Podcast Host: Dr. Andrew Huberman (Stanford Associate Professor - brain development, brain plasticity, and neural regeneration and repair fields).

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Key takeaways

Specialized stem cells create hair and can distribute and extend hair filaments.
Greying and hair loss might affect one's quality of life and mental health.
Research has shown the critical role of stem cells in hair growth and maintenance.
The process of hair growth is comprised of three distinct phases, namely anagen, catagen, and telogen.
"Minoxidil's efficacy relies on proper dosage and administration by a practitioner."
Various treatments promote hair growth via circulation and stem cells, but efficacy varies.
Microneedling stimulates hair growth and restores stem cells, especially with minoxidil.
Botox and Tidilofil show promise in promoting hair growth via blood circulation.

Overview and Purpose:

Oftentimes in conversation, podcast hosts/guests will reference a given study but aren't able to provide the entire context or citation link for listeners. To help underscore the impact of science podcasts, such as this one, we construct the posts to reference all studies discussed in their conversation as well as provide some more background/information on topics that we think the listeners may be interested in. If there are changes, you'd like to see to the format of these posts or any other feedback you'd like to provide - please let us know in the Discussion section below this post.

Note: In the ethos of Open Science and transparent publication, this is a living document that will undergo continuous improvement. If you have suggestions, expansions, or corrections please feel free to comment in this thread and we will adjust the document as well as award some RSC for your help.

Summary:

In this podcast episode, we will discuss the factors determining the duration of hair growth, including the cessation and eventual shedding of hair. Additionally, we will explore the factors that regulate stem cells and their ability to sustain hair growth. Irrespective of one's background, the entirety of hair biology can be comprehended by the conclusion of this podcast. The podcast will delve into various techniques aimed at mitigating, preventing, and potentially reversing hair loss. Furthermore, we will examine the phenomenon of androgenetic alopecia in both genders, which is hormonally linked to hair loss, and explore the impact of stress and mechanical stressors on hair growth. In addition, we will discuss various mechanical and chemical approaches aimed at halting and reversing hair loss. In addition, our discussion will encompass subjects such as thyroid, estrogen, minoxidil, dutasteride, ketoconazole, micro-needling, and the igf-1 pathway. Regardless of one's prior knowledge of biology, all of these captivating topics can be explored. We will also acquire knowledge of prevalent fallacies pertaining to alopecia and follicular restoration. It is inaccurate to assert that the balding pattern is solely inherited from either the mother or father. It is a well-established fact that specific individuals inherit distinct genetic variations that influence their predisposition to hair loss in particular regions of their body and specific areas of their scalp. The present discourse will delve into the typical process of hair growth and the underlying factors that determine its growth rate. This discussion will focus on the efficacy and potential adverse effects of various hair treatments.

Discussion and Publications by Section:

(01): 00:00:00 Hair

Hair is a topic of great interest to a significant number of individuals, with some experiencing hair loss and seeking to prevent or halt this process. Hair is a fascinating topic from the perspective of stem cells and cellular biology. The human brain and nervous system undergo a remarkable transformation from a small cluster of cells to a vast network of trillions of cells via the mechanism of cell replication, also referred to as the cell cycle or mitosis. The hair follicle contains a distinct stem cell niche that is responsible for the production of individual hairs for varying durations, contingent on the location of the hair on the human body. The biological perspective finds hair to be a subject of great fascination. The hair located on the human scalp exhibits a prolonged growth phase that can last for a duration of four to six years, and in some cases, even up to eight years. The eyebrow exhibits a comparatively abbreviated anagen phase, lasting for several months, thereby precluding the emergence of individuals with eyebrows of considerable length. The hair strands would undergo a growth phase that could last for a maximum of eight years. Nonetheless, in cases where individuals refrain from trimming their hair, it is not uncommon to observe individuals with hair on their heads that extend to their waist. The observed distinction highlights the remarkable nature of hair follicles and their resident stem cells. The remarkable ability of organisms to generate structures commonly known as hairs. Also, hair stem cells exhibit a robust capacity for proliferation and possess multipotent properties [1].

Figure 1. Dispersion of stem cells in hair follicles. K15+, CD34+, K19+, Sox9+, Lgr5+, and Gli1+ are the stem cells in the bulge (green) [1].

References

1. Joulai Veijouye, S., et al., Bulge Region as a Putative Hair Follicle Stem Cells Niche: A Brief Review. Iran J Public Health, 2017. 46(9): p. 1167-1175.

(02): 00:08:04 Psychological States & Hair

The field of biology encompasses a vast array of knowledge pertaining to hair, while the field of psychology delves into the intricate relationship between individuals and their hair. It is noteworthy that individuals who experience even slight hair loss often experience significant levels of anxiety. Excessive stress can lead to hair loss, implying that individuals who subject themselves to stress may experience negative consequences. Research has shown that there is a correlation between an individual's psychological well-being and the coloration and growth rates of their hair. The inverse relationship holds true as individuals undergo hair thinning, hair loss, or hair color changes, which may lead to heightened levels of anxiety or depression. It is evident that hair holds significant importance to individuals, as evidenced by the substantial financial investment made by many in attempts to prevent or reverse hair loss. It is a well-established fact that around the age of 50, roughly 50% of both men and women will have undergone hair loss of a significant nature. A significant proportion, up to 85%, of individuals will encounter anxiety that motivates them to seek ways to impede or reverse hair loss. At the age of 50, a significant consideration arises regarding the continuous occurrence of hair loss between the ages of 30 and 50. Upon reaching the age of 50, individuals may begin to observe hair loss upon self-examination in the mirror, as well as the emergence of thinning in specific regions [2].

The correlation between psychological states and hair growth or loss patterns has been observed. The phenomenon of hair graying has been found to have a significant impact on an individual's psychological well-being, thus garnering considerable attention and interest among the general populace [3].

References

2. Peters, E.M.J., et al., Hair and stress: A pilot study of hair and cytokine balance alteration in healthy young women under major exam stress. PLoS One, 2017. 12(4): p. e0175904.

3. Dhami, L., Psychology of Hair Loss Patients and Importance of Counseling. Indian J Plast Surg, 2021. 54(4): p. 411-415.

(03): 00:13:19 Hair Anatomy and Stem Cells

The study of hair biology, particularly stem cells, is a topic of interest. It is worth noting that the term "stem cells" often evokes thoughts of individuals receiving injections of these cells to address wrinkles, improve skin quality, increase hair growth on the scalp, or aid in the healing of injured joints or muscles. The stem cells in question are classified as exogenous stem cells, indicating their origin from outside of the organism.

Endogenous stem cells refer to the type of stem cells that are naturally produced within the human body and have the ability to differentiate into various types of cells, thereby serving as a source of cellular regeneration. This is essentially the fundamental characteristic of stem cells. Stem cells are ubiquitous in human development, arising at the point of fertilization when the egg cell undergoes duplication, resulting in the emergence of additional cells. The distinctive feature of stem cells is their capacity for self-replication. According to biologists, humans reach a stage in their development where they possess a complete body plan, consisting of a brain, spinal cord, limbs, and fingers, which are necessary for proper functioning. This occurs even during infancy when all the necessary body parts are present and remain constant throughout life. However, several stem cell populations tend to diminish after puberty, resulting in a limited production of new brain cells. This is due to the brain's low stem cell population in numerous instances, a multitude of stem cells have the capacity to generate a greater quantity of the same tissue throughout an individual's lifetime, with hair being one such tissue [4].

The hair follicle's stem cells are responsible for generating the hair strands found on the scalp. Each hair on the human body possesses a unique stem cell that is responsible for the growth and development of that specific hair. Upon closer examination of hair on the human body, it can be observed that it is composed of a hair root and a narrow trench located within the epidermis, which is the outermost layer of the skin. The hair shaft is the portion of hair that extends beyond the skin's surface. The visible body hair that we observe is comprised of the hair shaft.

A significant number of individuals are unaware of the existence of a cave or a small pocket resembling a bulb located at the base of the root. This cavity contains stem cells, which constitute a population of cells capable of undergoing mitosis, a mechanism through which a single parent cell divides into two new daughter cells. The stem cells are responsible for generating the daughter cells. Subsequently, these daughter cells proceed to generate hair. Hair is composed of keratin, a fibrous protein that confers structural integrity. These keratin molecules are arranged in a stacked configuration, forming the hair shaft.

Hair comprises cells that generate the hair pigment, commonly referred to as melanin. The coloration of hair exhibits significant variation owing to the presence of melanin. Certain individuals exhibit an albino mutation resulting in hair that is devoid of melanin, thus appearing truly white. Melanocytes, which are responsible for producing melanin, function as reservoirs of this pigment. Subsequently, the melanin is transferred into the keratin of hair, resulting in the manifestation of darker hair color. If an individual is interested in reversing greying hair, it is necessary to comprehend a particular gland located beneath the epidermis. The gland in question is commonly referred to as the sebaceous gland, responsible for the production of sebum, an oily substance. Sebum serves a dual purpose in the hair, creating a protective barrier at the point of hair emergence from the skin. The application of this seal renders the skin impervious to water. The human body's waterproofing capacity is reliant on the presence of sebum. Sebum possesses strong antibacterial properties, rendering it a crucial component of our immune system. Due to the presence of hair pores in our skin, microbes can easily penetrate it, however, sebum acts as a protective barrier against them.

The arrector pili muscle, situated obliquely between the hair bulb and the skin surface, is a significant constituent of the hair. The phenomenon of contracting muscles in response to cold or fear, resulting in the appearance of goosebumps, is attributed to the arrector pili muscle. This muscle contracts and pulls the skin surface down around the hair follicle, causing the characteristic appearance. The significance of this muscle lies in its ability to induce piloerection, wherein the hair follicles become erect upon its contraction. This physiological response is particularly crucial during periods of low temperature, as the erect hairs trap air between them, thereby facilitating body cooling [5].

Figure 2. Hair anatomy [6]

References

4. Egger, A., M. Tomic-Canic, and A. Tosti, Advances in Stem Cell-Based Therapy for Hair Loss. CellR4 Repair Replace Regen Reprogram, 2020. 8.

5. Zito., M.B.M.S.A.P.M. Anatomy, Hair. StatPEARLS 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK513312/.

6. Essentique. HAIR ANATOMY: A STRAND OF STRENGTH AND FLEXIBILITY. 2021; Available from: https://essentique.com/hair-anatomy-a-strand-of-strength-and-flexibility/.

(04): 00:26:05 3 Phases of Hair Growth

The growth of hair can be classified into three fundamental phases. During the initial stage, stem cells located in the bulb of the hair follicle differentiate into specialized cells responsible for synthesizing hair proteins, leading to the actual growth of hair. Hair growth originates from the root and subsequently protrudes through the surface of the skin. The period of hair growth known as the anagen phase is characterized by varying durations depending on the specific hair in question. The temporal extent of this phase ranges from two to eight years. Specifically, this pertains to refraining from trimming one's hair and allowing it to undergo natural growth for the aforementioned duration. Hair growth follows a natural cycle wherein it reaches a maximum length and subsequently ceases to grow. The hair growth cycle of eyebrows exhibited a distinct anagen phase, during which the hair grew at an average rate of approximately 4.2 millimeters per month. It has been observed that certain hairs of the eyebrows are longer in length compared to others. It is possible that the growth rate is higher, however, it is more likely that the stem cell population in the eyebrow follicle in question is longer than that of the others. Two principles govern hair growth, the first of which pertains to the varying durations of growth phases among different hairs on the body. The reason for the significantly longer growth of hair on the head, as compared to that of eyebrow hair, can be attributed to the comparatively longer anagen or growth phase of the former [7].

The Catagen phase also referred to as the transition phase, is a catabolic stage during which the hair recedes from the bulb region towards the skin surface and ultimately into the root. The duration of this phase varies among individuals. The internal recession of hair is a crucial phenomenon as it involves a modification in the bulb region. Typically, an interface exists between the stem cell population, melanocytes, and hair, which mutually support each other. It is noteworthy that the area receives nourishment from blood vessels.

The final stage of the hair growth cycle is known as the Telogen phase, which is characterized by a period of rest. During this phase, stem cells do not produce new hair proteins. The bulb located at the base of the hair follicle begins to constrict and detach from the surrounding tubes that connect to the skin surface. This process ultimately leads to the detachment and death of the hair follicle, resulting in the loss of stem cell population and melanocytes. Put simply, during the telogen phase, the population of stem cells that generate new hair and melanocytes responsible for hair pigmentation are depleted, resulting in the absence of hair in that area. Additionally, scalp hair undergoes a process of re-entry into the cell cycle, returning to the anagen phase and subsequently growing back.

The life cycle of hair consists of these three stages. If there are stem cells present and other crucial elements, such as adequate oxygen, a sufficient blood supply, and the right hormonal signal to stimulate development, certain hairs may be able to re-enter the life cycle and return to the anagen phase. The telogen phase becomes activated in the absence of hormonal input [8].

Figure 3. Four Stages of Hair Growth [9]

References

7. Schwartzenfeld, D.M. and J. Karamikian, Chapter 18 - Hair Transplantation, in Plastic Surgery Secrets Plus (Second Edition), J. Weinzweig, Editor. 2010, Mosby: Philadelphia. p. 123-127.

8. Flores., E.H.M.A.J.L. Physiology, Hair. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK499948/#:~:text=The%20growth%20of%20the%20hair,%2C%20and%20telogen%20(rest).

9. Roland, J. What Are the Four Stages of Hair Growth? healthline 2020; Available from: https://www.healthline.com/health/stages-of-hair-growth.

(05): 00:36:55 Minoxidil and Blood Flow

The first accelerator of hair growth is blood flow itself, which equates to the delivery of nutrients and oxygen. This is crucial, and it also explains why many treatments for stopping and reversing hair loss work. For example, one of the most well-known treatments for stopping and reversing hair loss is the so-called minoxidil. A medication called minoxidil sometimes referred to as Rogaine, was developed to treat hypertension. This cardiac medication lowers blood pressure by producing vasodilation, which allows more blood to flow to all of your body's hair, not just the hair on your scalp. In fact, it works well to slow down hair loss from other parts of your body as well. It does not simply slow down hair loss from the scalp. The anagen phase of hair development is lengthened in order to achieve this, as well. In persons who are just beginning to lose their hair, minoxidil has proven to be beneficial in decreasing the pace of hair loss [10].

Because minoxidil also has additional side effects, determining the proper dosage for this medication can be challenging. Depending on how sensitive a person is to that particular medicine, it can drop blood pressure. Therefore, doctors frequently start patients off on a lesser dose of minoxidil before gradually increasing it. Prolactin level rise has also been linked to minoxidil. Dopamine is a neuromodulator, whereas the hormone released by the pituitary acts as an antagonistic neurotransmitter. Therefore, those who use minoxidil, particularly if they are susceptible to it in large dosages, suffer a rise in prolactin and may have certain side effects, such as a decrease in libido and a general sensation of malaise. Additionally, in certain circumstances, excessively elevated prolactin levels result in gynecomastia, a male breast tissue enlargement. Women suffered the same adverse effects as men, including possible edema tissue swelling and headache, and dizziness from excessive vasodilation and low blood pressure.

If someone wants to take minoxidil to slow down hair loss rather than stop it. There are two main ways to administer minoxidil, also different people use it in different dosages. One is used topically as a cream, while the other is taken as a tablet. Use of oral minoxidil varies daily, from 0.25 to 5 milligrams. Additionally, a five percent concentration of topical minoxidil will be used once daily. Thought to only affect the scalp, topical use of minoxidil at a dose of 5% can enter the bloodstream generally and go systemically. But applying this medication topically does not work like taking it orally in the form of a pill or capsule [11].

Figure 4. Minoxidil Targeting Hair Follicles and enhance hair growth [12]

References

10. Olsen, E.A., et al., A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol, 2002. 47(3): p. 377-85.

11. Suchonwanit, P., S. Thammarucha, and K. Leerunyakul, Minoxidil and its use in hair disorders: a review. Drug Des Devel Ther, 2019. 13: p. 2777-2786.

12. Oaku, Y., et al., Minoxidil Nanoparticles Targeting Hair Follicles Enhance Hair Growth in C57BL/6 Mice. 2022. 14(5): p. 947.

(06): 00:45:37 Increase Blood Flow: Massage, Tadalafil, Platelet-Rich Plasma (PRP), micro-needling

Massaging the scalp can potentially enhance blood circulation in the hair. However, it is all transitory. The act of massaging the scalp for an adequate duration during the day has been suggested to enhance blood circulation. This, in turn, may reduce hypertension by dilating blood vessels and capillaries, thereby promoting hair retention. However, it is important to note that if an individual has a strong genetic predisposition to hair loss, this method is unlikely to completely halt or reverse the process. Nonetheless, it may serve as a means to slow down hair loss or maintain existing hair [13].

Another drug, Tadalafil, has been found to have similar effects as minoxidil at low doses. Tadalafil is commonly known by its brand name, Cialis, and is primarily used to treat erectile dysfunction at dosages ranging from 2.5 milligrams to 5 milligrams. The primary application of this treatment modality was to address prostate health concerns through the augmentation of blood circulation to the prostate gland, thereby mitigating certain age-related complications associated with the prostate. The mechanism of action involves augmentation of blood circulation to the stem cell microenvironment, thereby promoting hair maintenance. While it may not be effective in reversing hair loss, the utilization of low doses to decelerate hair loss can be viewed as a logical mechanistic approach akin to the rationale behind the use of minoxidil in mitigating hair loss rates. The main objective is to enhance the circulation of blood to facilitate the sustenance of the stem cell microenvironment situated beneath the hair follicle.

Currently, PRP (platelet-rich plasma) has emerged as a prevalent treatment for hair loss. Medical professionals in Europe, Canada, and the United States commonly administer PRP injections to stimulate the growth of healthy hair follicles. Additionally, PRP injections have been utilized to improve the fertility of women during their conception period. Additionally, individuals have utilized PRP injections as a means to promote joint health. However, it should be noted that the treatment in question does not fall under the category of stem cell therapy. Platelet-rich plasma (PRP) is a legally permissible medical procedure in the United States and numerous other regions worldwide. This technique entails the extraction of an individual's blood, which is then subjected to centrifugation at a specific velocity to isolate various blood constituents. Subsequently, the process involves the isolation of platelets from said components and their reintroduction into the bloodstream via a solution. The fundamental principle of Platelet-Rich Plasma (PRP) therapy is to stimulate targeted nutrient transportation to a specific bodily area through the utilization of an individual's own platelets. The platelets are enriched with a variety of nutrients. Individuals are also opting to receive Platelet-Rich Plasma (PRP) injections in their scalp, which differ from stem cell injections. These injections are costly and have demonstrated a moderate level of efficacy [14].

Microneedling is a treatment modality that involves the mechanical stimulation of hair follicles and the stem cell niche. The aforementioned therapy involves the utilization of multiple small needles, which are either arranged in a stamp-like configuration or integrated into a roller. The needles in question range in length from 0.5 millimeters to 2.5 millimeters. Furthermore, it causes discomfort to the skin on the scalp. Microneedling serves two primary purposes. Research has demonstrated the ability to reactivate a semi-quiescent population of stem cells that are in the telogen phase, inducing them to transition back into the anagen phase and subsequently promoting hair growth [15].

The administration of PRP and micro-needling injections has the potential to induce cellular changes in hair follicles. Specifically, these treatments may stimulate the reactivation of stem cells and telogen phase follicles that contain melanocytes and partially-dormant stem cells, thereby enabling them to reenter the cell cycle. All of these treatments, whether they involve medication or needling, share a common goal of enhancing blood circulation in the targeted area [16].

Figure 5. Process of PRP therapy [17]

References

13. Koyama, T., et al., Standardized Scalp Massage Results in Increased Hair Thickness by Inducing Stretching Forces to Dermal Papilla Cells in the Subcutaneous Tissue. Eplasty, 2016. 16: p. e8.

14. Jha, A.K., et al., Platelet‐rich plasma and microneedling improves hair growth in patients ofandrogenetic alopecia when used as an adjuvant to minoxidil. 2019. 18(5): p. 1330-1335.

15. Gupta, A.K., et al., Microneedling for Hair Loss. J Cosmet Dermatol, 2022. 21(1): p. 108-117.

16. Yepuri, V. and M. Venkataram, Platelet-Rich Plasma with Microneedling in Androgenetic Alopecia: Study of Efficacy of the Treatment and the Number of Sessions Required. J Cutan Aesthet Surg, 2021. 14(2): p. 184-190.

17. PRP Therapy at Revivo Hair. Available from: http://www.revivohair.com/prp-method/.

(07): 00:56:10 Microneedling, Minoxidil & “Dead Zones”

According to a systematic review, micro-needling has demonstrated favorable outcomes in individuals of all ages, irrespective of gender, particularly when administered in conjunction with other therapies, as elucidated in this podcast. Needle lengths ranging from one millimeter to approximately 2.5 millimeters have demonstrated greater efficacy compared to shorter needle lengths. Microneedling is a technique employed to stimulate hair growth by inducing scalp bleeding. While some individuals may experience discomfort, it is a widely utilized method. The physical disruption of the scalp skin is induced. The technique is associated with bleeding and inflammation [18].

The concurrent use of micro-needling and minoxidil has been demonstrated to yield superior outcomes compared to the individual application of either treatment. The utilization of a combination of minoxidil and micro-needling has been found to be a more efficacious approach in the restoration of "dead zones" - areas that exhibit complete or near-complete baldness and lack a stem cell population. This combination has been observed to facilitate the recovery of stem cell populations, thereby enabling the growth of new hair. However, it is important to note that the growth of hair in these "dead zones" may require a period of 30 to 50 weeks. It is noteworthy that neither minoxidil nor micro-needling alone has been found to stimulate stem cell proliferation in "dead zones", but their combination has been found to do so [19].

Figure 6. Mechanics of derma rollers for hair growth [20].

References

18. Fertig, R., et al., Microneedling for the treatment of hair loss? 2018. 32(4): p. 564-569.

19. English, R.S., Jr., S. Ruiz, and P. DoAmaral, Microneedling and Its Use in Hair Loss Disorders: A Systematic Review. Dermatol Ther (Heidelb), 2022. 12(1): p. 41-60.

20. TWO WAYS DERMA ROLLER CAN IMPROVE HAIR GROWTH. 2022; Available from: https://www.thehairfuel.com/derma-roller-can-improve-hair-growth/.

(08): 01:01:25 Botox Treatments

Botulinum neurotoxin, commonly known as Botox, is an additional therapeutic option for promoting hair growth. Botulinum is a bacterial toxin. The primary role of this function is to cleave proteins that are responsible for triggering the release of synaptic vesicles. Neurons engage in intercellular communication through the transmission of electrical impulses, which in turn facilitate the release of neurotransmitters into the synaptic cleft. The release of this chemical has the potential to either stimulate the subsequent neuron or inhibit the electrical activity of a different neuron. Botulinum neurotoxin cleaves the proteins present in neurons, thereby inhibiting the release of neurotransmitters that facilitate the activation of adjacent neurons. In the event of injection of this toxin into the muscle, paralysis of the muscle would ensue due to the absence of nerve signals that regulate contraction [21].

Botox toxin injections have been utilized for scalp tension release, resulting in decreased tensile properties of the scalp skin. This process promotes increased blood flow to the area, ultimately activating hair follicle stem cells. The administration of Botox treatment on the scalp has become increasingly prevalent in contemporary times. It is imperative that this procedure be carried out by a proficient medical practitioner, and certain prerequisites must be met. Excessive administration of Botox or improper injection placement can result in ptosis of the eyelids or brow. The effects of Botox are not permanent, as the botulinum neurotoxin dissipates over time. Proper administration and appropriate dosages ensure that the neurotoxin does not permanently damage the neurons responsible for skin tension. This administration of the injection necessitated frequent repetition [22].

The effectiveness of Botox in treating hair loss remains uncertain due to the limited number of clinical studies conducted on this topic. However, it appears that there exists at least one comparably secure substitute to minoxidil. To enhance blood circulation in the scalp, one may consider utilizing pharmaceuticals such as Tidilofil at a lower dose, which may potentially yield fewer adverse effects compared to minoxidil. Although Botox is an invasive medical intervention, certain individuals choose to undergo this treatment. Cutis vertices gyrate is a syndrome that has been identified in the medical literature. The term refers to the presence of a cluster of skin on the scalp. Individuals afflicted with this particular syndrome frequently encounter alopecia. This syndrome is correlated with hormonal imbalances related to androgens or testosterone. Research has demonstrated that the administration of Botox injections can result in a reduction of skin folds and an augmentation of hair growth in the treated region [23].

References

21. Zhou, Y., et al., Effectiveness and safety of botulinum toxin type A in the treatment of androgenetic alopecia. 2020. 2020.

22. Nassar, A., et al., Efficacy of botulinum toxin A injection in the treatment of androgenic alopecia: A Comparative Controlled Study. 2022. 21(10): p. 4261-4268.

23. Singh, S., S. Neema, and B. Vasudevan, A Pilot Study to Evaluate Effectiveness of Botulinum Toxin in Treatment of Androgenetic Alopecia in Males. J Cutan Aesthet Surg, 2017. 10(3): p. 163-167.

(09): 01:06:27 Androgens, Hair Growth & Pattern Hair Loss; Scalp vs. Beard Hair

It is important to note the presence of certain chemicals that play a significant role in this context. One such chemical is insulin growth factor one (IGF-1), which is a growth factor produced by the liver. However, it is noteworthy that the release of IGF-1 is stimulated by the brain and pituitary. This particular agent serves as a potent regulator of hair growth, functioning to expedite the process of hair growth. The process involves the extension of Anagen, which is the growth phase of hair. The intervention did not accelerate the rate of growth but rather prolonged it over an extended duration. Furthermore, cyclic adenosine monophosphate (cAMP), a secondary messenger pathway, is known to have a significant impact on promoting the growth of hair follicles. The cellular function of signal transduction involves the mediation of intercellular communication by relaying extracellular signals to intracellular targets. Examples of genetic regulation include the activation and deactivation of specific genes. The process involves the regulation of gene expression through the guidance of stem cells towards the continuation of daughter cells or the extension of the lifespan of hair cells [24].

The interruptions in the process of hair growth are attributed to factors that either curtail the anagen phase or prolong the catagen or telogen phases. Hair growth interruptions are attributed to the presence of PDE or phosphodiesterase and TGF beta 2, a growth factor that paradoxically does not promote growth. It is a well-established fact that a significant proportion of individuals experience hair loss by the age of 50, attributable to Androgen-related alopecia. This condition, also known as testosterone derivative-induced hair loss, affects both men and women. It has been observed that younger men exhibit higher levels of testosterone in comparison to older men. However, it is noteworthy that some men in their 40s, 50s, or even 80s maintain testosterone levels similar to those of younger men. Nevertheless, in the majority of cases, testosterone levels tend to decline with age. Females possess testosterone in addition to estrogen, with testosterone levels often surpassing those of estrogen. Females exhibit higher levels of estrogen and lower levels of testosterone compared to males [25].

Androgens, including testosterone and its derivative dihydrotestosterone, have been found to inhibit the activity of IGF-1 and cyclic AMP. Dihydrotestosterone (DHT) is synthesized from testosterone via the enzymatic activity of 5-alpha reductase in both male and female individuals. Dihydrotestosterone (DHT) exhibits a five-fold higher binding affinity to the androgen receptor compared to testosterone, thereby conferring greater androgenic potency in humans. DHT plays a crucial role in various physiological processes, including mental and physical vigor, libido, and strength. The DHT phenomenon does not inherently possess negative connotations. It is widely acknowledged that testosterone levels are greater in both males and females during their youth compared to later stages of life. However, with age, there is an increase in five alpha-reductase activities, leading to a greater conversion of testosterone to dihydrotestosterone. This hormone has been found to impede hair growth by diminishing the levels of igf-1 and cyclic AMP. Hair loss can occur in different patterns among individuals, with some experiencing hair loss in the crown region and back of the head, while others may experience hair loss in the front of the head, flanks, or midline. This variation in hair loss patterns is attributed to differences in genetics and androgen receptor patterns among individuals. The inheritance of the androgen receptor pattern is indeed a significant factor [26].

Figure 7. Androgen-mediated hair follicle [27]

References

24. Trüeb, R.M.J.S.a.d., Further clinical evidence for the effect of IGF-1 on hair growth and alopecia. 2018. 4(2): p. 90-95.

25. Tazdanian, N., S. Mozafarpoor, and A.J.D.T. Goodarzi, Phosphodiesterase inhibitors and prostaglandin analogues in dermatology: A comprehensive review. 2021. 34(1): p. e14669.

26. Miranda, B.H., et al., Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life. Faseb j, 2018. 32(2): p. 795-806.

27. Yip, L. and R. Sinclair, Antiandrogen therapy for androgenetic alopecia. Expert Review of Dermatology, 2006. 1: p. 261-269.

(10): 01:15:46 Topical Caffeine & Slowing Hair Loss

Another significant chemical that has the potential to promote hair growth is caffeine, a stimulant that is commonly consumed. In addition to its effects on the nervous system, caffeine has been found to have various other properties. This substance exhibits considerable potency as a phosphodiesterase (PDE) inhibitor. Its PDE inhibitory properties indirectly promote the stimulation of insulin-like growth factor 1 (IGF-1), as PDE has been shown to suppress IGF-1. The consumption of caffeine or the application of topical caffeine ointment has been observed to effectively inhibit PDE, thereby leading to an increase in IGF-1 levels and promoting hair growth. The efficacy of topical caffeine application has been found to be comparable to that of minoxidil application while avoiding the potential side effect of reduced blood pressure. Caffeine-containing ointments and creams are considered to be a favorable choice for promoting healthy hair. The administration of this therapy may be conducted thrice weekly, while the degree of caffeine concentration in various ointments exhibits significant variation. The majority of research conducted on the potential benefits of caffeine for enhancing the stem cell niche has been carried out in vitro or in a laboratory setting. When evaluating the cost, side effects, and efficacy of minoxidil and caffeine, it appears that caffeine may be a more favorable option. As opposed to minoxidil, caffeine was found to lack any associated adverse effects. Caffeine has been observed to not only stimulate insulin-like growth factor 1 (IGF-1), but also to exhibit potential in reducing apoptosis, a naturally occurring phenomenon of cell death in the hair stem cell niche [28].

References

28. Völker, J.M., et al., Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review. Skin Pharmacology and Physiology, 2020. 33(3): p. 153-169.

(11): 01:21:06 IGF-1: Growth Hormone & Sermorelin; Insulin Sensitivity: Myo-Inositol

One of the key methods for promoting hair growth involves elevating IGF-1 levels through the utilization of growth hormones. Sermorelin, a peptide, has been found to increase growth hormone levels by stimulating its secretion. This, in turn, leads to an increase in insulin-like growth factor 1 (IGF-1) levels. It is important to note that both growth hormone and IGF-1 have potential side effects, including the promotion of tissue growth, such as height in children, hair growth, and improved skin appearance. However, they also encountered issues pertaining to the proliferation of small tumors and heightened susceptibility to cancer. Sermorelin is a method of indirectly augmenting IGF-1 levels, which in turn promotes hair growth. Its efficacy is notable, particularly when administered in conjunction with other therapies.

One noteworthy aspect regarding the promotion of endogenous igf-1 synthesis is its dependence on insulin, as implied by its nomenclature as insulin growth factor one. This dependence manifests in various ways, including its effects on hair follicle and stem cell activity. It is important to avoid insulin resistance and strive for insulin sensitivity. Individuals who are afflicted with obesity or type 2 diabetes, which is indicative of insulin resistance, are advised to address their condition. Presently, there are several prescription interventions available for this purpose, with glp-1 being a particularly promising option that has garnered considerable enthusiasm. Obesity has been linked to hair loss. Certain supplements, such as myoinositol, have been suggested to be effective when consumed at a dosage of approximately 900mg prior to bedtime. Berberine and metformin are recognized for their ability to enhance insulin sensitivity [29].

Figure 8. Growth hormone and Hair Growth [30].

References

29. Horesh, E.J., J. Chéret, and R. Paus, Growth Hormone and the Human Hair Follicle. Int J Mol Sci, 2021. 22(24).

30. Horesh, E.J., J. Chéret, and R. Paus, Growth Hormone and the Human Hair Follicle. 2021. 22(24): p. 13205

(12): 01:25:52 Iron and Hair Growth

Adequate iron intake is crucial for maintaining optimal hair growth, as it promotes a longer anagen phase of hair growth. Iron and ferritin are crucial components in the cellular growth pathways that extend from stem cells to the stimulation of keratin production within the hair. Excessive iron intake may result in toxicity, while inadequate consumption may lead to anemia. The recommended daily intake of iron for females ranges from 25 to 100 milligrams, while for males it ranges from 30 to 150 milligrams. Iron is a vital element in the anagen phase of hair growth. Ensuring adequate levels of iron in the bloodstream can be achieved through the use of supplements or dietary modifications, thereby mitigating the effects of iron deficiency [31].

References

31. Park, S.Y., et al., Iron plays a certain role in patterned hair loss. J Korean Med Sci, 2013. 28(6): p. 934-8.

(13): 01:27:04 5-Alpha Reductase & Saw Palmetto; Curcumin

The discussion pertains to dihydrotestosterone and its negative impact on hair maintenance and growth, specifically its ability to abbreviate the anagen phase. Therefore, the hair will experience a reduced duration of growth. Secondly, this can be attributed to the existence of androgen receptors in the stem cell niche region. The process effectively reduces the size of the follicle and stem cell niche, thereby decreasing the population of cells responsible for generating additional hair proteins. This reduction can potentially lead to the complete elimination of these cells. Consequently, any intervention that reduces the activity of 5 alpha reductases and subsequently lowers DHT levels can help sustain or prolong the anagen phase of hair growth while also preventing the onset of the telogen phase.

Saw palmetto, an extract derived from salt palmetto berry, has the potential to inhibit 5-alpha reductase. There were no observed side effects. When administered at a daily dosage of approximately 300 milligrams, it has been observed to promote hair retention and potentially stimulate the growth of new hair follicles. The treatment in question lacks efficacy in reversing hair loss. Although it may not be highly efficacious, the product in question boasts a relatively low cost and widespread availability in the market [32].

Certain herbal compounds exhibit potent biological effects that promote hair growth, albeit through synergistic interactions among them. The majority of supplements containing herbal compounds typically comprise a combination of five, ten, or more ingredients, rendering it exceedingly challenging to discern the efficacious components and optimal dosages. It has been suggested that the consumption of green tea extract, racy mushroom, pumpkin oil, zinc, and curcumin may promote hair growth. Curcumin, also referred to as turmeric, has been observed to function as a potent inhibitor of 5-alpha reductase and DHT in certain individuals [33].

Figure 9. Inhibition of 5-Alpha Reductase [34]

References

32. Tracy, T.S.J.H.P.T. and C. Pharmacology, Saw Palmetto. 2007: p. 165-175.

33. Pumthong, G., et al., Curcuma aeruginosa, a novel botanically derived 5α-reductase inhibitor in the treatment of male-pattern baldness: a multicenter, randomized, double-blind, placebo-controlled study. J Dermatolog Treat, 2012. 23(5): p. 385-92.

34. English, R. Part 2 Of 4: Attacking DHT By Inhibiting 5-Alpha Reductase. 2022; Available from: https://perfecthairhealth.com/part-2-of-4-a-master-guide-of-the-best-and-worst-ways-to-fight-dht-for-hair-loss/.

(14): 01:33:22 Ketoconazole & Offsetting Hair Loss

Ketoconazole, also known as Nizoral, is a compound that has been found to stimulate hair growth. It is commonly used as an anti-fungal agent and was initially developed to treat dandruff and psoriasis. Nizoral is a brand name of shampoo that contains ketoconazole. The treatment has demonstrated a high level of efficacy in promoting an increase in both hair count and hair thickness. One of the potential adverse outcomes is the manifestation of dryness, thinning, and brittleness in the hair. The mechanism of action of this substance is intriguing as it has the ability to impede certain fungal growth on the scalp. Ketoconazole functions as an antifungal agent that appears to enhance the sebum's ability to prevent other fungal infections. Consequently, it leads to a slight decrease in dihydrotestosterone (DHT) levels. The application of ketoconazole shampoos at a frequency of two to four times per week, with a scalp contact duration of approximately three to five minutes, has demonstrated an 80% success rate in preserving hair that would otherwise be lost. The efficacy of ketoconazole shampoos in promoting hair regrowth remains uncertain. The conventional suggestion is to engage in scalp contact for a duration of approximately three to five minutes, with a frequency of two to four times per week [35].

In the event that one chooses to utilize ketoconazole as a strategy for mitigating hair loss, it is imperative to acquire a shampoo containing a minimum of two percent concentration of ketoconazole. There is a plethora of hair products available in the market that contain 1%. Ketoconazole may elicit side effects such as mild scalp irritation, as well as hair thinning and brittleness [36].

Figure 10 Ketoconazole as anti-fungal [37]

References

35. Piérard-Franchimont, C., et al., A multicenter randomized trial of ketoconazole 2% and zinc pyrithione 1% shampoos in severe dandruff and seborrheic dermatitis. 2002. 15(6): p. 434-441.

36. Fields, J.R., et al., Topical ketoconazole for the treatment of androgenetic alopecia: A systematic review. Dermatol Ther, 2020. 33(1): p. e13202.

37. Goularte-Silva, V. and L.C. Paulino, Ketoconazole beyond antifungal activity: Bioinformatics-based hypothesis on lipid metabolism in dandruff and seborrheic dermatitis. 2022. 31(5): p. 821-822.

(15): 01:38:46 Topical & Oral Finasteride

Finasteride is a different substance that inhibits 5 alpha reductases and lowers DHT to promote hair growth. Because it affects the type 2 isoenzyme of 5 alpha reductases, it lowers DHT. Additionally, the number of hairs grows by 20%. In addition, it can cut hair loss in half for everyone who takes it and boost hair thickness by 20 to 30 percent. Additionally, it might produce thick, fresh hair. Additionally, it keeps the hair that was on your scalp. Finasteride had some negative consequences as well. There are two types of it: topical and oral. The dosage of topical finasteride is equal to one milligram of systemic finasteride and is administered as a one percent solution [38].

Finasteride was frequently prescribed for prostate enlargement and other conditions related to the prostate that is brought on by increasing DHT with aging. With the intention of entering hair follicles, where it would suppress DHT and promote greater growth, topical finasteride was created. Finasteride dosage varies depending on the person. So it's okay to take as little as 0.01 mg and as much as 5 mg daily.

The logarithmic distribution of finasteride is noteworthy, as it results in a 50% reduction of systemic DHT with a dosage of 0.01mg. The linear relationship between the increase in dosage of oral finasteride, ranging from 0.2mg to 1mg to 5mg per day, and the corresponding reduction in dihydrotestosterone is not observed. Specifically, the percentage reduction in dihydrotestosterone does not increase linearly with each incremental increase in dosage, as evidenced by the lack of a consistent pattern in the reduction percentages observed at each dosage level. The trend is one of gradual increase, with a slight incline observed as the dosage escalates from 0.2mg to 5mg. The reduction of DHT may result in adverse effects such as sexual side effects or decreased motivation.

The prolonged use of Finasteride is purported to mitigate hair loss and promote hair growth. However, a common concern with Finasteride usage is the initial administration of low doses such as 0.1 or 0.2mg, which results in a reduction of Dihydrotestosterone (DHT). Due to the extended duration of the anagen phase, individuals may not observe significant changes in their hair growth during the initial month of treatment. Subsequently, upon increasing the dosage, the individual encounters a heightened occurrence of adverse reactions. The topical application of 0.25% finasteride in a quantity of one milliliter can produce equivalent results to the oral administration of 2.5mg of finasteride. Research has shown that a concentration of 0.2 mg of finasteride in the bloodstream has the ability to promote the growth of new hair while simultaneously preserving existing hair [39].

The correlation between dosage and side effects of Finasteride is observed to be positive, with some individuals exhibiting heightened sensitivity to the drug. The recommended dosage of Finasteride, as supported by medical professionals and clinical research, is typically within the range of 0.5 to 1 milligram per day, administered orally in tablet form, and has been demonstrated to be both efficacious and well-tolerated. However, it is necessary for the individual who has taken this dosage to wait and observe whether there has been any hair growth or not. It is not advisable to escalate the dosage in the absence of favorable outcomes. The topical formulation of finasteride has been demonstrated to be less commonly associated with adverse effects compared to the oral formulation, as evidenced by a study reporting 30 to 50% fewer severe side effects [40].

References

38. Hirshburg, J.M., et al., Adverse effects and safety of 5-alpha reductase inhibitors (finasteride, dutasteride): a systematic review. 2016. 9(7): p. 56.

39. Kang, D.W., et al., Pharmacokinetic-pharmacodynamic modeling approach for dose prediction of the optimal long-acting injectable formulation of finasteride. 2021. 601: p. 120527.

40. Todeschini, D., I.P. Martinez, and M.D. Duque. Topical finasteride dose evaluation for treatment of androgenetic alopecia using computer simulations. in Annales Pharmaceutiques Françaises. 2022. Elsevier.

(16): 01:51:00 Post-Finasteride Syndrome

The occurrence of Post-Finasteride Syndrome is attributed to the utilization of finasteride. Finasteride has been recommended as a therapeutic agent for managing prostate-related conditions, with a standard dosage of approximately five milligrams per day. The dosage administered is considerably high, and for a prolonged period, there was no discourse regarding post-finasteride syndrome. In males, the administration of finasteride at varying dosages ranging from one to five milligrams per day for the treatment of prostate or hair loss, followed by discontinuation due to reasons such as financial constraints or side effects, has been observed to result in the manifestation of a severe syndrome known as Post Finasteride Syndrome. The symptoms of this syndrome include a significant reduction in libido, and erectile function, and the onset of depression. Sufficient medical attention has been devoted to the phenomenon of post-finasteride syndrome. It appears that younger males who consume finasteride in high doses for the purpose of enhancing hair growth experience this syndrome to a greater extent than their older counterparts. The phenomenon appears to exhibit a higher incidence rate among male individuals aged between 20 and 30 years [41].

It is understood that dihydrotestosterone played a significant role in the initial stages of embryonic development, specifically in the development of male genitalia. Throughout puberty, dihydrotestosterone plays a significant role in promoting the growth of male genitalia and facilitating the onset of puberty. However, the phenomenon of post-finasteride syndrome suggests that dihydrotestosterone may have additional effects on male maturation, as well as on the maturation of hypothalamic regions of the brain [42].

Figure 11 Mechanism of Action of Finasteride [43]

References

41. Maksym, R.B., A. Kajdy, and M.J.T.A.M. Rabijewski, Post-finasteride syndrome–does it really exist? 2019.

42. Tadi., B.H.S.P. 5 Alpha Reductase Inhibitors. 2022; Available from: https://www.ncbi.nlm.nih.gov/books/NBK555930/.

43. Oh, S.-h., et al., Resistance Training Ameliorates Finasteride-Induced Disturbance in Protein Homeostasis in Skeletal Muscle of Rats. Exercise Science, 2019. 28: p. 159-167.

(17): 01:56:01 Dutasteride

Dutasteride is a chemical compound that bears resemblance to finasteride. Significantly, it effectively suppresses all three variants of the alpha-reductase enzyme with high potency. The standard oral dutasteride dosage ranges from 0.5 mg to 2.5 mg, administered orally. Its efficacy in promoting hair growth and reducing DHT levels by 90% is notably superior to that of finasteride, with a correspondingly faster onset of action. Additionally, it is accompanied by a multitude of adverse effects that are linked to the DTH pathway. In addition to causing a decrease in libido and motivation, this condition disrupts other physiological pathways, such as elevating levels of estrogen and prolactin, and occasionally inducing the growth of male breast tissue. Dutasteride has been observed to exhibit a comparatively expedited onset of action, ranging from two to five times faster than finasteride. Consequently, certain individuals may elect to forego the waiting period for finasteride outcomes and instead pursue dutasteride [44].

Figure 12. Side effects of Dutasteride [45]

References

44. Hirshburg, J.M., et al., Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. J Clin Aesthet Dermatol, 2016. 9(7): p. 56-62.

45. Saengmearnuparp, T., et al., The connection of 5-alpha reductase inhibitors to the development of depression. Biomedicine & Pharmacotherapy, 2021. 143: p. 112100.

(18): 01:58:53 Mechanical & Chemical Stimulation for Hair Growth

The efficacy of combination therapies involving both mechanical and chemical stimuli has been demonstrated to surpass that of either stimulus in isolation. Among mechanical stimuli, micro-needling has been found to be particularly effective. The concomitant use of micro-needling and finasteride has been shown to yield robust and impressive hair regrowth, even in cases of baldness. This combination therapy holds promise for significant hair regrowth. Ketoconazole shampoo or saw palmetto can also be utilized. It is important to exercise caution when combining treatments that inhibit the DHT pathway, as excessively reducing DHT levels should be avoided. Individuals exhibit varying responses to these treatments. To mitigate adverse effects linked with these medications, it is advisable to commence with a lower dosage [46].

Figure 13. Mechanical and Chemical Stimulation of hair Growth [47]

References

46. Chu, S.-Y., et al., Mechanical stretch induces hair regeneration through the alternative activation of macrophages. 2019. 10(1): p. 1524.

47. Gu, Y., et al., Hair follicle-targeting drug delivery strategies for the management of hair follicle-associated disorders. Asian Journal of Pharmaceutical Sciences, 2022. 17(3): p. 333-352.

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