I’ll get right to the point. Diffuse Unpatterned Alopecia (DUPA) and retrograde forms of hair loss, in my opinion, are moreso aesthetics rather than conditions in their own right. This means that people who present with DUPA and retrograde may have a similar distribution of hair loss, but their underlying reasons may differ. This is important because, in some cases, finasteride and dutasteride simply WILL NOT WORK (or at least not on their own).
To illustrate my point, imagine two people, Person A and Person B, both missing their right hands. At first glance, their conditions might seem identical. However, closer examination reveals significant differences.
Person A lost their right hand due to an accident. An X-ray would show jagged bone ends and possibly signs of surgical intervention like pins or plates. There might also be scarring and bone remodeling around the stump. In contrast, Person B was born without their right hand due to a congenital condition like amniotic band syndrome. Their X-ray would show naturally tapered or underdeveloped bones with smooth contours and no signs of trauma or surgery. Genetic testing would confirm the congenital defect in Person B but not in Person A.
This distinction highlights that outward appearances can be deceiving. Should we describe these individuals as having a “missing right-hand syndrome”? Or is it more accurate to call Person A an amputee and Person B someone with a congenital condition?
https://sci-hub.se/10.1016/j.jaad.2006.12.029
https://www.researchgate.net/figure/The-BASP-classification-system-includes-four-basic-types-L-M-C-and-U-and-two_fig3_230645756
Applying this logic to hair loss, androgenetic alopecia (AGA) can appear in various patterns, including diffuse unpatterned alopecia (DUPA). Hamilton’s classification of common baldness, Beom Jun Kim’s Modified Basic and Specific classification system, and Kamishima et al.'s research on AGA progression show that AGA can be diffuse or localized.
So, if you have DUPA or retrograde hair loss, it could just be plain old androgenetic alopecia. But at the very least, this needs to be fully confirmed because you could have comorbid causes of hair loss caused by other issues: this is where scalp biopsies are important.
https://www.sciencedirect.com/science/article/abs/pii/S0190962203000458
A scalp biopsy is a medical procedure in which a small piece of scalp tissue, including hair follicles, is removed for examination. This is typically performed to diagnose various hair and scalp disorders, such as alopecia, scalp infections, or inflammatory scalp conditions. The procedure is usually done under local anesthesia to minimize discomfort.
The area of the scalp to be biopsied is first cleaned and numbed with a local anesthetic. A small, circular tool called a punch is then used to remove a core of tissue, usually about 4 millimeters in diameter. The sample includes skin, hair follicles, and underlying tissue.
After the tissue is removed, the site may be closed with a few stitches or left to heal on its own, depending on the size of the biopsy and the location on the scalp. It should be noted that the area where the biopsy is done creates fibrosis (scarring). But honestly, scarring 50 hairs is worth it if it can tell you the potential fate of 100,000 or more hairs on your scalp.
The extracted tissue is then sent to a pathology lab, where it is processed and examined under a microscope. Pathologists look for specific signs of disease, such as inflammation, scarring, or abnormal hair follicle structures. The biopsy results help doctors make an accurate diagnosis and determine the most appropriate treatment plan for the patient.
So, scalp biopsies are a valuable diagnostic tool, providing detailed information that can confirm or rule out conditions that might not be identifiable through clinical examination alone.
But the thing is, when was the last time you had a scalp biopsy?
Seriously, most examinations I’ve seen, especially when talking to doctors, are done by visually inspecting the scalp and referring to a checklist. Sometimes they use a dermatoscope to check for any obvious signs of inflammation. While this approach works for the majority of cases, as most hair loss is due to DHT and the genetics of AGA, the literature on biopsies for conditions like lichen planopilaris (LPP) shows that it tends to be diagnosed mostly in post-menopausal women.
According to Kenia Lepe, Ali Nassereddin, Hasnain A. Syed, and Francisco J. Salazar in “Lichen Planopilaris,” StatPearls, the incidence of cicatricial alopecias is not precisely known. Lichen planopilaris is reported as the most frequent primary scarring alopecia, accounting for 43% of cases in a series involving 72 patients. This condition typically affects women between the ages of 40 and 60 more often than men. Up to 50% of patients may develop characteristic lichen planus lesions affecting the skin, mucous membranes, or nails. The authors emphasize the importance of understanding the autoimmune nature of LPP and its impact on patient care.
However, is this truly the case? Is LPP primarily a condition affecting post-menopausal women, or is there a strong bias against performing biopsies on men?
When a balding man walks into a clinic, it’s often assumed that he has typical androgenetic alopecia. From my observations, dermatologists might prescribe finasteride or dutasteride, recommend platelet-rich plasma (PRP) treatment, and perhaps order some blood work. A diagnosis of AGA is given without a biopsy.
In contrast, hair loss in women tends to raise alarms among physicians. Even if it’s related to androgenetic alopecia, like polycystic ovarian syndrome (PCOS) or menopausal changes, doctors are more likely to run tests, including a biopsy, beyond the initial examination. This is more or less confirmed as a practice from
This creates a selection bias in the data. Men aren’t biopsied as frequently as post-menopausal women. Additionally, biopsies might be underutilized in women with slow-progressing hair loss conditions, like a gradual progression of LPP that destroys follicles over years. These women might be excluded from biopsy data for a considerable amount of time.
The point I’m trying to make is that scalp biopsies should be more common for everyone than they currently are. This would lead to more accurate diagnoses and better treatment plans.
I talked to Dr. William Rassman, the inventor of the FUE hair transplant procedure, on my podcast, HairStacks. During our conversation, Dr. Rassman mentioned that some of his colleagues at the Bernstein Medical Center for Hair Restoration make it a standard practice to biopsy anyone seeking a transplant. This is done to rule out other potential causes of hair loss besides androgenetic alopecia (AGA).
Dr. Rassman explained that through this more rigorous analysis, both he in his own practice as well as Dr. Shaver and staff at Bernstein Medical Center have identified comorbid conditions of hair loss, such as AGA and LPP, and other issues. While there aren’t many studies on this topic, some research indicates that women are more thoroughly investigated for their hair loss concerns than men.
The review titled “Evaluation and Treatment of Male and Female Pattern Hair Loss” by Elise A. Olsen et al. (2005) provides insight into the emerging practices of the early 2000s regarding when to use biopsies for determining the histopathology of a person presenting with hair loss. In men, the authors state that biopsies are “usually not necessary unless a female pattern of hair loss, diffuse hair loss, or scalp changes suggestive of cicatricial alopecia confuse the diagnosis.” This suggests that male patients often bypass the detailed diagnostic step of a biopsy unless their condition deviates from the typical male pattern baldness.
In contrast, the review points out that biopsies in women are deemed “sometimes necessary to exclude chronic telogen effluvium, diffuse alopecia areata, or cicatricial hair loss such as early central centrifugal cicatricial alopecia seen commonly in African American women.” This indicates a more cautious approach toward diagnosing hair loss in women, reflecting a concern for accurately distinguishing between different types of hair loss conditions that might be masked by a generalized thinning pattern.
But this isn’t beneficial for anyone. This gender disparity in the use of biopsies raises important questions about the potential underdiagnosis of certain hair loss conditions in men. Conditions like lichen planopilaris (LPP), which can present in a patterned form similar to androgenetic alopecia (AGA), might be overlooked.
In the study “Lichen Planopilaris in Women: A Retrospective Review of 232 Women Seen at Mayo Clinic From 1992 to 2016” by Sydney C. Larkin et al., published in 2020, the researchers provide detailed insights into the prevalence and characteristics of LPP among women. The study found that out of the 232 women diagnosed with LPP, an overwhelming 92.7% presented with hair loss, highlighting the commonality of this symptom in LPP patients. Furthermore, the study reported that 217 of these women underwent confirmatory biopsies, reinforcing the importance of biopsies in diagnosing LPP.
The study also notes that LPP predominantly affects women, with a mean age of diagnosis at 59.8 years. The inclusion of a large number of women who were biopsied underscores the thorough diagnostic approach typically taken for female patients experiencing hair loss. The authors specifically state that “men were excluded from this study to more accurately determine the association of hormonal factors in LPP pathogenesis.” This exclusion removes us from knowing the possibilities and any potential histopathological differences that LPP may present in males, or even hormonal factors that could possibly exist beyond DHT.
I’m particularly concerned about the study’s population selection, which mostly skews towards postmenopausal or menopausal women. The study finds that these women presented with LPP along with other comorbid conditions like diabetes, skin cancer, nutritional deficiencies, and much more. Not having a more rigorous investigation leaves out a lot of people – including, as I previously mentioned, women who may not be menopausal/postmenopausal but have a slow-progressing scarring alopecia condition like LPP.
We should want to know this data because if LPP, an autoimmune scarring alopecia condition, is correlated with other health issues, it may indicate that other autoimmune conditions may be likely to occur for that patient in the future, or perhaps the patient may be living with an undiagnosed one. It should be noted that LPP and other autoimmune conditions may largely be asymptomatic.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00457-9/abstract
We can refer to the study, “Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK” by Nathalie Conrad et al., published in 2023, highlights that autoimmune diseases often co-occur. The study found that individuals with one autoimmune condition are at a higher risk of developing additional autoimmune diseases. For example, individuals with childhood-onset type 1 diabetes had significantly higher rates of Addison’s disease, coeliac disease, and thyroid disease, which suggests that there are some sort of shared pathogenetic mechanisms or predisposing factors among autoimmune diseases.
https://onlinelibrary.wiley.com/doi/10.1111/jocd.16177?af=R
For additional context, Kamishima et al.'s paper, titled “Divergent Progression Pathways in Male Androgenetic Alopecia and Female Pattern Hair Loss: Trichoscopic Perspectives,” provides a comprehensive analysis of how hair loss develops differently in men and women. This paper may also help us understand what is happening in a condition like Diffuse Unpatterned Alopecia (DUPA).
(note: MAGA means Male Androgenetic Alopecia and FPHL means female pattern hair loss)
The nine quantitative trichoscopic factors identified in the study include Hair Diameter Diversity, which measures the variation in the thickness of individual hairs within the same area of the scalp. This factor is significant because greater diversity in hair diameter often indicates the presence of miniaturized hairs, a hallmark of androgenetic alopecia.
Hair Density is another factor representing the number of hairs per square centimeter of the scalp. Lower hair density is a common characteristic observed as hair loss progresses, providing a clear indication of how much hair has been lost in a given area.
The Percentage of Thin Hairs is a critical factor that evaluates the proportion of hairs below a certain diameter threshold, highlighting the extent of follicular miniaturization. This factor helps quantify the number of finer hairs compared to normal, thicker hairs, which is crucial in assessing the severity of hair thinning.
In men, androgenetic alopecia typically follows the patterns of the Hamilton-Norwood scale. The early stages often involve a receding hairline and thinning at the crown. As the condition progresses, extensive baldness occurs in the frontal and vertex regions of the scalp. However, the occipital and parietal areas, known as ‘safe’ donor zones in hair transplantation, are generally spared because they are less affected by DHT.
One of the early signs of male androgenetic alopecia, as described by Kamishima et al., is a significant reduction in hair diameter. This thinning of hair strands indicates the onset of follicular miniaturization. As the condition advances, the diameter reduction becomes more pronounced. Additionally, there is a decrease in the number of hairs per follicular unit, leading to an increase in single-hair follicular units. This reduction in hair clusters reflects a decline in overall hair density, as fewer hairs grow together in groups.
Female pattern hair loss, often assessed using the Ludwig scale, differs from male androgenetic alopecia. Women typically experience diffuse thinning over the crown while maintaining their frontal hairline. Unlike the distinct recession patterns seen in male baldness, female pattern hair loss involves a uniform reduction in hair density across the scalp.
And finally, Diffuse Unpatterned Alopecia (DUPA) presents a hair loss pattern that closely mirrors aspects of female pattern hair loss, despite occurring in both males and females. This similarity shows that there is a need to understand that although the diffuse pattern seems more common in females, males can also experience such conditions.
Therefore, it is crucial not to be overly fixated on the terminology if a male is experiencing a hair loss pattern similar to DUPA, which is typically associated with female pattern hair loss. Conversely, females may experience hair loss patterns more commonly seen in males.
So let’s backtrack a bit so we can refocus:
As reported by Olsen et al. in the 2005 review, “Evaluation and Treatment of Male and Female Pattern Hair Loss,” men are biopsied only when they present with a female pattern kind of loss. However, this approach overlooks cases of men who could have patterned forms of conditions like LPP. A study performed by Martin S. Zinkernagel and Ralph M. Trüeb in 2000, titled “Fibrosing Alopecia in a Pattern Distribution: Patterned Lichen Planopilaris or Androgenetic Alopecia With a Lichenoid Tissue Reaction Pattern?”, indicates that even scarring alopecias like LPP can present in patterns similar to androgenetic alopecia.
Additionally, it is possible for both conditions to occur simultaneously. This highlights the importance of biopsying both men and women, regardless of the pattern of hair loss. Yes, a biopsy involves sacrificing a small area of hair, but losing around 50 hairs to understand the fate of 100,000 or more hairs is a worthwhile trade-off.
Gendering hair loss isn’t a good idea! Biopsy for all!
Lichen planopilaris (LPP) is one of the most prevalent forms of scarring alopecia, a group of disorders resulting in irreversible hair loss due to the destruction and fibrosis of hair follicles. The study titled “Scarring Alopecias: Pathology and an Update on Digital Developments” by Donna M. Cummins, Iskander H. Chaudhry, and Matthew Harries et al., published in Biomedicines in 2021, offers comprehensive insights into the pathological mechanisms, diagnostic challenges, and technological advancements in managing scarring alopecias.
Scarring alopecias, including LPP, are characterized by the destruction of the hair follicle’s epithelial stem cell niche, known as the bulge. This region, located at the lower part of the hair follicle just above the attachment point of the arrector pili muscle, contains epithelial hair follicle stem cells (eHFSCs) that are essential for the regeneration and cyclical growth of hair follicles. The destruction of these stem cells in the bulge region leads to permanent hair loss because it prevents the hair follicle from regenerating.
In LPP, the perifollicular inflammatory infiltrate targets the bulge, leading to the collapse of immune privilege.
Now, this part is important in its own right and it concerns Immune privilege. Immune privilege is a state where certain areas on and in the body are protected from immune system attacks to maintain tissue integrity and function.
This collapse exposes hair follicle antigens to the immune system, resulting in an autoimmune response that damages the eHFSCs.
Now, for a nonscarring alopecia like alopecia areata, this immune privilege collapse seems to occur at the base of the dermal papilla hair follicle. So, in this case, there is no actual destruction of the hair follicle as the stem cell niche bulge is not destroyed. So, using a jak-inhibitor or topical corticosteroid injections in many cases helps the hair come back after a while.
Androgenetic alopecia: new insights into the pathogenesis and mechanism of hair loss - PMC.
Also, Androgenetic Alopecia (AGA) is also a form of non scarring alopecia. But, there is some reason to believe that it eventually becomes a form of scarring alopecia, or perhaps in my thought which I will elaborate later, the condition of AGA, primarily caused by DHT, may be implicated in OTHER HAIR LOSS CONDITIONS. THIS IS MAJOR.
Understanding immune privilege and its collapse is crucial as it underscores why these autoimmune reactions occur and why they lead to irreversible hair loss. The study by Cummins et al. highlights that the destruction of the sebaceous glands is a common early feature in all types of scarring alopecias before significant hair loss occurs.
Sebaceous glands, which are small oil-producing glands connected to hair follicles, play a vital role in maintaining the health and integrity of hair follicles by producing sebum, which lubricates and protects the hair and skin. Their loss or dysfunction is considered an early marker of disease activity and can precede noticeable clinical symptoms of hair loss.
In scarring alopecias such as Lichen Planopilaris (LPP), Frontal Fibrosing Alopecia (FFA), Central Centrifugal Cicatricial Alopecia (CCCA), Discoid Lupus Erythematosus (DLE), Folliculitis Decalvans (FD), and Pseudopelade of Brocq (PsB), the sebaceous glands are among the first structures to be destroyed. This early destruction is significant across various types of scarring alopecias, indicating the onset of irreversible hair loss before the hair follicles are visibly affected.
From Scarring Alopecias: Pathology and an Update on Digital Developments - PMC , here it shows scar tissue replacing the hair follicle
Lichen planopilaris (LPP) is characterized by a lichenoid inflammatory infiltrate around the isthmus and infundibulum of the hair follicle. The study notes that in LPP, sebaceous glands are typically destroyed early in the disease process, often before significant hair loss becomes clinically apparent. This early destruction leads to perifollicular fibrosis and eventual follicular dropout.
Frontal fibrosing alopecia (FFA), a variant of LPP, also shows early sebaceous gland loss. FFA is marked by a progressive recession of the frontal hairline, and the histological features are similar to those of classic LPP. The study emphasizes that in FFA, the early loss of sebaceous glands and the presence of a lichenoid infiltrate contribute to the progressive and scarring nature of this condition.
Central centrifugal cicatricial alopecia (CCCA) predominantly affects women of African descent and presents as a slowly expanding patch of scarring alopecia on the crown or vertex of the scalp. The paper highlights that in CCCA, the sebaceous glands are destroyed early in the disease course, which is a critical factor in the pathogenesis and progression of the condition. The loss of sebaceous glands in CCCA is accompanied by concentric lamellar fibrosis and lymphocytic inflammation around the hair follicles.
Discoid lupus erythematosus (DLE) is another form of PCA where sebaceous gland destruction is a prominent feature. Here, the inflammatory process targets the hair follicles and the sebaceous glands, leading to follicular plugging, perifollicular inflammation, and scarring. The study notes that DLE can mimic other scarring alopecias histologically, but the early loss of sebaceous glands and the presence of mucin in the dermis are distinguishing features.
Folliculitis decalvans is a neutrophilic form of PCA characterized by the destruction of sebaceous glands and hair follicles due to intense inflammatory infiltrates. The study indicates that in FD, the sebaceous glands are among the first structures to be destroyed, followed by the formation of follicular pustules and crusting.
Pseudopelade of Brocq is a less common form of PCA, presenting with small, non-inflammatory patches of alopecia. Although the exact pathogenesis is unclear, early sebaceous gland loss is a feature seen in histological examinations, contributing to the characteristic “footprints in the snow” appearance of the scarring alopecia patches. I’m not sure why but this “strange alopecia” or class of “strange alopecias” are honestly worrisome to me as it could imply environmental factors at play. There simply needs to be more research.
Given these conditions, the early identification of sebaceous gland loss through scalp biopsies can serve as an important diagnostic marker; this will guide timely and appropriate interventions to manage and potentially mitigate the progression of scarring alopecias.
https://www.sciencedirect.com/science/article/pii/S2667026722000212
But wait just one moment, why are all of these different kinds of scarring alopecias have a major histopathology similarity - that is the loss of sebaceous glands? Like mentioned before, anatomically speaking, the sebaceous glands are close to the stem cell niche. What is going on with the sebaceous glands for them to become destroyed by white blood cells (lymphocytes primarily) ? When you look at the When you look at the patients themselves, they seem to have different conditions considering how the manifests in phenotype, and yet, they have similar foundations…/.
https://www.reddit.com/r/tressless/comments/1eelmzr/57_increased_chance_of_pattern_hair_loss/
https://www.sciencedirect.com/science/article/abs/pii/S0924224421004362
In the paper titled “The ‘bald’ phenotype (androgenetic alopecia) is caused by the high glycaemic, high cholesterol and low mineral ‘western diet’” by Nicholas John Sadgrove, the author explores the relationship between diet and androgenetic alopecia (AGA). The paper suggests that poor glucose control and high cholesterol, characteristic of the ‘western diet,’ are significant contributors to the development of AGA. It highlights that balding follicles demonstrate accelerated oxidative damage and increased fatty acid synthesis, with overactive PPAR-γ receptors playing a role in these processes. However, this perspective seems somewhat backward. While it suggests that high sugar diets may trigger AGA, it appears more plausible that individuals with AGA may already have defective PPAR-γ receptors or produce high amounts of toxic lipids that their PPAR-γ receptors cannot adequately regulate. These defective receptors could make them more susceptible to the effects of DHT and other metabolic disturbances. While diet might impact AGA, attributing the condition primarily to dietary factors seems like an exaggeration.
We know that DHT alone can cause significant issues within tissues. Increased 5-alpha reductase activity in the sebaceous glands leads to heightened sebum output. Conditions like seborrheic dermatitis and acne vulgaris are exacerbated by this overproduction of sebum, which feeds local microbial life and is rich in triglycerides and cholesterol. This sebum can be toxic, and DHT can induce excessive sebaceous gland activity, producing harmful sebum independent of diet.
https://www.sciencedirect.com/science/article/pii/S0022202X15525864
In the paper “The Role of Sebaceous Gland Activity and Scalp Microfloral Metabolism in the Etiology of Seborrheic Dermatitis and Dandruff” by Byung In Ro and Thomas L. Dawson, the authors discuss the intricate relationship between sebaceous gland activity, scalp microflora, and the pathogenesis of scalp disorders such as dandruff and seborrheic dermatitis (D/SD). The study highlights the crucial role that sebum composition and metabolism by scalp microflora, particularly Malassezia species, play in the development of these conditions. Sebum, produced by sebaceous glands, is a complex mixture of triglycerides, fatty acids, wax esters, sterol esters, cholesterol, cholesterol esters, and squalene. Its composition changes as it is secreted onto the skin surface. Initially, sebum primarily consists of triglycerides and esters, which are then broken down by commensal microbes into diglycerides, monoglycerides, and free fatty acids.
Malassezia species, which are lipid-dependent fungi, play a significant role in the metabolism of sebum. These fungi have a specific preference for saturated fatty acids, consuming them and leaving behind unsaturated fatty acids. This metabolic activity alters the composition of sebum on the scalp, resulting in an increased presence of irritating unsaturated fatty acids. These modified sebaceous secretions can penetrate the stratum corneum, breaking down the skin barrier and leading to inflammation, irritation, and scalp flaking, which are characteristic of D/SD. This study shows us that while dandruff and seborrheic dermatitis are often considered superficial disorders of the stratum corneum, they involve more complex changes, including epidermal hyperproliferation, excess lipids, interdigitation of the corneal envelope, and parakeratosis. The pathogenic role of Malassezia in D/SD has been well elucidated, focusing on their lipid metabolism. The fungi degrade sebum, freeing multiple fatty acids from triglycerides, and consume specific saturated fatty acids necessary for their proliferation, leaving behind unsaturated fatty acids. These changes in sebum composition due to Malassezia metabolism are directly linked to the symptoms of dandruff and seborrheic dermatitis.
https://www.sciencedirect.com/science/article/pii/S0022202X15308691
from: https://www.sciencedirect.com/science/article/pii/S0022202X15308691
Similarly, the article “Regulation of Human Sebaceous Glands” by Diane Thiboutot discusses the mechanisms that regulate sebum production and the role of various factors, including androgens, growth hormones, and retinoids. Thiboutot highlights how these elements influence sebaceous gland function and their implications for conditions like acne. The pathogenesis of acne involves the interplay between sebum production, bacterial colonization by Propionibacterium acnes, follicular hyperkeratinization, and inflammatory mediator release. A significant part of this process involves the sebaceous glands, which produce a lipid-rich fluid called sebum. This fluid is essential for the nourishment of P. acnes, playing a critical role in acne development. Androgens, such as testosterone and DHT, significantly stimulate sebum production by acting through androgen receptors located in the basal layer of the sebaceous glands and hair follicle keratinocytes, leading to increased lipid production and gland size.
A major aspect of the paper is the regulation of sebum production by various hormones and receptors. Androgens, such as testosterone and dihydrotestosterone (DHT), are known to significantly stimulate sebum production. These androgens act through androgen receptors located in the basal layer of the sebaceous glands and hair follicle keratinocytes, leading to increased lipid production and gland size.
Furthermore, the article “The Annual Changes of Clinical Manifestation of Androgenetic Alopecia Clinic in Korean Males and Females: An Outpatient-Based Study” by Woo Sun Jang et al. explores the association between AGA and other conditions, particularly seborrheic dermatitis. AGA, characterized by the progressive thinning of scalp hair, is the most common type of baldness affecting both men and women. This study examines the clinical manifestations of AGA, including the age of onset, severity, family history, and associated diseases in Korean patients.
The study found a significant comorbidity between AGA and seborrheic dermatitis in both male and female patients. Seborrheic dermatitis was identified as the most common associated condition, affecting 51.2% of males and 45.7% of females with AGA. This elevated prevalence of seborrheic dermatitis among AGA patients contrasts sharply with its general population prevalence of 1-3%, suggesting a notable link between the two conditions. Both AGA and seborrheic dermatitis are influenced by DHT, a potent androgen hormone. The role of DHT in AGA is well-documented, as it contributes to hair follicle miniaturization and subsequent hair loss. Similarly, seborrheic dermatitis is related to increased DHT levels, which stimulate the sebaceous glands and exacerbate the condition.
In addition to seborrheic dermatitis, the study also talked about other conditions commonly associated with AGA, including hypertension, hyperlipidemia, and diabetes mellitus. The prevalence of these conditions among AGA patients reflects broader trends in modern Korean society, where lifestyle changes, such as adopting a Western diet, have led to increased rates of metabolic disorders. This association between AGA and metabolic conditions supports previous findings that link early-onset AGA with insulin resistance and related disorders like obesity, hypertension, and dyslipidemia.
I made this video about a year ago, and, I’m happy to come full circle on the matter,
The chronic and toxic buildup of lipids can trigger seborrheic dermatitis as well as microbial species. If there is a genetic defect in PPAR-γ receptors that causes them to become downregulated, individuals might have a predisposition to scarring alopecia like LPP. This predisposition could be triggered by DHT’s activity in the sebaceous glands, leading to high lipid concentration and subsequent pathological effects. Therefore, while diet might influence the severity or progression of AGA, the underlying genetic and hormonal factors play a more crucial role in its development.
Additionally, many skin diseases, such as acne and psoriasis, involve abnormal or excessive inflammatory responses. It has been demonstrated that AR in macrophages can promote inflammation, especially via up-regulation of TNFα expression, to suppress wound healing. According to Lai et al. in “The Role of Androgen and Androgen Receptor in the Skin-Related Disorders,” this suggests that AR may also be involved in the regulation of other skin diseases characterized by dysregulation of inflammatory responses. For example, in autoinflammatory conditions like pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, symptoms include acne at puberty (with increased androgen and IGF-1 signaling) and chronic inflammation with impaired wound healing. Treatment with a TNFα blocker could improve the pathology of PAPA syndrome, indicating that reducing AR activity might be beneficial for such diseases. The ultimate goal is to efficiently attenuate the disease states of these androgen/AR-involved conditions with minimized side effects.
Androgenetic alopecia: new insights into the pathogenesis and mechanism of hair loss - PMC.
In their 2015 paper published in F1000Res, Rodney Sinclair and colleagues provide new insights into the mechanism and progression of androgenetic alopecia (AGA), commonly known as male or female pattern baldness. They explain that in the advanced stages of AGA, hair loss becomes permanent because the hair follicles lose their connection to a critical part called the stem cell niche, which is essential for hair regeneration. This condition can be considered a type of scarring alopecia, where the hair follicles undergo irreversible changes.
One of the key findings from Sinclair et al. is the role of the arrector pili muscle (APM), which is the tiny muscle responsible for making hair stand up (like when you get goosebumps). This muscle attaches to the hair follicle at the level of the bulge, a region housing important stem cells. While the APM was once thought to be irrelevant to hair diseases, new 3D computer models show that it plays a crucial role in AGA. Specifically, the APM’s loss of attachment to the hair follicle bulge leads to permanent miniaturization of the follicles, meaning the hair becomes finer and eventually stops growing.
The paper further distinguishes the differences in hair loss patterns between men and women. Women with AGA tend to experience diffuse thinning (a general reduction in hair density) rather than the more obvious bald spots seen in men. This difference can be explained by the APM’s interaction with the hair follicles. When the APM loses its connection to the bulge, the resulting miniaturization of hair follicles is permanent in AGA but not in other types of hair loss like alopecia areata.
Sinclair et al. emphasize that the hair follicle is a complex mini-organ, making it an excellent model for studying various biological processes, including stem cell activity, organ regeneration, and cloning. In AGA, local and systemic androgens (hormones like testosterone) transform large, terminal hair follicles into smaller, vellus-like ones. This process, known as follicular miniaturization, is the hallmark of AGA. It leads to diffuse thinning and increased hair shedding, often years before baldness becomes noticeable.
In androgenetic alopecia, the proximal arrector pili muscle (red) is progressively replaced by adipose tissue (yellow) and loses its attachment to the hair follicle bulge (purple).
The authors propose a new model for the progression of AGA. Initially, the APM remains attached to the primary follicles but loses attachment to some of the smaller, secondary follicles within a group of follicles (follicular unit or FU). As miniaturization progresses, the APM detaches from more secondary follicles, leading to noticeable hair thinning and volume loss without visible baldness. Eventually, the primary follicles also miniaturize and lose muscle attachment, resulting in visible baldness. Once the primary follicles lose their muscle attachment, hair loss becomes irreversible.
Sinclair et al. highlight the importance of the interaction between the APM and the hair follicle bulge in maintaining hair growth. This interaction is similar to the relationship between the dermal papilla (another critical component derived from mesenchyme) and the hair follicle matrix. Disruption of this attachment in AGA causes hair follicle miniaturization and permanent hair loss.
Therefore, maintaining the connection between the APM and the bulge is crucial to prevent irreversible hair loss in AGA: So, end stage androgenetic alopecia is a scarring alopecia!
If you have Diffuse Unpatterned Alopecia (DUPA) or retrograde hair loss, it is crucial to consider getting a scalp biopsy. Although these conditions may appear similar to androgenetic alopecia (AGA), the underlying causes can be vastly different. A biopsy allows for a thorough examination of the scalp tissue, which can reveal conditions that might not be visible through a regular clinical examination. This is essential because treatments like finasteride and dutasteride, commonly used for AGA, may not be effective if another condition is contributing to your hair loss.
A biopsy involves taking a small sample of scalp tissue to analyze the health and structure of hair follicles. This can identify inflammatory conditions like lichen planopilaris (LPP), which may coexist with AGA or mimic its symptoms. Identifying these conditions early can lead to more targeted and effective treatments, potentially saving thousands of hairs in the long run.
The lack of routine biopsies, particularly for men, has led to a significant underdiagnosis of various hair loss conditions. By undergoing a biopsy, you can ensure that your treatment plan is based on a comprehensive understanding of your specific situation. This step can prevent the misapplication of treatments and allow for a more personalized and effective approach to managing your hair loss.
So, if you are experiencing DUPA or retrograde hair loss, ask your dermatologist about getting a scalp biopsy. It’s a small sacrifice that could lead to a significant improvement in your understanding and management of your hair health.
If the PPAR-γ receptor is not functioning properly, it might be downregulated, leading to an inability to metabolize harmful lipids effectively. To address this, we can use a type of drug called an agonist. Unlike antagonists, which block receptor activity, agonists stimulate receptors, effectively “upregulating” them to improve their function. This is particularly relevant when exploring treatments for Lichen Planopilaris (LPP), a form of primary cicatricial alopecia.
Returning to the study titled “PPAR-γ Agonists and Their Role in Primary Cicatricial Alopecia” by Sarawin Harnchoowong and Poonkiat Suchonwanit, published in PPAR Research in 2017, the authors explore the therapeutic potential of PPAR-γ agonists, specifically pioglitazone, in treating LPP. Pioglitazone is well-known for its use in managing diabetes mellitus due to its ability to increase insulin sensitivity. However, it also possesses anti-inflammatory properties, making it a candidate for treating inflammatory conditions like LPP.
Keep in mind, pioglitazone and other PPAR-γ receptor agonists are primarily diabetes drugs that are used to improve insulin sensitivity and regulate blood sugar levels in patients with type 2 diabetes. They are usually prescribed when patients have not adequately responded to other diabetes medications such as metformin or sulfonylureas. These drugs help by activating the PPAR-γ receptor, which plays a crucial role in glucose metabolism and fat storage, ultimately enhancing the body’s response to insulin. Could topical metformin or sulfonylureas also be used as well? What about other diabetes drugs? Could they be explored in dermatology for lipid production?
The authors discuss several case reports and clinical trials that highlight the efficacy of pioglitazone in managing LPP.
So, it seems that PPAR-γ drugs are important for scarring alopecias. But what I also noticed in the literature are case reports of topical metformin being used to treat Central Centrifugal Cicatricial Alopecia (CCCA).
One study, “Topical Metformin for the Treatment of Central Centrifugal Cicatricial Alopecia” by Erinolaoluwa F. Araoye, Jamael A. L. Thomas, and Crystal U. Aguh, published in JAAD Case Reports in 2020, presents two cases of hair regrowth after the use of topical metformin for CCCA. The study highlights that CCCA is a progressive scarring alopecia predominately occurring in women of African descent. Metformin, commonly used for glycemic control in type 2 diabetes, has shown efficacy in improving fibrosis in fibroproliferative disorders through the activation of adenosine monophosphate-activated protein kinase (AMPK). The patients in this study experienced substantial hair regrowth after the topical application of 10% metformin cream over several months.
Both PPAR-γ receptor agonists and metformin have significant anti-inflammatory effects. Chronic inflammation is a key factor in the pathogenesis of scarring alopecias like LPP and CCCA. Therefore, any drug effective at reducing inflammation may help prevent further follicular damage and scarring.
However, this might be a secondary benefit. The primary issue seems to be dysfunction of the sebaceous glands and the various sebocytes. The inability of their PPAR-γ receptors causes toxic lipids to build up. PPAR-γ agonists play a crucial role in lipid metabolism and homeostasis.
In scarring alopecias, disrupted lipid metabolism can contribute to the pathological process. By improving lipid metabolism, PPAR-γ agonists may help restore the normal function of sebaceous glands and hair follicles by reactivating PPAR-γ receptor activity, thus increasing the metabolism of local lipids and essentially “cleaning” the toxic lipids, reducing the inflammatory response, and preventing scarring.
On the other hand, metformin helps with lipid metabolism primarily through its activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK activation by metformin inhibits the synthesis of fatty acids and cholesterol by downregulating the expression of enzymes involved in lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). This reduces the accumulation of lipids in cells.
Metformin also promotes the oxidation of fatty acids by enhancing the activity of carnitine palmitoyltransferase 1 (CPT1), an enzyme critical for the transport of fatty acids into mitochondria where they are oxidized to produce energy. This process helps reduce lipid levels in tissues.
So, I think the interplay between the two is this: PPAR-γ agonists help the cells in the sebaceous glands and hair follicles metabolize lipids, clearing the toxic buildup of lipids in the tissue. Metformin, meanwhile, reduces overall lipid production, which can help attenuate the amount of toxic lipids.
The study titled “Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA” by Vikas Chandra, Pengxiang Huang, et al., provides a comprehensive analysis of how Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) and Retinoid X Receptor Alpha (RXR-α), two nuclear receptors, interact with each other and DNA to regulate gene expression. This research is particularly noteworthy as it reveals, for the first time, the structure of these receptors in their fully intact form, rather than as isolated parts.
The authors explain that PPAR-γ and RXR-α form a non-symmetric complex, where the ligand-binding domain (LBD) of PPAR-γ interacts with multiple domains in both proteins, thereby enhancing their ability to bind to DNA. This interaction is crucial for regulating the expression of genes involved in important processes like metabolism and inflammation.
To explain this in simpler terms, PPAR-γ and RXR-α function together like a specialized team of switches. PPAR-γ acts as a switch that can be activated by specific molecules known as ligands—these ligands are like keys that fit into a lock. When PPAR-γ is activated by a ligand, it pairs up with RXR-α, another switch that is already prepared to assist. This partnership allows the complex to bind to specific regions of DNA, much like a key fitting into a lock to open a door.
For instance, in sebocytes—cells that produce sebum, the oily substance in the skin—this binding can either activate or deactivate the production of certain proteins by influencing how the DNA is interpreted, similar to how adjusting settings on a machine can change its output. This collaboration between PPAR-γ and RXR-α is essential for controlling various cellular processes, including those related to skin health and metabolic functions. In this case, we are interested in how cells regulate their lipid metabolism as well as possible genetic defects that could make conditions like Androgenetic alopecia and Lichen Planopilaris worse.
I believe it would be valuable for researchers to investigate the potential of combining a PPAR-GAMMA agonist with a retinoid as a treatment for conditions like Lichen Planopilaris. This idea is supported by the fact that the PPAR-GAMMA receptor works in tandem with the Retinoid X Receptor (RXR-α), as demonstrated in the study by Vikas Chandra, Pengxiang Huang, et al. The study reveals how these receptors form a complex that regulates gene expression, particularly in metabolic and inflammatory pathways.
Given that Lichen Planopilaris and similar autoimmune scarring alopecias are thought to involve dysfunctions in PPAR-GAMMA receptors, it stands to reason that there could also be issues with retinoid receptors. Since these receptors are so closely linked in their function, addressing both could potentially lead to more effective treatments.
Combining a PPAR-GAMMA agonist, like pioglitazone, with a retinoid, such as a low dose of oral isotretinoin or topical tretinoin, could enhance the therapeutic effects, targeting the underlying dysfunction more comprehensively.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are a class of drugs used to manage type 2 diabetes by enhancing insulin sensitivity and regulating lipid metabolism.
Among these, pioglitazone is a well-known example, widely prescribed for its effectiveness in controlling blood glucose levels and providing cardiovascular benefits.
And now, we even have additional information that PPAR-GAMMA receptor agonists drugs like pioglitazone may be useful in dermatological conditions that concern poor lipid metabolism: here we set our focus on Lichen Planopolaris.
But, the use of pioglitazone, like other PPAR-gamma agonists, is not without potential risks.
Pioglitazone is generally safe and effective but it is associated with several side effects, including weight gain, fluid retention, and an increased risk of heart failure—side effects that are typically manageable under medical supervision.
PPAR-GAMMA receptor agonists are commonly prescribed to older patients with type-2 diabetes. As a result, some of the reported side effects might actually be amplifications of pre-existing conditions or simply associations with the underlying health issues that these patients already have.
The most serious concern, however, has been the potential link between pioglitazone and cancer, particularly bladder cancer.
This concern was first raised by Sciarra et al. in a study where an increased incidence of bladder tumors was observed in male rats treated with pioglitazone.
Although subsequent studies in humans have produced mixed results, with some suggesting a potential increased risk of bladder cancer and others finding no significant association, the possibility of a cancer risk has remained a significant consideration in the drug’s risk profile.
In light of these concerns, I’ll be making pioglitazone as a reference point for evaluating the broader safety implications of PPAR-gamma agonists, particularly in the context of long-term treatment.
According to the paper titled, “Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis”, by Filipova et al., the authors conducted a meta-analysis to evaluate the potential link between pioglitazone use and the risk of bladder cancer in patients with type 2 diabetes.
Concerns about this link initially arose from preclinical studies, particularly in male rats, where pioglitazone treatment was associated with an increased incidence of urothelial hyperplasia and malignant tumors in the urinary bladder.
Further concerns were raised by the PROactive study, which observed more cases of bladder neoplasm in the pioglitazone group compared to the placebo group (14 cases vs. 6 cases).
Although this finding was not statistically significant (p = 0.069), it contributed to the apprehension regarding pioglitazone’s safety.
Additionally, several observational studies in humans, such as those by Azoulay et al., reported an increased risk of bladder cancer associated with pioglitazone use, especially in long-term users.
These studies were mostly epidemiological and observational, meaning they identified correlations but could not definitively establish causality.
So, Filipova et al. performed a comprehensive meta-analysis, incorporating data from 14 studies using risk ratio (RR) and 12 studies using hazard ratio (HR).
The analysis included both retrospective and prospective cohort studies, case-control studies, and randomized controlled trials, all conducted in human populations.
The overall RR was found to be 1.13 with a 95% confidence interval (CI) of 0.96–1.33, and the summary HR was 1.07 (95% CI: 0.96–1.18), indicating no significant connection between pioglitazone use and an increased risk of bladder malignancy.
The meta-analysis showed no substantial evidence linking pioglitazone to bladder cancer in humans.
Also, concerns about PPAR-GAMMA upregulation, which pioglitazone targets, and its potential link to cancer were addressed.
The authors emphasized that these fears might be overstated, as the evidence did not support a significant cancer risk.
They suggested that the increase in bladder cancer cases observed in some studies might be due to other factors, such as the characteristics of the diabetic population or the use of other medications, rather than pioglitazone itself.
Some other studies to consider…
https://www.sciencedirect.com/science/article/abs/pii/S187140210700094X
https://www.sciencedirect.com/science/article/abs/pii/S1056872716301039
Lichen Planopilaris (LPP) is a seemingly rare scarring alopecia that leads to irreversible hair loss—or at least, that’s what we currently believe. However, some cases in the literature suggest that with treatments like topical steroids (e.g., Clobetasol propionate at 0.05% concentration), topical calcineurin inhibitors (e.g., 1% Tacrolimus or 1% Pimecrolimus), and oral Pioglitazone (15mg to 50mg), LPP may be halted, and hair loss might even be reversed.
With that said, I found studies from the Mayo Clinic that reveal significant discrepancies and oversights in medical literature, raising concerns about how data is collected and interpreted.
https://www.mayoclinicproceedings.org/article/S0025-6196(20)30212-3/abstract
This post will examine two pivotal studies on LPP, highlighting a major oversight that could impact our understanding and treatment of this condition.
In September 2022, a cross-sectional study titled “Prevalence of Lichen Planopilaris in the United States: A Cross-Sectional Study of the All of Us Research Program,” authored by Tejas P. Joshi, Harrison Zhu, Zain Naqvi, Swathi Holla, Anthony Duruewuru, and Vicky Ren, was published in JAAD International. The study aimed to estimate the prevalence of LPP across a diverse, nationwide sample of U.S. patients. Out of 327,654 participants, only 142 were identified as having LPP, representing an overall prevalence of 0.043% (95% CI, 0.042-0.044). The study found that 91.6% of LPP patients were female, and White participants had the highest prevalence. The average age of diagnosis was 62.4 years.
To me, this is highly questionable. Out of 327,654 people with hair loss, only 142 had LPP? How was this determined? Was every case confirmed through biopsy in this retrospective data set? I’m concerned because if this wasn’t the case, and most forms of hair loss were not confirmed through biopsy but rather through a clinical assessment (where the physician simply looked with their eyes or perhaps used a dermatoscope), we may be facing significant bias in the literature.
I believe this bias is further emphasized when researchers ignore data to fit preconceived notions—in this case, the assumption that LPP primarily affects women, particularly postmenopausal women.
A 2020 retrospective review titled “Lichen Planopilaris in Women: A Retrospective Review of 232 Women Seen at Mayo Clinic From 1992 to 2016,” authored by Sydney C. Larkin, Hafsa M. Cantwell, Reese L. Imhof, Rochelle R. Torgerson, and Stanislav N. Tolkachjov, was published in Mayo Clinic Proceedings. This review examined 232 female patients with LPP seen at the Mayo Clinic from 1992 to 2016. The study deliberately excluded men to focus on hormonal factors in the pathogenesis of LPP. Despite this exclusion, the review concluded that a typical LPP patient was a 60-year-old female with vertex scarring alopecia.
Hormonal and autoimmune factors were heavily emphasized, with 30.6% of participants having thyroid disease and nearly 45.7% experiencing depression.
The stark contrast between these two studies, particularly the exclusion of men in the Mayo Clinic study, raises serious questions about the assumptions made in the medical field.
Despite both studies aiming to understand the prevalence and characteristics of LPP, the Mayo Clinic’s exclusion of men based on the assumption that hormonal factors are the primary contributors to LPP pathogenesis seems not only unwarranted but also a potential source of bias.
This exclusion may lead to a distorted view of the disease’s true prevalence across genders and the role of non-hormonal factors.
The All of Us study, which included a diverse population of both genders, found a prevalence of 0.029% among Black participants, 0.021% among Hispanic participants, and 0.009% among Asian participants.
The Mayo Clinic study, however, does not account for this level of ethnic diversity, and its focus on a predominantly White population may overlook other potential factors that could influence the manifestation of LPP in different demographics.
Additionally, we’re left uncertain as to whether everyone in the data set had their condition confirmed through biopsy.
We know conditions like LPP and frontal fibrosing alopecia (FFA) can mimic androgenetic alopecia in Norwood patterns.
Here is some literature:
This significant oversight suggests that medical research may be constrained by narrow frameworks, particularly in rare diseases like LPP. By focusing solely on female patients and assuming a hormonal basis, researchers may miss other crucial pathophysiological insights. Furthermore, while the reliance on clinicopathologic correlation and biopsies is important, it should not limit the scope of research, especially when national databases like All of Us offer more comprehensive and diverse data sets.
The Mayo Clinic study’s failure to include male patients undermines the generalizability of its findings and could contribute to slowing down progress in understanding the disease as a whole. In fact, it even harms women who are not postmenopausal, as they are not adequately represented in the data set either.
Moving forward, the medical community must prioritize broad-based research efforts that include diverse populations and genders to better understand rare diseases like LPP.
Without a shift towards more inclusive and holistic research methodologies, the medical field risks reinforcing misconceptions that could stall advancements in treatment and care for those affected by this condition.
This could even hurt research into androgen alopecia as well believe it or not as their could be an interplay between Androgen receptors, PPAR-gamma receptors, DHT, and ligands associate with PPAR-gamma receptor activation.
Perhaps solving something the an LPP helps us understand hair follicle biology a bit more to the point where we can regenerate and/or restore hair follicles.
