Alopecia — Androgenic, Alopecia Areata

Androgenetic Alopecia

• Androgen-dependent follicle miniaturization: AGA is driven by the conversion of dihydrotestosterone (DHT) from testosterone by the enzyme 5-alpha reductase (5-AR) in genetically susceptible hair follicles. DHT binds to androgen receptors (AR) on dermal papilla fibroblasts, which possess the highest concentration of both 5-AR and AR in the body. This binding initiates a cascade of molecular events including increased transforming growth factor-beta (TGF-β) signaling and decreased insulin-like growth factor-1 (IGF-1), leading to catagen phase induction and progressive shortening of the anagen (growth) phase from 3-7 years in terminal hairs to weeks or months in miniaturized hairs. The follicle undergoes progressive miniaturization wherein the hair shaft diameter, matrix size, and dermal papilla volume all decrease, resulting in finer, shorter, unpigmented hairs that are less visible. This process is genetically predetermined and depends on the presence of AR gene polymorphisms and 5-AR gene variants that confer androgen sensitivity.

• Genetic predisposition and inheritance patterns: The condition demonstrates complex polygenic inheritance with both autosomal dominant and X-linked contributions. The AR gene on the X chromosome carries multiple polymorphisms in the CAG repeat region; shorter CAG repeats correlate with increased AR transactivation activity and greater androgen sensitivity. Genome-wide association studies have identified >250 genetic loci associated with AGA susceptibility, including variants in the DHCR24, EBF1, and FOXO3 genes. A family history of alopecia is present in approximately 50-80% of affected individuals, making genetic counseling important when discussing prognosis.

• Follicular growth cycle dysregulation: In AGA, there is relative lengthening of telogen (resting) phase duration and shortening of anagen duration. The proliferative capacity of follicular stem cells in the bulge region may be impaired through altered Wnt/β-catenin signaling and increased oxidative stress. Additionally, insulin resistance and hyperinsulinemia have been implicated in some cases, particularly in women with polycystic ovary syndrome (PCOS), where elevated androgens and altered carbohydrate metabolism may contribute to or exacerbate hair loss. Chronic inflammation in the perifollicular dermis, mediated by T lymphocytes (primarily CD8+) and macrophages, contributes to follicle deterioration even in the absence of overt scarring.

Alopecia Areata

• Autoimmune attack on hair follicles: AA is fundamentally a T cell-mediated autoimmune disease in which CD8+ cytotoxic T lymphocytes infiltrate the hair follicle, primarily targeting the follicular matrix and lower outer root sheath. These T cells produce pro-inflammatory cytokines including interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2), creating a dense inflammatory infiltrate described as a "swarm of bees" on histopathology. The inflammatory attack disrupts the normally immune-privileged microenvironment of the follicle, transforming it from an immune-protected site to an active site of immune rejection. This results in abrupt catagen induction and premature telogen conversion, causing hair loss that occurs over days to weeks.

• Loss of immune privilege and breakdown of immune tolerance: The hair follicle's lower portion exists in an immune-privileged state maintained by transforming growth factor-beta (TGF-β), neuroendocrine factors, and low expression of MHC Class I and II antigens. In AA, this immune privilege collapses, allowing T cell infiltration. Multiple factors contribute to this breakdown: exposure of follicular antigens that cross-react with pathogenic T cells, reduced production of immune-suppressive factors (IL-10, TGF-β), increased expression of MHC molecules on follicular epithelium, and upregulation of adhesion molecules (ICAM-1, VCAM-1) that promote lymphocyte recruitment. The disease may be triggered by physical trauma (Koebner phenomenon), infection, stress, or vaccinations in genetically predisposed individuals.

• Genetic susceptibility and association with autoimmune diseases: AA has strong genetic associations with HLA alleles, particularly HLA-DRB1 and HLA-DQ loci. Family history is present in 10-25% of cases, indicating hereditary predisposition to autoimmune activation. AA is associated with other organ-specific autoimmune conditions in 10-25% of patients, including Hashimoto's thyroiditis (most common association), vitiligo, celiac disease, systemic lupus erythematosus, and type 1 diabetes. This suggests shared mechanisms of autoimmune dysregulation and loss of self-tolerance, possibly related to alterations in regulatory T cell (Treg) function, which normally suppress autoreactive T cells. CD4+CD25+ Tregs are reduced in number and function in active AA, allowing unopposed Th1 and Th17 cell responses.

• Molecular mimicry and antigen sensitization: Current evidence suggests that hair follicle-associated autoantigens (such as lysyl-tRNA synthetase, melanin-associated proteins, and follicular epithelial antigens) become targets of aberrant T cell responses, potentially through molecular mimicry mechanisms where cross-reactivity with infectious agents or environmental antigens triggers recognition of similar follicular epitopes. Melanin-containing melanocytes in the follicle appear to be primary targets, explaining why hair regrowth is often initially non-pigmented (white hair) before gradual repigmentation occurs.

Androgenetic Alopecia

• Genetic predisposition (primary requirement): Inheritance of androgen-sensitive follicle phenotype through polygenic mechanisms is the essential requirement for AGA development. Without genetic susceptibility, elevated androgens alone do not cause hair loss. Approximately 50% of men will experience some degree of AGA by age 50, and the prevalence doubles in men with a family history. Similarly, in women, family history is one of the strongest predictors of developing AGA in later decades.

• Elevated androgen levels: While AGA is primarily genetically determined, androgen levels influence severity and age of onset. Postmenopausal women experience relative increases in androgen-to-estrogen ratios contributing to hair loss onset. Polycystic ovary syndrome (PCOS) is associated with elevated testosterone and androstenedione, leading to earlier and more severe AGA in affected women. Androgenizing tumors (adrenal or ovarian) and hyperprolactinemia (which suppresses estrogen and increases androgens) can accelerate hair loss. Anabolic steroid use in athletes causes dose-dependent hair loss through supratherapeutic androgen exposure.

• Age and natural androgen decline paradox: Interestingly, AGA prevalence increases with age despite the decline in serum testosterone after age 30-40. This is explained by cumulative lifetime androgen exposure, increased 5-AR activity and AR sensitivity in aging skin, and follicle-level androgen metabolism that remains elevated independent of serum levels. Miniaturized follicles also demonstrate increased expression of 5-AR type 2 and altered androgen receptor distribution.

• Metabolic factors and insulin resistance: Insulin resistance and metabolic syndrome are increasingly recognized as contributing factors, particularly in women. Hyperinsulinemia stimulates androgen synthesis in the ovary and adrenal gland and reduces sex hormone-binding globulin (SHBG), increasing bioavailable androgens. This mechanism partially explains the association between AGA and PCOS, obesity, and type 2 diabetes. Studies show correlation between AGA severity and fasting insulin levels in some populations.

Alopecia Areata

• HLA genetic susceptibility and autoimmune diathesis: Carriers of specific HLA alleles (HLA-DRB1*04, HLA-DQ2, HLA-DQ3) have significantly increased risk for AA. However, HLA typing is not clinically used for diagnosis. The strongest predictor of AA development is personal or family history of other autoimmune or atopic diseases, including thyroiditis, vitiligo, and systemic lupus erythematosus. Twin studies demonstrate ~80% concordance in identical twins, confirming strong genetic influence.

• Psychophysiologic stress and neurogenic factors: Psychological stress is reported as a triggering factor in 50-80% of AA patients, though establishing causality remains challenging. Multiple mechanisms link stress to AA: stress hormones (corticotropin-releasing hormone) alter immune privilege maintenance in the follicle; catecholamine effects on Langerhans cells and dendritic cells enhance T cell priming; and neuropeptide substance P levels increase in affected scalp, promoting immune activation. The onset often follows major life stressors by 2-12 weeks.

• Infections and Koebner phenomenon: Viral infections (cytomegalovirus, Epstein-Barr virus, hepatitis C) have been detected with increased frequency in AA patient sera, suggesting potential triggers through molecular mimicry. Physical trauma or mechanical irritation to the scalp can precipitate AA in predisposed individuals (true Koebner phenomenon). Oral antibiotic use and vaccinations have been reported as temporal triggers, though causal relationships remain unproven.

• Associated systemic autoimmune diseases: AA occurs with increased prevalence in patients with Hashimoto's thyroiditis (5-10% of AA patients have thyroid antibodies), vitiligo (occurs concurrently in 5% of AA cases), celiac disease, type 1 diabetes, and systemic lupus erythematosus. These associations indicate shared mechanisms of autoimmune dysregulation and emphasize the importance of screening for concurrent autoimmune conditions, particularly thyroiditis.

• Down syndrome and chromosomal abnormalities: AA prevalence is increased 5-10 fold in Down syndrome patients, suggesting that the genetic abnormalities predisposing to autoimmune disease accompany trisomy 21. Similarly, increased prevalence occurs in Turner syndrome.

• Atopic conditions: Patients with eczema, asthma, and allergic rhinitis have modestly increased risk for AA, supporting the hypothesis that broader immune dysregulation contributes to AA pathogenesis.

Androgenetic Alopecia

• Pattern and distribution of hair loss: In men, AGA presents with a characteristic pattern beginning at the frontotemporal regions and vertex, progressing according to the Norwood-Hamilton scale (grades I-VII, with grade V representing significant balding of the crown and frontal regions with preserved occipital hair). In women, loss typically follows the Ludwig scale, with preserved frontal hairline but progressive diffuse thinning over the crown and vertex, often described as a "Christmas tree" pattern of widening central part. The distribution pattern is determined by androgen-sensitive follicle localization—scalp follicles in androgen-sensitive areas miniaturize while occipital and temporal hair is relatively preserved due to lack of androgen receptors.

• Gradual onset and progressive course: Hair loss is characteristically insidious and slowly progressive, occurring over years to decades. Patients typically notice increased hair loss when shampooing, brushing, or on pillows. Unlike AA, there are no bald patches; rather, hairs become progressively finer, shorter, and less pigmented. The anagen to telogen ratio shifts from the normal 85:15 to more balanced ratios, accounting for increased shedding. Men often notice onset in the 20s-30s, while women typically notice onset after age 40-50.

• Hair density and quality changes: Clinical examination reveals progressive decrease in hair density in the affected vertex and frontotemporal areas, with preserved density in the occipital scalp. Individual hairs transition from terminal hairs (thick, long, pigmented) to vellus hairs (thin, short, light-colored, barely visible). The width of the part widens over time, and the scalp may become increasingly visible. In men with advanced disease, complete baldness of the vertex and frontal regions with preserved occipital hair results in a characteristic "male pattern."

• Preserved scalp health and lack of inflammation: Unlike scarring alopecias, the scalp remains healthy without erythema, scale, or follicular inflammation on examination. The follicular architecture is preserved on dermoscopy, and histology shows miniaturized follicles without permanent destruction.

• Psychological impact and quality of life: Many patients experience significant psychological distress, including depression, anxiety, and reduced self-esteem, particularly younger men affected early and women who often delay seeking treatment due to social stigma. The psychological burden correlates with degree of hair loss and perceived importance of appearance.

Alopecia Areata

• Sudden-onset circumscribed patches of hair loss: The hallmark presentation is rapid onset of one or more well-demarcated round or oval patches of complete hair loss, often discovered incidentally by the patient or noticed within days. The patches are typically 1-4 cm in diameter initially but may expand to involve larger areas. Onset is acute and sudden, distinguishing AA from the gradual progression of AGA. Patches commonly appear on the scalp, eyebrows, eyelashes, and beard, but may involve any hair-bearing area including axillae, pubis, and body.

• "Exclamation mark" hairs at patch periphery: The pathognomonic diagnostic finding is the presence of exclamation mark or exclamation point hairs at the periphery of expanding patches. These are short (3-4 mm), easily extracted hairs that are thickened and pigmented proximally but taper to thin, unpigmented distal ends, creating a characteristic appearance on magnification. These hairs are partially dystrophic due to ongoing immune attack and represent the active disease margin. Presence of exclamation mark hairs is highly specific for AA.

• Nail changes and associated findings: Approximately 10-15% of AA patients develop nail changes, including trachyonychia (longitudinal ridging and pitting producing a "sandpaper" appearance), onycholysis (separation of nail from nail bed), nail thinning, and leukonychia. Nail involvement often correlates with severity and duration of AA. These changes may persist for months after hair regrowth.

• Alopecia totalis and universalis: In severe cases, AA may progress to alopecia totalis (complete scalp hair loss) or alopecia universalis (complete loss of all body hair). These represent more severe disease phenotypes associated with worse prognosis for hair regrowth. Alopecia universalis affects <1% of AA patients and carries the poorest prognosis.

• Sensory symptoms and scalp changes: During active disease, patients may report itching, burning, or pain at the affected area. The affected scalp typically appears erythematous and slightly edematous during the active inflammatory phase. However, many patients are asymptomatic during active disease. Post-inflammatory erythema may persist for weeks after hair loss.

• Rapid progression phases: Some patients experience cyclical patterns of hair loss with periods of activity followed by spontaneous remission and regrowth. Approximately 80-90% of patients with localized AA experience spontaneous remission within 1 year, but recurrence rates are high (10-25% of patients experience recurrent episodes). Conversely, some patients experience continuous hair loss with progressive involvement of new areas and persistent disease lasting years.

• Repigmentation patterns in regrowing hair: When regrowth occurs, hair initially regrows as fine, unpigmented (white or gray) hairs, often described as lanugo-like, that gradually thicken and repigment over weeks to months. This pattern of initial white hair regrowth is characteristic and helps distinguish AA-related regrowth from regrowth in other conditions.