What are the upstream causes of androgenic alopecia in adult women, considering genetic, hormonal, and environmental factors, including conditions like polycystic ovary syndrome (PCOS), thyroid disorders, and autoimmune diseases?

Upstream Causes of Androgenic Alopecia in Women

Genetic Factors

The most fundamental upstream cause of androgenic alopecia in women is polygenic inheritance, with the androgen receptor (AR) gene being the only definitively identified genetic contributor to date. 1, 2

• The inheritance pattern is polygenic, meaning multiple genes contribute to susceptibility, though most remain unidentified 1, 2
• The androgen receptor gene encodes the receptor through which dihydrotestosterone (DHT) exerts its effects on hair follicles 2
• Genetic susceptibility determines which follicles will respond to androgens with miniaturization 1, 3

Hormonal and Enzymatic Mechanisms

Androgen Metabolism at the Follicular Level

• In genetically susceptible hair follicles, 5-alpha reductase converts testosterone to dihydrotestosterone (DHT), which then binds to androgen receptors 1, 3
• Women with androgenic alopecia have higher levels of 5-alpha reductase and androgen receptor expression in frontal hair follicles compared to occipital follicles 1
• The hormone-receptor complex activates genes responsible for progressive transformation of terminal follicles to miniaturized follicles 1

Protective Enzymatic Factors

• Women have significantly higher levels of cytochrome p-450 aromatase in frontal follicles compared to men, which converts androgens to estrogens and provides relative protection 1
• Aromatase levels are even higher in occipital follicles, explaining why these areas are relatively spared 1

Endocrine Disorders as Upstream Causes

Polycystic Ovary Syndrome (PCOS)

• PCOS is the most common cause of elevated androgens of ovarian origin that can trigger androgenic alopecia 4
• PCOS diagnosis in adult females requires 2 of 3 criteria: androgen excess (clinical or biochemical), ovulatory dysfunction, or polycystic ovaries on ultrasound 4
• Women presenting with androgenic alopecia alongside hirsutism, severe acne, irregular menses, infertility, or truncal obesity warrant hormonal evaluation 4

Thyroid Disorders

• Thyroid disease is part of the differential diagnosis for women presenting with androgenic alopecia and should be excluded 4, 5
• Both hypothyroidism and hyperthyroidism can contribute to hair loss patterns 5

Other Endocrine Causes

• Prolactin excess (hyperprolactinemia) can contribute to hair loss in women 5
• Nonclassical congenital adrenal hyperplasia causes androgen excess and can manifest with androgenic alopecia 4

Nutritional Deficiencies as Contributing Factors

Vitamin D Deficiency

• Vitamin D deficiency (<20 ng/mL) shows strong association with hair loss, with 70% of alopecia patients being deficient versus 25% of controls 5
• The vitamin D receptor (VDR) plays a critical role in hair follicle cycling 5
• Lower vitamin D levels correlate inversely with disease severity 5

Iron Deficiency

• Serum ferritin levels are lower in women with androgenetic alopecia, with iron deficiency being the most common nutritional deficiency worldwide 5
• Iron deficiency is a sign of chronic diffuse telogen hair loss 5

Zinc and Folate

• Zinc serves as a cofactor for multiple enzymes and plays a role in hair follicle function, with serum zinc levels tending to be lower in patients with hair loss 5
• Folate deficiency may contribute to hair loss 5

Autoimmune Associations

• Women with androgenic alopecia may have coexisting autoimmune conditions including thyroid disease, vitiligo, and lupus erythematosus 4, 5
• Approximately 22% of women with hair loss have autoimmune disease, 42% have autoantibodies, and 60% have one or more autoimmune-related phenomena 4

Proposed Mechanical and Inflammatory Mechanisms

• Chronic scalp tension transmitted from the galea aponeurotica may induce an inflammatory response in genetically susceptible tissues 6
• DHT increases as part of this inflammatory response and co-mediates tissue dermal sheath thickening, perifollicular fibrosis, and calcification 6
• These conditions remodel tissues, restricting follicle growth space, oxygen, and nutrient supply, leading to progressive miniaturization 6

Clinical Algorithm for Identifying Upstream Causes

When to Pursue Hormonal Evaluation

• Hormonal testing is indicated when women present with androgenic alopecia plus signs of androgen excess: hirsutism, severe cystic acne, irregular menses, infertility, clitoromegaly, or truncal obesity 4
• Most women with androgenic alopecia have normal menses, pregnancies, and hormone levels, making extensive testing unnecessary in typical presentations 1, 7

Recommended Hormonal Panel When Indicated

• Free and total testosterone, DHEA-S, androstenedione, luteinizing hormone, and follicle-stimulating hormone 4
• Sex hormone binding globulin (SHBG) levels 5
• Prolactin level if hyperprolactinemia suspected 5
• TSH and thyroid peroxidase (TPO) antibodies if thyroid dysfunction suspected 5

Nutritional Assessment

• Check serum ferritin, vitamin D, zinc, and folate levels in women presenting with hair loss 5
• These deficiencies are modifiable upstream factors that may contribute to or exacerbate androgenic alopecia 5

Common Pitfalls to Avoid

• Ordering extensive hormonal panels in women with isolated androgenic alopecia and no signs of hyperandrogenism wastes resources, as most will have normal hormone levels 1, 7
• Failing to recognize that androgenic alopecia can begin as early as age 12-40 years in genetically susceptible women 1
• Overlooking nutritional deficiencies as modifiable contributing factors that should be corrected regardless of genetic predisposition 5
• Missing PCOS diagnosis in women with androgenic alopecia who also have irregular menses or other subtle signs of androgen excess 4