Pattern hair loss

Pattern hair loss, also known as androgenetic alopecia, is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss, the hair loss typically presents itself as either a receding front hairline, loss of hair on the crown and vertex of the scalp, or a combination of both. Female-pattern hair loss typically presents

Pattern hair loss, also known as androgenetic alopecia,[1] is a hair loss condition that primarily affects the top and front of the scalp.[2][3] In male-pattern hair loss, the hair loss typically presents itself as either a receding front hairline, loss of hair on the crown and vertex of the scalp, or a combination of both. Female-pattern hair loss typically presents as a diffuse thinning of the hair across the entire scalp.[3] The condition is caused by a combination of male sex hormones and genetic factors.[4]

Some research has found evidence for the role of oxidative stress in hair loss,[5] the microbiome of the scalp,[6][7] genetics, and circulating androgens; particularly dihydrotestosterone.[3] Men with early onset androgenic alopecia (before the age of 35) have been deemed the male phenotypic equivalent for polyendocrine metabolic ovarian syndrome.[8][9][10][11]

The cause of female pattern hair loss remains unclear;[3] androgenetic alopecia for women is associated with an increased risk of polyendocrine metabolic ovarian syndrome.[12][13][14]

Management of hair loss may include styling the remaining hair in a creative manner to make hair loss less apparent[15] or shaving one's head to improve the aesthetic aspect of the condition.[16] Otherwise, common medical treatments include platelet-rich plasma, low-level laser therapy, minoxidil, finasteride, dutasteride, or hair transplant surgery.[3] Use of finasteride and dutasteride in women is not well-studied and may result in birth defects if taken during pregnancy.[3]

By the age of 50, pattern hair loss affects about half of males and a quarter of females.[3] It is the most common cause of hair loss. Both males aged 40–91[17] and younger male patients of early onset androgenetic alopecia (before the age of 35) had a higher likelihood of metabolic syndrome (MetS)[18][19][20][21] and insulin resistance.[22] With younger males, studies found metabolic syndrome to be at approximately a 4× increased frequency, which is deemed clinically significant.[23][24] Abdominal obesity, hypertension, and lowered high-density lipoprotein were also significantly higher for younger groups.[25]

Signs and symptoms

Pattern hair loss is classified as a form of non-scarring hair loss.[citation needed]

Male-pattern hair loss begins above the temples and at the vertex (calvaria) of the scalp. As it progresses, a rim of hair at the sides and rear of the head remains. This has been referred to as a "Hippocratic wreath" and rarely progresses to complete baldness.[26]

Female-pattern hair loss more often causes diffuse thinning without hairline recession; similar to its male counterpart, female androgenic alopecia rarely leads to total hair loss.[27] The Ludwig scale grades severity of female-pattern hair loss. These include Grades 1, 2, 3 of balding in women based on their scalp showing in the front due to thinning of hair.[28]

In most cases, receding hairline is the first starting point; the hairline starts moving backwards from the front of the head and the sides.[29]

Causes

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.[citation needed]

Hormones and genes

KRT37 is the only keratin that is regulated by androgens.[30] 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.[30]

Although it is generally accepted that male pattern baldness follows a pattern of autosomal dominant inheritance, more recent research has shown that approximately 80% of bald men have bald fathers. This is greater than would be expected if pattern balding were a purely autosomal trait, and may suggest that there is an important paternal route of inheritance, either through a Y-chromosome gene or a paternal imprinting effect.[31]

The initial programming of pilosebaceous units of hair follicles begins in utero.[32] 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.[11] 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.[33][34][non-primary source needed]

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'.[35]

Men with androgenic alopecia typically have higher 5α-reductase, higher total testosterone, higher unbound/free testosterone, and higher free androgens, including DHT.[36] 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.[37] The genetic corollary that codes for this enzyme has been discovered.[38] Prolactin has also been suggested to have different effects on the hair follicle across gender.[39]

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.[35] Other research suggests the enzyme prostaglandin D2 synthase and its product prostaglandin D2 (PGD2) in hair follicles as contributive.[40]

These observations have led to a study at the level of the mesenchymal dermal papillae.[41] Types 1 and 2 5α reductase enzymes are present at pilosebaceous units in papillae of individual hair follicles.[42] They catalyze the formation of the androgen dihydrotestosterone from testosterone, which in turn regulate hair growth.[35] Androgens have different effects at different follicles: they stimulate IGF-1 at facial hair, leading to growth, but can also stimulate TGF β1, TGF β2, dickkopf1, and IL-6 at the scalp, leading to catagenic miniaturization.[35] Hair follicles in anaphase express four different caspases. Significant levels of inflammatory infiltrate have been found in transitional hair follicles.[43] Interleukin 1 is suspected to be a cytokine mediator that promotes hair loss.[44]

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.[45]

Metabolic syndrome

Multiple cross-sectional studies have found associations between early androgenic alopecia, insulin resistance, and metabolic syndrome,[22][46] with low HDL being the component of metabolic syndrome with highest association.[47] Linolenic and linoleic acids are 5 alpha reductase inhibitors.[48] Premature androgenic alopecia and insulin resistance may be a clinical constellation that represents the male homologue, or phenotype, of polyendocrine metabolic ovarian.[49] Others have found a higher rate of hyperinsulinemia in family members of women with polyendocrine metabolic ovarian.[50] With early-onset androgenetic alopecia having an increased risk of metabolic syndrome, poorer metabolic profiles are noticed, including metrics for body mass index, waist circumference, fasting glucose, blood lipids, and blood pressure.[51]

In support of the association, finasteride improves glucose metabolism and decreases glycated hemoglobin HbA1c, a surrogate marker for diabetes mellitus.[52] The low SHBG seen with premature androgenic alopecia is also associated with, and likely contributory to, insulin resistance,[53] and for which it still is used as an assay for pediatric diabetes mellitus.[54]

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.[55] In vivo, insulin stimulates both testosterone production and SHBG inhibition in normal and obese men.[56] 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.[57] Patients with Laron syndrome, with resultant deficient IGF, demonstrate varying degrees of alopecia and structural defects in hair follicles when examined microscopically.[58]

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.[11] Measurement of subcutaneous and visceral adipose stores by MRI, demonstrated inverse association between visceral adipose tissue and testosterone/DHT, while subcutaneous adipose correlated negatively with SHBG and positively with estrogen.[59] 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.[60]

Female patients with mineralocorticoid resistance present with androgenic alopecia.[61]

IGF levels are lower in those with metabolic syndrome.[62] Circulating serum levels of IGF-1 are increased with vertex balding, although this study did not look at mRNA expression at the follicle itself.[63] 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.[64]

The expression of insulin resistance and metabolic syndrome, androgenetic alopecia is related to being an increased risk factor for cardiovascular diseases, glucose metabolism disorders,[65] type 2 diabetes,[66][67] and enlargement of the prostate.[68]

Age

Several hormonal changes occur with aging:

1. Decrease in testosterone
2. Decrease in serum DHT and 5-alpha reductase
3. Decrease 3AAG, a peripheral marker of DHT metabolism
4. Increase in SHBG
5. Decrease in androgen receptors, 5-alpha reductase type I and II activity, and aromatase in the scalp[69][70]

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.[71]

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.[72] 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.[73]

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.[74]

Diagnosis

The diagnosis of androgenic alopecia can usually be established based on clinical presentation in men. In women, the diagnosis usually requires a more complex diagnostic evaluation. Further evaluation of the differential requires exclusion of other causes of hair loss, and assessing for the typical progressive hair loss pattern of androgenic alopecia.[75] Trichoscopy can be used for further evaluation.[76] Biopsy may be needed to exclude other causes of hair loss,[77] and histology would demonstrate perifollicular fibrosis.[78][79] The Hamilton–Norwood scale has been developed to grade androgenic alopecia in males by severity.[citation needed]