How do androgens cause pattern hair loss ?

Introduction: Pattern hair loss, or androgenetic alopecia, represents a multifaceted interplay between genetic, hormonal, and environmental factors, with androgens playing a pivotal role in this condition. Understanding the mechanisms through which androgens influence hair follicle dynamics is crucial for grasping the pathophysiology of pattern hair loss. This article delves into the complex world of androgens and their impact on hair follicles, shedding light on the various elements that contribute to the development of androgenetic alopecia.

An Overview of Androgens: Androgens are steroid hormones that play a vital role in the regulation of various biological processes in our bodies. They are primarily responsible for the development and maintenance of male characteristics, but they also have significant effects in females. The main androgens in the body include testosterone and dihydrotestosterone (DHT), with DHT being a more potent derivative of testosterone. These hormones exert their effects by binding to androgen receptors, which are present in many tissues, including hair follicles.

Mechanisms of Androgenetic Alopecia: The pathogenesis of androgenetic alopecia involves several key factors related to androgen metabolism and hair follicle response:

1. Blood Androgen Levels: The concentration of androgens in the bloodstream, both low and high potency, can influence hair follicle behavior. Low potency androgens, such as testosterone, can be converted into high potency androgens like DHT in the skin and hair follicles through the action of enzymes. As such, testosterone might arrive in the skin via the blood, but then gets converted to DHT, which then has a local impact on hair follicles in the vicinity of the conversion.
2. Enzymatic Conversion of Androgens: Enzymes within the hair follicles, notably 5 alpha-reductase, convert low potency androgens into more potent forms such as DHT. The presence and activity level of these enzymes can significantly affect the local androgen concentration within the hair follicle environment. The density of these enzymes can vary from region to region in the skin, and also may be different in different people. As such, the level of DHT conversion in skin can be quite varied.
3. Enzymatic antagonists to Androgen Conversion: While the enzyme 5 alpha-reductase catalyzes the conversion of testosterone to DHT, thereby amplifying the androgenic effect on hair follicles, other enzymes can antagonize this process, mitigating the production of DHT. For example, enzymes such as 3 beta-hydroxysteroid dehydrogenase and 17 beta-hydroxysteroid dehydrogenase can metabolize testosterone into weaker androgens or convert DHT into less active metabolites, thereby reducing its potency and the subsequent androgenic impact on hair follicles. These enzymatic activities can serve as a counterbalance to the effects of 5 alpha-reductase, potentially providing a partial protective mechanism against excessive hair follicle miniaturization and hair loss.
4. Hair Follicle Sensitivity: Hair follicles vary in their response to androgens. While some are androgen-independent and remain unaffected by hormonal fluctuations, androgen-dependent follicles can either proliferate or undergo miniaturization in response to androgen exposure. Despite a fair amount of research into why these differences in response to androgen signalling occur, there is still no clear data to explain them.
5. Androgen Receptors: The number and sensitivity of androgen receptors in hair follicles dictate the follicular response to androgens. Variation in response might be due the density of androgen receptors the cells express. Increased receptor numbers on cells can enhance the androgenic effect, leading to follicular miniaturization. Some research is ongoing where it is hypothesized that some androgen receptors might be more sensitive to DHT than other androgen receptors – though there is no clear evidence available to confirm that view right now.
6. Metabolic Rate of Androgens: The rate at which androgens are metabolized and cleared from the system also affects their impact on hair follicles. A slower breakdown rate can lead to prolonged androgen exposure, potentially exacerbating hair loss.

Hair Follicle Signalling: It is clear that dihydrotestosterone (DHT) is instrumental in the development of androgenetic alopecia, affecting hair follicles by binding to their androgen receptors, which alters gene expression and leads to follicular miniaturization. The degree of follicle sensitivity to androgens contributes to the varied patterns of hair loss seen in individuals. Immunohistochemistry using antibody-based stains reveals the distribution of androgen receptors in hair follicles, predominantly in the dermal papilla and lower dermal sheath cells, although some receptors are also found in keratinocytes.

Studies indicate that DHT’s interaction with androgen receptors in dermal papilla cells triggers a signaling cascade that induces cellular senescence, effectively accelerating their aging process. Continuous exposure to DHT exacerbates this effect, causing a decline in dermal papilla cell numbers, which in turn reduces the papilla’s size. This reduction is crucial as the size of the dermal papilla correlates with the thickness of the hair fiber produced; larger papillae facilitate the growth of thicker hair fibers. Dermal papilla cells in robust terminal hair follicles emit signals that influence keratinocyte cells, dictating the hair fiber’s dimensions and the duration of the anagen (growth) phase. A diminished dermal papilla weakens these signals, resulting in less keratinocyte stimulation and the production of finer, slower-growing hair fibers. How much signal the dermal papilla cells receive from androgens depends on the parameters described above.

Genetic and Environmental Factors: While hormonal factors determine the miniaturization process in pattern hair loss affected hair follicles, it genetic predisposition that plays a crucial role in determining the onset and extent androgenetic alopecia (about 70% impact). Individuals with a family history of pattern hair loss are more likely to experience similar conditions. Studies have shown that the AR gene (Androgen Receptor gene) is crucial for determining the sensitivity of hair follicles to androgens. Variations in the AR gene can influence the activity of androgen receptors in hair follicles, affecting how strongly they respond to androgens like DHT. Equally, 5-alpha reductase genes (SRD5A1 and SRD5A2) are also important. These genes encode the enzymes responsible for converting testosterone into the more potent DHT. Variations in these genes can affect the levels of DHT in hair follicles and thus the progression of hair loss. Environmental factors, such as diet, stress, and medication, can also influence the onset and progression of hair loss (about 30% impact), interacting with the hormonal and genetic landscape.

Therapeutic Implications: Understanding the role of androgens in hair loss has led to the development of targeted therapies. Inhibitors of 5 alpha-reductase, such as finasteride and dutasteride, reduce the conversion of testosterone to DHT, thereby mitigating its impact on susceptible hair follicles. Active research is ongoing to identify other parts of the androgenetic alopecia process that can be targeted with drug treatments to block the process.

Conclusion: The interplay between androgens and hair follicles in androgenetic alopecia is complex and multifactorial. Factors such as androgen levels, enzymatic activity, hair follicle sensitivity, and genetic predisposition collectively determine the individual’s susceptibility to pattern hair loss. Continued research in this field is essential for the development of more effective treatments and a deeper understanding of the underlying mechanisms of androgenetic alopecia. This comprehensive approach, integrating hormonal, genetic, and environmental perspectives, is crucial for devising personalized and effective interventions for those affected by pattern hair loss.

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