The cause of pattern hair loss is not yet fully understood. It appears to be the result of genetic changes that make the activity of hair follicles on the scalp become sensitive to the presence of
androgenic hormones,
cholesterol, and proteins such as
insulin-like growth factor.
Hormones and genes KRT37 is the only
keratin that is regulated by androgens. This sensitivity to androgens was acquired by
Homo sapiens and is not shared with their great ape cousins. Although Winter et al. found that KRT37 is expressed in all the hair follicles of chimpanzees, it was not detected in the head hair of modern humans. As androgens are known to grow hair on the body but decrease it on the scalp, this lack of scalp KRT37 may help explain the paradoxical nature of Androgenic alopecia as well as the fact that head hair anagen cycles are extremely long. to cause hair loss The initial programming of
pilosebaceous units of hair follicles begins
in utero. The physiology is primarily
androgenic, with
dihydrotestosterone (DHT) being the major contributor at the
dermal papillae. Men with premature androgenic
alopecia tend to have lower than normal values of
sex hormone-binding globulin (SHBG),
follicle-stimulating hormone (FSH),
testosterone, and
epitestosterone when compared to men without pattern hair loss. Although hair follicles were previously thought to be permanently gone in areas of complete hair loss, they are more likely dormant, as recent studies have shown the scalp contains the
stem cell progenitor cells from which the follicles arose.
Transgenic studies have shown that growth and dormancy of hair follicles are related to the activity of
insulin-like growth factor (IGF) at the dermal papillae, which is affected by DHT.
Androgens are important in male sexual development around birth and at puberty. They regulate
sebaceous glands,
apocrine hair growth, and libido. With increasing age, androgens stimulate hair growth on the face, but can suppress it at the temples and scalp vertex, a condition that has been referred to as the 'androgen paradox'. Men with androgenic alopecia typically have higher
5α-reductase, higher total testosterone, higher unbound/free testosterone, and higher free androgens, including DHT. 5-alpha-reductase converts free testosterone into DHT, and is highest in the scalp and prostate gland. DHT is most commonly formed at the tissue level by 5α-reduction of testosterone. The genetic corollary that codes for this enzyme has been discovered.
Prolactin has also been suggested to have different effects on the hair follicle across gender. Also, crosstalk occurs between androgens and the
Wnt-beta-catenin signaling pathway that leads to hair loss. At the level of the somatic
stem cell, androgens promote differentiation of facial hair dermal papillae, but inhibit it at the scalp. These observations have led to a study at the level of the
mesenchymal dermal papillae.
Types 1 and 2 5α reductase enzymes are present at
pilosebaceous units in papillae of individual
hair follicles. They catalyze the formation of the androgen dihydrotestosterone from testosterone, which in turn regulate hair growth. Interleukin 1 is suspected to be a cytokine mediator that promotes hair loss. The fact that hair loss is cumulative with age while androgen levels fall as well as the fact that finasteride does not reverse advanced stages of androgenetic alopecia remains a mystery, but possible explanations are higher conversion of testosterone to DHT locally with age as higher levels of 5-alpha reductase are noted in balding scalp, and higher levels of
DNA damage in the dermal papilla as well as
senescence of the dermal papilla due to androgen receptor activation and environmental stress.
Metabolic syndrome Multiple cross-sectional studies have found associations between early androgenic alopecia,
insulin resistance, and
metabolic syndrome, with low
HDL being the component of metabolic syndrome with highest association. Linolenic and linoleic acids are
5 alpha reductase inhibitors. Premature androgenic alopecia and insulin resistance may be a clinical constellation that represents the male homologue, or
phenotype, of
polycystic ovary syndrome. Others have found a higher rate of
hyperinsulinemia in family members of women with polycystic ovarian syndrome. With early-onset AGA having an increased risk of metabolic syndrome, poorer metabolic profiles are noticed in those with AGA, including metrics for
body mass index, waist circumference,
fasting glucose,
blood lipids, and blood pressure. In support of the association, finasteride improves glucose metabolism and decreases glycated hemoglobin
HbA1c, a surrogate marker for diabetes mellitus. The low SHBG seen with premature androgenic alopecia is also associated with, and likely contributory to, insulin resistance, and for which it still is used as an assay for pediatric diabetes mellitus. Obesity leads to upregulation of insulin production and a decrease in SHBG. Further reinforcing the relationship, SHBG is downregulated by
insulin in vitro, although SHBG levels do not appear to affect insulin production.
In vivo, insulin stimulates both testosterone production and SHBG inhibition in normal and obese men. The relationship between SHBG and insulin resistance has been known for some time; decades prior, ratios of SHBG and
adiponectin were used before glucose to predict insulin resistance. Patients with
Laron syndrome, with resultant deficient IGF, demonstrate varying degrees of alopecia and structural defects in hair follicles when examined microscopically. Because of its association with metabolic syndrome and altered glucose metabolism, anyone with early androgenic hair loss should be screened for impaired glucose tolerance and diabetes mellitus II. SHBG association with fasting blood glucose is most dependent on intrahepatic fat, which can be measured by MRI in and out of phase imaging sequences. Serum indices of hepatic function and surrogate markers for diabetes, previously used, show less correlation with SHBG by comparison. Female patients with mineralocorticoid resistance present with androgenic alopecia. IGF levels are lower in those with metabolic syndrome. Circulating serum levels of
IGF-1 are increased with vertex balding, although this study did not look at mRNA expression at the follicle itself. Locally, IGF is mitogenic at the dermal papillae and promotes elongation of hair follicles. The major site of production of IGF is the liver, although local mRNA expression at hair follicles correlates with an increase in hair growth. IGF release is stimulated by growth hormone (GH). Methods of increasing IGF include exercise, hypoglycemia, low fatty acids, deep sleep (stage IV
REM),
estrogens, and consumption of
amino acids such as
arginine and
leucine. Obesity and
hyperglycemia inhibit its release. IGF also circulates in the blood bound to a large protein whose production is also dependent on GH. GH release is dependent on normal thyroid hormone. During the sixth decade of life, GH decreases in production. Because growth hormone is pulsatile and peaks during sleep, serum IGF is used as an index of overall growth hormone secretion. The surge of androgens at puberty drives an accompanying surge in growth hormone. The expression of
insulin resistance and metabolic syndrome, AGA is related to being an increased risk factor for cardiovascular diseases, glucose metabolism disorders,
type 2 diabetes, and enlargement of the
prostate.
Age Several hormonal changes occur with aging: • Decrease in
testosterone • Decrease in serum DHT and 5-alpha reductase • Decrease 3AAG, a peripheral marker of DHT metabolism • Increase in
SHBG • Decrease in androgen receptors, 5-alpha reductase type I and II activity, and aromatase in the scalp This decrease in androgens and androgen receptors, and the increase in SHBG, are opposite to the increase in androgenic alopecia with aging. This is not intuitive, as testosterone and its peripheral metabolite, DHT, accelerate hair loss, and SHBG is thought to be protective. The ratio of T/SHBG, DHT/SHBG decreases by as much as 80% by age 80, in numeric parallel to hair loss, and approximates the pharmacology of antiandrogens such as
finasteride. Free testosterone decreases in men by age 80 to levels double that of a woman at age 20. About 30% of the normal male testosterone level, the approximate level in females, is not enough to induce alopecia; 60%, closer to the amount found in elderly men, is sufficient. The testicular secretion of testosterone perhaps "sets the stage" for androgenic alopecia as a multifactorial
diathesis stress model, related to hormonal predisposition, environment, and age. Supplementing eunuchs with testosterone during their second decade, for example, causes slow progression of androgenic alopecia over many years, while testosterone late in life causes rapid hair loss within a month. An example of premature age effect is
Werner's syndrome, a condition of
accelerated aging from low-fidelity copying of mRNA. Affected children display premature androgenic alopecia. ==Diagnosis==