp, dryness and flaking. Accidental application of minoxidil to the face can result in growth of unwanted facial hair, and the risk of facial hair growth from absorption is about 3% in most studies. Repeated, large applications of minoxidil have been associated with a drop in blood pressure in a few reported cases, presumably due to systemic absorption. There are also infrequent reports of heart palpitations, which require discontinuation of use.
Some patients may develop a true allergy with associated swelling and hives. In these cases, minoxidil can’t be used. The older pregnancy classification is a C. Newer classifications recommend not using minoxidil during pregnancy, with at least one case report of possible teratogenicity, though a causal relationship with minoxidil has not been shown.
Final Comments
Minoxidil can stimulate all hair, and the topical formulation is currently the only drug approved for treatment of female pattern hair loss.
Minoxidil can be a valuable retardant to hair loss even in cases where it does not appear to regrow hair. Often patients discontinue minoxidil after several months if they haven’t noticed increased growth. However, for responders, the effect of retarding hair loss can be important compared to continued hair loss over the years. A patient who sheds after discontinuing this therapy is a likely responder, and may wish to reconsider resuming the medication if this occurs. Also, combined with oral finasteride, minoxidil appears to synergistically enhance hair regrowth effect of finasteride. Hair doctors commonly recommend the combination of these drugs, provided patients are committed to the daily regimen that topical minoxidil requires.
References:
1) Zappacosta AR. Reversal of baldness in patient receiving minoxidil for hypertension. New England Journal of Medicine 1980;303:1480.
2) Zins GR. The history of the development of minoxidil. Clinical Dermatology 1988;6:132–47.
3)Medical treatments for male and female pattern hair loss, Rogers, N.; Avram, M.; J Am Acad Dermatol, Vol 59, No 4, pp547-566, 2008
4)A multicenter, randomized, placebo-controlled, double blind clinical trial of a novel formulation of 5% minoxidil topical foam vs placebo in the treatment of androgenetic alopecia in men; Olsen, E.; Whiting, D.; Bergfeld, W.; Miller, J.; Hordinsky, M.; Wanwer, R.; Zhang, P.; Kohut, B.’ J Am Acad Derm, Nov., 767-774, 2007
5)Minoxidil Sulfate is the Active Metabolite that Stimulates Hair Follicles, Buhl, A.; Waldon, D.; Baker, C.; Johnson, G.; The Journal of Investigative Dermatology, pp553—557,1990
- Minoxidil sulfotransferase activity influences the efficacy of Rogaine topical solution (TS): enzyme studies using scalp and platelets. Buhl, AE,; Baker, CA.; Dietz, AJ.; J Invest Dermatol, 1994; 102:534
- Molecular Biology of the human cytosolic sulfotransferase gene superfamily impolicated in the bioactivation of minoxidil and cholesterol in skin, Dooley, T.P.; Exp Derm, Aug 8(4); pp328-9, 1999
8) Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone.
Sinclair RD, International Journal of Dermatol, 2018, Jan;57 (1): 104-108
- Minoxidil: mechanisms of action on hair growth.
Messenger AG1, Rundegren J., Br J Dermatol, 2004 Feb; 150 (2): 186-94
Photobiomodulation
Low Level Laser Therapy (LLLT) aka Photobiomodulation (PBM) and the Effectiveness of current Devices for Treating Hair loss
Photobiomodulation (PBM), also called low level laser therapy (LLLT), is a treatment used to stimulate hair follicles to grow. It is often used in conjunction with other hair loss therapies. While some patients have seen a benefit, others have not. To know if you are more or less likely to be helped, then read on. There are many types of devices with varying energy output. Some devices may be purchased directly by consumers, and others are only to be used in the physician’s office. Despite a burgeoning array of such devices on the market today, important questions about dosing and efficacy remain unanswered. Consumers should be aware of these unanswered questions in order to make an informed decision. ISHRS recommends seeking the advice of a hair loss specialist who is knowledgeable about various types of hair loss and the full array of options to appropriately and effectively treat them.
Commonly asked Questions
Would I be a good candidate for PBM device therapy? Should I buy one of these devices? The answer is, there is much we don’t know about the optimal wavelengths and dosing for PBM therapy to treat hair loss. Despite the studies that have been performed, important questions remain unanswered. For patients, it is advisable that prior to making the decision to purchase an OTC device to treat their hair loss all therapies and options should be reviewed with a hair loss specialist.
How does PBM work for stimulating hair growth?
Researchers are not certain how PBM works to stimulate hair growth, but believe it has to do with stimulating hair to enter the growth phase (anagen re-entry), prolongation of the growth cycle (prolongation of anagen), proliferation of hair in the active growth cycle (anagen), and prevention of premature catagen (the rest phase of hair growth). It has even been postulated to have an effect on modulating 5 alpha reductase activity—the enzyme that converts testosterone into dihydrotestosterone (DHT)—with the latter considered to be a cause of hair loss in androgenetic alopecia (AGA). (5) Studies are ongoing to further identify cellular targets and the mechanisms of action for hair growth stimulation, as this will assist researchers to identify the optimal wavelengths and dosing.
Is there an optimal wavelength for stimulating hair growth?
The short answer is, probably, but it may not yet be available in current devices. Some researchers believe the chromophore responsible for PBM response in hair growth stimulation is Cytochrome C oxidase, found inside of mitochondria. Tissue culture experiments have shown peak DNA production in 4 wavelength ranges, felt to be a reflection of Cytochrome C oxidase activity : 614-624nm; 668-684n, 751-772nm and 813-846nm. (ref 1, 6) More recent research specific to hair growth evaluated the response of various wavelengths on the shaven backs of Sprague-Dawley rats using diodes of 632, 670, 785 and 830nm. The higher wavelengths of 830 nm and 785 nm resulted in a significant effect on hair growth stimulation, with 830 nm being most effective (ref Lasers Med Sci). The original study by Mester used a ruby laser with wavelength 694 nm to achieve the first hair growth resulting from PBM therapy. Interestingly, none of the currently marketed devices use a wavelength of 694 nm, 785 nm or 830nm. To date most of the FDA cleared devices in the US use lower wavelengths varying from 635nm, 650nm, and 655nm with one at 678 nm. The reasons for this have little to do with the previously mentioned scientific studies, and everything to do with the cost of FDA pre market approval (PMA) vs the 510K clearance process for low risk medical devices. The impact of the regulatory process on device development will be further discussed below. Importantly, human study results from some of these available devices suggest a hair growth benefit for some patients. However, closer scrutiny raises questions about methodology and whether study conclusions can apply in real use settings, as well as whether any benefits identified would be greater if optical parameters were optimized.
What are the optimal dosing regimens for PBM devices? (How often can someone use it?)
Important optical parameters for PBM include wavelength, as well as irradiance or power density (mW/cm2)—how bright the light is, distance of the target from the light source, and frequency and duration with which light is applied to the head/scalp (ex 3 times weekly for 20 minutes); as well as the duration or course of therapy (6 months, 12 months etc). Determining optimal dosing seems especially important given the characteristic of LLLT known as the biphasic dose response , a phenomenon believed to occur in both animals and humans—where too little energy results in no response, and too much energy could actually have a detrimental effect on target tissue. Researchers investigating optimal dosing regimens for hair growth performed a review of 90 published studies and observed a confusingly wide array of dosing schedules and irradiance or power densities which varied by as much as two orders of magnitude—making it impossible to identify ” optimal” parameters. (ref) Furthermore, none of the OTC devices published any justification for their recommended dosing, nor did they address why there were no dosing adjustments based on Fitzpatrick skin typing. The latter classification was developed to aid in dosing for skin phototherapy based on the presence of the chromophore, melanin, in skin and hair which absorbs laser light. The FDA apparently recognized this factor, however, and has only approved the OTC devices for Fitzpatrick Skin types 1-4 which does not include patients with darker skin and hair where melanin would be expected to absorb a considerable amount of the light before it could reach other cellular targets.
What is FDA 510K clearance and how does this impact LLLT or PBM device development?
For low risk medical devices, the US- FDA allows companies to go through a markedly faster and cheaper process to bring their products to the marketplace. This process is called 510K clearance, and is not the equivalent of “FDA approval.” For this clearance process, a company is required to establish their device as equivalent in safety to a previously approved device with similar characteristics (the predicate device). In contrast, the Pre-market “Approval “(PMA) process requires safety and efficacy studies, takes more time time, and usually costs millions of dollars. Several of the PBM devices being marketed today with 510K clearance have no studies to prove efficacy. For companies that went through the PMA process to produce the first predicate device, there is little incentive to produce another novel device that may be used by another company as a predicate at a much lower development cost. Because of this, the 510K clearance process encourages “copy cat” wavelengths and device styles, rather than novel and possibly more effective wavelengths or devices. For example, the first PBM device to achieve 510K clearance listed as predicates, a variety of FDA approved and unapproved laser based devices including non hair growth devices intended for hair removal and pain relief. Since then this first device has been listed on subsequently 510 K cleared PBM devices on the market to treat hair loss.
Another limitation of direct to consumer sales of PBM devices is the necessity to adhere to laser safety precautions for Class 3a or 3R lasers. The latter limits the device power to 5 mW(.005 W) to avoid eye hazards, regardless of whether a higher power device could be more effective. The incentive for companies to market direct to consumers for higher sales volume and profits is clear. However, this may obviate the development of devices with higher and possibly more effective power levels because it would place them in a laser class that could not be sold directly to consumers. Currently there are many studies documenting PBM efficacy for various tissues and therapies, with devices exceeding 5 mW.
Are there any reliable studies on the effectiveness of the LLLT (PBM) devices?
There have been studies evaluating the effectiveness of a variety of PBM devices to treat hair loss, including 655 nm laser combs, and helmets which combined 650 nm, or 655 nm laser diodes with LED lights. However, questions have been raised about possible flaws in the methodology of these studies. First of all, while it is generally accepted the gold standard for evidence based medical studies is the randomized, controlled trial, where patients with the same medical condition are randomly selected to be treated with the real medical therapy vs a placebo (not real, but looks alike ) —the data required to prove effectiveness of a hair growth promoter is very specific. Patient self report is deemed too subjective and found to be unreliable and is often positive in placebo groups. Even global photographs can have a degree of subjective bias if performed improperly. Strict adherence to standardized photo position, lighting, hair color and hair style do offer some measure of credible evidence. Nevertheless, while most studies do include the use of global photographs the gold standard for establishing hair growth is phototrichogram evidence. The latter are areas of treated scalp trimmed to approximately 1 mm so hairs do not overlap, but are not so short as to be unseen, and tattooed so the precise area is measured for hair counts at intervals to determine if an increase or decrease has occurred. New hairs generally take about 3 months to grow out from a follicle, so growth promoter assessment is often done at monthly intervals assessing the emergence of new hairs, as well as the possibility of improvements in hair fiber caliber.
Did these studies present photo-trichograms to prove effective increased hair growth?
Out of a sample size of 269 patients the laser comb study did present one very credible phototrichogram to document improved caliber and growth. However, skeptics point out there should have been more than one credible phototrichogram out of this sample to document efficacy. Other studies did not publish credible and easily assessed phototrichograms. Notably there were several patients in the placebo groups of all studies with equivalent and small hair count increases to many patients in the treated group. For example, there were reports of 100% increased hair counts among placebo patients in the helmet studies, suggesting some type of counting error. The helmet studies also suffered from small sample sizes.
Did the studies have sufficiently large sample size and study duration to provide adequate medical evidence to recommend them?
All sample sizes for each of the dfferent devices studied were <100 patients. (several different laser combs were used in the largest study) None of the studies were longer than 26 weeks (~6 months), with no published evidence to date to determine if any hair growth benefits from PBM devices would be enduring with long term use.
Were there any other concerns about the studies? There was no documented scientific justification behind the dosing schedules. Energy doses were highly variable. No adjustments were made for hair and skin color (Fitzpatrick skin type), and none of the devices were cleared for use on darker skin patients (Fitzpatrick Type 5-6). Furthermore, since areas of hair growth assessment had to be shaved for hair counts, and light was beamed directly on these areas, it necessarily provided added opportunity for a PBM effect that would not necessarily be expected on areas of the scalp covered by hair. Computer models have calculated that hair coverage can impede light transmission by > 30%, especially with dark hair. This raises questions about whether patients who did respond to the PBM device under study conditions, would actually experience the same response without shaving the hair.
History: The word laser is an acronym (Light Amplification by Stimulated Emission of Radiation) and not long after the discovery in 1960 the first medical laser was developed for heating, cutting, cauterizing or destroying tissue. However, in 1967 a Hungarian physician, Dr. Endre Mester serendipitously discovered that low power, “cool” laser light which did not heat, cut or destroy tissue, could actually stimulate it to create a physiologic response. Beaming a low power, 694 nm ruby laser on the backs of shaved mice, he sought to determine if it was carcinogenic, instead he observed more rapid regrowth of hair. Since that time there have been over 100 randomized controlled trials evaluating the use of low power lasers to biostimulate various therapeutic responses in human tissue. This low level laser light therapy is now referred to in the medical literature as photobiomodulation or PBM. While considerable study was done to evaluate PBM in various tissues, it was over 40 years after the original experiment by Mester before a direct to consumer PBM medical device to treat hair loss was developed. This was a laser comb. Despite a burgeoning array of such devices on the market today, important questions about dosing and efficacy remain unanswered. Consumers must be aware of these unanswered questions in order to make an informed decision whether to purchase and use a PBM device to treat their hair loss. It is advisable to seek the advice of a hair loss specialist who is knowledgeable about various types of hair loss and the full array of options to appropriately and effectively treat them.
Defining Low level laser therapy light or PBM: Laser light is collimated, that is, it is not diffuse and light waves are focused in a beam or column until they hit a target that either reflects, transmits, scatters or absorbs it. A chromophore is a tissue target that absorbs a particular wavelength of light. Various tissue chromophores include water, hemoglobin, melanin or other cellular components such as mitochondria. The wavelength for various PBM therapies includes the visible light spectrum from 500nm-1100nm; the other defining characteristic is low power from 1mW-500mW and power density from 1mW-500mW/cm2. This low power does not heat tissue. Two factors are most important for achieving an effect from photobiomodulation. First of all, in order for the PBM to cause bio-stimulation , light of a particular wavelength must reach and be absorbed by a particular tissue target or chromophore. Secondly, the wavelength must be carried by energy or power through the skin, to reach the target, such as a hair follicle. The range of low power which can biostimulate without tissue heating, as previously noted, is 1 mW-500 mW. However, all over the counter PBM devices are limited by laser safety regulations to just 5mW of power—in order to protect consumer’s eyes, not based on efficacy to achieve a tissue response. A device with 100 times the power of over the counter (OTC) devices would still be considered a ‘cool’ laser– and would not burn or destroy tissue, but could not be sold direct to consumers in most countries because it exceeds regulated power limits for ocular safety. This limitation must be kept in mind as we review currently available OTC devices for treating hair loss.
The formula for converting mW/cm2 to Joules/cm2 is: mW/cm2/1000 x Time (sec)=Joules/cm2.
Lasers Med Sci. 2015 Aug;30(6):1703-9. doi: 10.1007/s10103-015-1775-9. Epub 2015 Jun 6.
Evaluation of wavelength-dependent hair growth effects on low-level laser therapy: an experimental animal study.
Abstract
In this study, we aimed to investigate the wavelength-dependent effects of hair growth on the shaven backs of Sprague-Dawley rats using laser diodes with wavelengths of 632, 670, 785, and 830 nm. Each wavelength was selected by choosing four peak wavelengths from an action spectrum in the range 580 to 860 nm. The laser treatment was performed on alternating days over a 2-week period. The energy density was set to 1.27 J/cm(2) for the
first four treatments and 1.91 J/cm(2) for the last four treatments. At the end of the experiment, both photographic and histological examinations were performed to evaluate the effect of laser wavelength on hair growth. Overall, the results indicated that low-level laser therapy (LLLT) with a 830-nm wavelength resulted in greater stimulation of hair growth than the other wavelengths examined and 785 nm also showed a significant effect on hair growth.
References
- Hamblin M.R. Mechanisms of laser induced hair regrowth, Source: Welllman Center for Photomedicine, March/April 2006, pp28-33
- Avci, P., et al, LLLT for treatment of hair loss. Lasers in Surgery and Medicine. 2013 9999:1,
3) Evaluation of wavelength-dependent hair growth effects on low-level laser therapy: an experimental animal study. Kim, TH; Kim NJ; Youn, JI, Lasers Med Sci 2015 Aug 30 (6):1703-9
4)Photobiomodulation devices for hair regrowth and wound healing: a therapy full of promise but a literature full of confusion, Mignon, Charles, Botchkareva, N.V., Uzunbajakava, N.E., Tobin, D.J., Experimental Dermatology, July 13, 2016, pp745-49
Clin Diagn Res. 2015 Dec; 9(12): ZL01–ZL02.
Published online 2015 Dec 1. doi: 10.7860/JCDR/2015/15561.6955
PMCID: PMC4717791
Energy and Power Density: A Key Factor in Lasers Studies
Jacek Matys,1 Marzena Dominiak,2 and Rafal Flieger3
Robi Combi
DermaLight Psoracomb
Quantum WARP 10 Light Delivery System Lumiphase-R
TerraQuant MQ2000 Laser Therapy Device MLT R694 Ruby Laser System
L600 Hair Removal
Violet Ray Device
Vacuum Cap
Raydo and Wonder Brush
The devices that the Lasercomb proved itself equivalent to were a variety of FDA approved laser based/non hair growth devices intended for hair removal and pain relief, and 2 non FDA approved non laser based/hair growth devices such as the Raydo & Wonder Brush and the Vacuum Cap. These last two devices were sold in the early 1900’s and are well established as medical quackery, but they were legal to market at the time which does satisfy the FDA’s 510k SE criterea.
mW/
The formula for converting milliwatts/cm2 to Joules/cm2
mW/cm2 ´TIME=J/cm2 1,000
Example: 100 mW/cm2 intensity for 1 minute equals an exposure of 100×60 = 6 J/cm2 1000
PRP
Platelet Rich Plasma, also known as PRP, is a relatively new addition to the list of hair loss treatments. The theory is this; platelets store growth factors to help stimulate wound healing and tissue growth where it is needed. Blood contains platelets in varying concentrations. If you take a patient’s own platelets and re-inject them into an area that needs healing and growth, the body’s own mechanisms will improve the regeneration of the tissue.
PRP injections have been verifiably used to help the growth and healing of slow growing tissues like bones and teeth. Early experiments in its use with hair have been mixed however. Most studies have concentrated on using PRP injections to possibly help the growth of the native hair (and possibly the grafts if surgery was done) in the areas of hair loss and thinning. What these studies have shown so far is that the treatments do not help hair to re-grow on a completely bald head, so the earlier a treatment is started the better. Higher concentrations of platelets, more frequent injections, and possibly activating the platelets or causing micro-injuries to the scalp may also provide better results. No study has been conclusive, however, and many variations within the research make it difficult to compare and draw conclusions.
Since this use of PRP is not yet fully tested, it is impossible to know how much of an effect it would have in an individual case. That being said, it is a patient’s own “blood product,” and thus not likely to be detrimental. It is useful to remember that like most treatments, some patients have great results and others have results that are not as significant. A standard treatment regimen has not yet been developed with most practitioners advocating treatment schedules that range from monthly to every three months. Also, like all medical hair treatments it may require ongoing maintenance treatments. Whichever treatment frequency is used, at least 6 months are needed to see results.