Androgenic alopeica
Androgenic alopecia

TYPES OF HAIR LOSS; ANDROGENIC ALOPECIA

Androgenic alopecia is an androgen dependant type of hair loss that involves recession of hair at the temples to form a characteristic “M” pattern.  Hair also thins at the crown area near the top of the head.  This type of hair loss can range from mild to severe.

In women, the extent of hair loss is generally less than in men.   In women, hair tends to become thinner all over the head but often there is still a clear pattern of hair loss evident at the temple and crown.

Androgenic alopecia is associated with insulin resistance, inflammation, genetic predisposition, low levels of vitamin D and can be treated with FDA approved medication or other hair growth stimulators and nutritional therapies.

It has been assumed that the hormonal basis for androgenic alopecia is similar in women and men, though the hyperandrogenic symptoms may not correlate with high levels of androgens in the body.

Causes of androgenic alopecia

ANDROGENIC ALOPECIA AND ANDROGEN EXCESS

Most patients with androgenic alopecia show no other clinical or biochemical evidence of androgen excess. The family history of women with androgenic alopecia is not as straightforward as those of men with similar pattern hair loss.  Regardless of the origin, the hair follicle’s sensitivity and follicular changes in androgenic alopecia in males and females appear the same.  There is a final common pathway of follicular miniaturisation.

This includes:

  • Progressive reduction of the time the hair follicle spends in anagen phase.
  • A prolonged period before anagen starts after the hair has been shed.
  • Hair follicles gradually reducing production of terminal hairs resulting in slow growing hair and less scalp coverage.

Excess androgens often lead to excess hair on face and body, severe acne, irregular menstrual cycles, polycystic ovaries.  Less than 40% of women with androgenic alopecia display hyperandrogenism in blood tests.

CLINICAL FEATURES OF ANDROGENIC ALOPECIA

This hair loss condition is characterised by hair thinning over the frontal area first, the rest of the scalp becomes more visible thereafter. Over time, the thinning usually develops in a patterned fashion.  The most pronounced thinning is seen over the frontal and parietal scalp area, and greater hair density is found over the occipital scalp.  Miniaturised hairs (the shorter and thinner hairs of various lengths and diameter) are the hallmark of androgenic alopecia and result from the shortening of growth phase and reduction in hair fibre size.

The clinical feature of androgenic alopecia varies slightly between men and women.  Women typically retain a rim of hair along the frontal hairline, even when the scalp is visible behind the hairline.  Increased spacing between hairs makes the central parting appear wider over the frontal scalp compared to the occipital scalp.

Less commonly, hair density appears normal at the scalp (proximal) area, but the hair no longer grows to its previous length, resulting in wispy ends; in this case, the shortening of the anagen phase progresses more rapidly than the reduction in thickness of the hair fibre.

THE CURRENT UNDERSTANDING OF ANDROGENIC ALOPECIA

Androgenic alopecia is understood to be an androgen dependent type of hair loss coordinated by the two androgens: testosterone and dihydrotestosterone (DHT).  Whilst there is no definitive explanation regarding the cause of androgenic alopecia there are several known factors that are the basis of the current understanding of the development of the condition.

1 | 5-alpha reductase activity is responsible for the conversion of testosterone to DHT.

2 | High levels of DHT are found in balding and thinning areas of scalp.

3 | The number of DHT receptors on the hair follicles increases in balding scalp.

4 | Blocking the conversion of testosterone to DHT delays the progression of androgenic alopecia.

5 | Studies show that balding and non-balding men and women have similar levels of testosterone.

6 | Testosterone declines with age but the incidence of hair loss increases with age.

Based on these findings, DHT is held responsible for the pattern miniaturisation of the hair follicles.  As testosterone is needed for hair growth, it would be expected that DHT (5-8 times more potent than testosterone) would drive more growth.  In the body, DHT encourages thicker hair growth, but on the scalp, it appears to cause baldness in specific areas.

The selective effect of DHT dependant hair loss relies on the concept of opposite effects of androgens on the scalp when compared to the action of the body.  Using these concepts, balding scalp hair or hair that is reduced by the presence of DHT is designated as DHT sensitive.  Hair that is not reduced by the presence of DHT is designated as DHT insensitive.  This androgen sensitive / androgen insensitive model divides the scalp into two separate areas.

THE CONCEPT OF ANDROGEN SENSITIVITY AND ITS CONTRIBUTION TO HAIR LOSS

DHT is accepted to be the androgen that binds to androgen receptors in the hair follicle to effect follicle miniaturisation.  This conclusion is based in the findings that there is an increased level of DHT in the balding scalp compared to a non-balding scalp.  The concept that the hair follicles in the balding scalp are more sensitive to androgens still does not explain why a stronger androgen than testosterone would produce the opposite effect in one specific area of the body.

The mechanism of androgenic alopecia is highly complex, but there is a simple theory that can explain this paradox.  Pressure on the hair follicles caused by collagen fibrosis, dehydration, connective tissue and a thin extracellular matrix is operative in the progression of this type of hair loss.  The pressure causes compression against the calvarial bones on the scalp.  The calvaria is the top part of the skull, the exact shape varies explaining the slight variation in areas of hair loss between individuals.

Normally, pressure on the hair follicle is buffered by the surrounding subcutaneous fat tissue.  Subcutaneous fat is the fat just below the skin.  The thickness and volume of the subcutaneous fat tissue reduces with age.  Normally, subcutaneous fat tissue is well hydrated.

Factors that decrease the volume of subcutaneous fat tissue or lead to the degradation of the extracellular matrix decreases the buffer and increases the pressure on the hair follicles.  One specific factor that reduces subcutaneous fat is testosterone, DHT reduces this fat at a faster rate.  Testosterone effected reduction in subcutaneous fat tissue does not normally occur as drastically in women due to the presence of estrogens.

DHT SHOULD INCREASE HAIR GROWTH IN THE SCALP

At the start of the hair growth cycle, the hair follicle has a reduced cushion and must strive against increased pressure.  More androgens are needed to counteract the extra pressure so the hair can grow to normal length and thickness.  To facilitate the increased demand the cell can locally upregulate the action of testosterone by metabolising more testosterone into DHT.

DHT is increased to help the hair fibre grow as normal in the face of increased pressure and decrease in cushioning tissues.  DHT increases hair growth but cannot counteract the pressure in the hair follicle, eventually the hair fibre will grow smaller and smaller until almost invisible.

EXPLAINING THE CLASSIC PATTERN APPREARANCE OF ANDROGENIC ALOPECIA

Androgenic alopecia is a progressive condition and there are several factors that can be effective on when hair loss starts and how it progresses in different individuals.  Although androgenic alopecia has a different pathway for everyone, the pattern of hair loss is remarkably similar.  Emin Ustuner, MD offers a fresh perspective, specifically looking at the pressure forces around the scalp [1].

“If the pressure created by the weight and compression of the scalp is responsible for the hair loss in androgenic alopecia, it would be expected that hair at the top of the head would be lost first.

The downward pull caused by gravity is not distributed equally around the circumference of the head. The scalp area around the ears is firmly fixed and take on the pull exertion above and around them.  The scalp skin is continuous with the skin of the face between the ears and both sides of the face.  This means the weight of the facial tissues and structures adds pressure to the frontal area of the scalp.”

GENETIC FACTORS THAT INFLUENCE ANDROGENIC ALOPECIA

Several reports have documented a genetic predisposition to androgenic alopecia as a major contributor to the development of the hair loss condition.  Most research pertaining to androgenic alopecia have concentrated on single nucleotide polymorphisms, a common type of genetic variation among people.  Genetic variations in androgen receptors are highly associated with androgenic alopecia through the role of androgens and the sensitivity of the hair follicle to the androgen metabolite DHT.

DHT determines whether androgenic alopecia will occur and to what degree.  The sensitivity of the hair follicle to DHT will dictate how vulnerable the follicle is to be circulating DHT, but the concentration of DHT has been shown to be a more significant predictor of hair loss than genetic factors [2, 3].

Whilst most research pertaining to androgenic alopecia has focused on androgen receptor variations, other research have identified genes not related to this type of mutation.  The identification of non-androgen receptor genes demonstrates other factors contribute to the development of androgenic alopecia.

A study by Michel et al in 2017 found that in patients with androgenic alopecia, there were several differences in expressed genes.  In patients with alopecia, 325 genes were found to be upregulated when compared to controls and 390 genes were downregulated.  A Benjamin-Hochberg correction for multiple testing gave a final number of 149 significantly upregulated genes and 184 significantly downregulated candidate gene sequences in the patient group when compared to the control group [4].

Upregulated genes in patients with alopecia when compared to controls:

Innate immunity | Increases the migration of inflammatory cells.

Extracellular matrix (some collagens) | Contributes to fibrosis around the hair follicle units.

Receptor signalling | Increases androgen receptor sensitivity.

Response to toxins | Increases sensitivity to environmental and biological toxins.

B-cell immunity | Increases inflammatory response and production of antibodies.

T-cell immunity | Increases vigour of immune response.

Cell adhesion | Elevated in the frontal area of the scalp.

Downregulated genes in patients with alopecia when compared to controls:

Cytoskeleton | Reduces anchorage of the hair fibre to the extracellular matrix.

Keratin-associated proteins | Reduces the expression of non-keratinous proteins that form part of the hair fibre.

Subset of keratins | Reduces the expression of keratinous proteins that make up the fibre.

Connexins / cell communication | Affects cell-to cell communication.

Transforming growth factor – beta | Plays a role in the miniaturisation of the hair follicle.

ANDROGENIC ALOPECIA IS LINKED TO VITAMIN D AND CALCIUM

The vitamin D receptor gene was found to be downregulated in androgenic alopecia patients when compared to controls.  The altered metabolism of vitamin D and associated calcitriols were heavily implicated in androgenic alopecia.

Michaletti supports this theory by demonstrating that calcium levels were a major regulator in keratin cell development [5].  It was shown that lower levels of calcium in keratin cells led to an increase in protein misfolding and metabolic changes.

Vitamin D status has long been associated with hair loss, though it has no clear role in hair follicle health.  It appears that the role of vitamin D in calcium uptake is the link to hair loss.  These studies used transcriptomics and genomics to identify a link that would have been less obvious without a multi-omics approach.

Both studies assert vitamin D is essential for hair growth and is a potential biomarker for hair loss.  These studies move the focus from the ‘usual suspects’ being androgen receptors and DHT, providing an interesting insight into other contributors to androgenic alopecia.  Overall, genes that promoted inflammation and heightened innate immunity were promoted whilst genes that would promote growth and development of keratin cells were downregulated.  The data from this integrative systems biology approach indicates androgenic alopecia should be classed as an autoimmune condition linked to inflammation.

ANDROGENIC ALOPECIA IS LINKED TO INFLAMMATION AND AUTOIMMUNITY

A functional analysis was used to give an overview of biological pathways and processes in androgenic alopecia.  Functional interpretation of major genes that are expressed differently and associated families using PredictSearch showed severe inflammation and intense immune reactivity in patients with androgenic alopecia when compared to controls.

Antimicrobial creams and antibiotics may help reduce the progression of hair loss in cases of androgenic alopecia by reducing the number of microbe flora and reducing microinflammation of the hair follicle.  Pierard et al found the topical application of antimicrobials, piroctone olamine and triclosan reduced hair loss and follicle inflammation in 20 men [6].

Another study looking at the effectiveness of minoxidil therapy found that the concentration of zinc in the blood was a predictor of how effective the treatment would be.  Zinc reduces inflammation and lowers autoimmune activity by regulating proinflammatory response, controlling oxidative stress and regulating inflammatory cytokines [7].

Increased DHT is not only found in balding scalps, but also in inflamed body tissue.  Evidence shows that DHT helps regulate inflammation, and that in some tissues DHT is an anti-inflammatory [8]. This suggests that increased DHT is part of the inflammatory process.  DHT bind to tissues after inflammation occurs, it is likely that chronic inflammation of the hair follicles contributes to chronically elevated levels of DHT in the balding scalp.

INSULIN RESISTANCE CONTRIBUTES TO ANDROGENIC ALOPECIA

Insulin resistance has an additional role in the excessive miniaturisation of the hair follicle which contributes to the disturbance of the microcirculation around the hair follicle.  Insulin resistance induces constriction of blood vessels and stimulates thickening of the blood vessel walls reduces blood flow to the hair follicle.  The excessively compacted architecture surrounding the hair follicle leads to low oxygen which is a secondary effect of reduced microcirculation.

Insulin resistance increases the concentration of insulin-like growth factor.  The activity of the insulin-like growth factor regulates the ageing process of the cell and androgens are a part of regulating the signalling system.

The increase of insulin-like growth factor increases the uptake of androgens to the cell, this will increase the binding of DHT to the cell.

It is widely accepted that visceral fat in the abdominal area mediate insulin resistance.  A study by Bergman et al in 2006, found free fatty acids are among the most important products of visceral fat to promote insulin resistance.  The anatomical position of visceral fat in the abdominal area plays an important role in the pathogenesis of insulin resistance.  Visceral fat initially increases rapidly when body fat increases before reaching a plateau, extra fat is then stored in subcutaneous tissue. Researchers found that moderate abdominal fat resulted induced liver insulin resistance while sensitivity to insulin remained normal in other tissues.  When levels of body fat increases, insulin sensitivity is reduced in other tissues.

Studies have shown that you can reduce visceral fat or prevent its growth with both aerobic activity and strength training.

FDA APPROVED TREATMENT OPTIONS FOR ANDROGENIC ALOPECIA

Currently, there are two effective treatments available for the treatment of androgenic alopecia in males and females. Minoxidil and finasteride have well established therapeutic effect in the management of androgenic alopecia.  Minoxidil relaxes blood vessels to increase the exchange of waste and nutrients to the hair follicle and finasteride systemically inhibits DHT production.  Minoxidil and Finasteride can be used independently or in conjunction with each other.

MINOXIDIL FOR THE TREATMENT OF ANDROGENIC ALOPECIA

Minoxidil is FDA approved to treat male and female pattern hair loss at concentrations of 2% and 5%.  Originally marketed for the treatment of high blood pressure, it was found to prevent the development of androgenic alopecia.  Minoxidil is a vasodilator that works by widening blood vessels and opening potassium channels. Vasodilators prevent hair loss by providing the hair follicles with more fuel it enables the follicle to grow thicker hair.  Minoxidil is usually applied to thinning areas of the scalp and takes around 12 months to achieve maximum result.

A 12 month observational study funded by the Pfizer group found the 5% solution was very effective in 15.9% of patients, effective in 47.8& of patients, moderately effective in 20.6% of patients and ineffective in 15.7% of patients.

Clinical trials show a 5% topical solution is superior to 2% minoxidil after 48 weeks of therapy, though side effects such as allergic reaction and contact dermatitis were more common in the 5% minoxidil group.

Whilst minoxidil is normally a safe and effective topical treatment.  Cessation of minoxidil therapy will mean new hair growth is likely to be lost and hair loss may progress further.  Minoxidil is likely to be more beneficial in cases where insulin resistance reduces blood flow due to vasoconstriction and where there is no evidence of scalp fibrosis (skin thickening).

FINASTERIDE AND ANDROGENIC ALOPECIA

Finasteride is an inhibitor of 5-alpha reductase, inhibiting the conversion of testosterone to DHT.   Finasteride is sold under the brand names Propecia and Proscar (among others) and is prescribed in the UK to treat hair loss and for the treatment of benign prostatic hyperplasia in men.  Finasteride can also be used to treat hirsutism (excessive body hair) in women and as part of hormone therapy for male to female sex change.

Some men report adverse side effects such as depression, breast enlargement and sexual disfunction.  In a few, these side effects persist even after stopping the medication.  An update by the FDA in 2012 noted an increase in reports of difficulty ejaculating and decreased sex drive.

Treatment with finasteride slows hair loss and can provide approximately 30% hair regrowth in balding areas.  The lowering of DHT in the scalp increases the amount of hair in anagen (growing) phase and inhibits the miniaturising effects of DHT.  An oral dosage of 1 or 5mg per day decreases circulating levels of DHT by around 65 to 70% and increases circulating testosterone by around 10% [9].

ALTERNATIVE GROWTH THERAPIES FOR ANDROGENIC ALOPECIA

Treatment with FDA approved medication have the benefit of being extensively trialled.  There is also the added safety guard of controlled manufacture and distribution to ensure patient safety.  Whilst these controls do ensure you receive the right product with a controlled dose, no medication is able to offer long term hair loss recovery and hair loss will proceed when treatment is stopped.

Alternative growth therapies such as supplements and serums are often a good option, but they do not have the data that is generated from large scale randomised clinical trials.  Most supplements and serums that target hair regrowth use compounds made up of ingredients that have been trialled independently and use this data to formulate their own specific products.

Look out for:

Zinc | Zinc is essential for the protein synthesis and cell changes needed for an epidermal cell to develop into a mature keratin cell within the hair matrix.  Zinc also balances immune response by modulating the behaviour of the immune system.  Zinc supplementation has been shown to support recovery from telogen effluviumalopecia areata and androgenic alopecia.

Liposomal peptides | Liposomal peptides are engineered peptides reacted with lipids (fats) to introduce peptides into living cells.  Specific liposomal peptides can specifically and selectively stimulate keratin production within the cell increasing the size hair growth and density.

Caffeine | Several clinical trials show that there is a marked increase in hair growth after topical application of caffeine.

Phytoestrogens | The interaction of phytoestrogens with estrogen receptors makes it a powerful compound for the reversal hormone dependent hair loss disorders.

Hydrolysed alpha-keratin | Hydrolysed alpha-keratin increases the water content of the epidermis by reducing transdermal water loss.  The water-hating nature of the amino acids that make up keratin reinforces the waterproof barrier of the outer skin layer.  A decrease in water loss increases the volume of the intermediate skin layers (70-30% depth) and this increases the depth of the hair follicle canal.

The sale of supplements and serums for hair regrowth is currently unregulated.  This lack of regulation means the product may not be quality controlled and the dosage on the label may not reflect the dosage in the final product.

BLOOD TESTS FOR ANDROGENIC ALOPECIA

Free testosterone / total testosterone /DHT | Androgenic alopecia implies a dependence on a higher concentration of androgens, but androgenic alopecia does not require an absolute elevation of androgens in the blood.

Dehydroepiandrosterone sulphate | This test is often done for women who show signs of having excess male hormones. Some of these signs are hair loss, excess facial and body hair growth, oily skin, acne, irregular periods, or problems becoming pregnant.

Sex hormone-binding globulin (SHBG) | Most testosterone is bound to sex hormone-binding globulin protein and is not active. If you have a low level of sex hormone-binding globulin, you may have a high level of free.  Low levels of SHBG are associated with insulin resistance.

Vitamin D |  Androgenic alopecia is associated with low levels of vitamin D and other fat-soluble vitamins.

Cholesterol / triglycerides | An abnormal lipid profile can contribute to hair loss.  Cholesterol helps to repair and heal your body; you will produce more if there is a great deal of inflammation occurring in your body. So, any factor that would raise inflammation, can raise your cholesterol too. A high level of triglycerides can indicate poor sugar regulation, or the start of insulin resistance.

Zinc | Low levels of serum zinc are linked to all types of hair loss.  Due to metabolic compensation, you do not need to be zinc deficient to experience hair loss related to zinc levels.  Zinc levels below 80 µg/dl are thought to be a contributor to hair loss.  Low levels of zinc are associated with insulin resistance, increased cortisol, increased conversion of testosterone to DHT and increased immune activity.

HbA1c | This test determines your average blood sugar levels for the last 90 days.  This test can give a doctor some insight into the blood glucose management of the patient and the potential for insulin resistance.

THE FINAL WORD

Androgenic alopecia responds well to a combination of hair loss therapy that includes the of FDA approved medication or the use of topical serums and nutritional therapy.  Insulin resistance can be reduced by following a healthy diet high in fruit, vegetables and fibre with moderate amounts of protein and fat.  Exercise can also help reduce the visceral fat associated with higher levels of circulating insulin.  Depending on the severity of hair loss, graded by the Savin scale, hair loss typically takes around 4-6 months for an initial therapeutic response.

REFERENCES

  1. Cause of androgenic alopecia: crux of the matter. Plastic and Reconstructive Surgery Global Open1(7).
  2. SNP variation in male pattern hair loss in Russians with different dihydrotestosterone levels. Meta Gene19, pp.219-224.
  3. Genetic prediction of male pattern baldness. PLoS genetics13(2), p.e1006594.
  4. Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signalling pathways. British Journal of Dermatology177(5), pp.1322-1336.
  5. Multi-omics profiling of calcium-induced human keratinocytes differentiation reveals modulation of unfolded protein response signaling pathways. Cell cycle18(17), pp.2124-2140.
  6. Improvement in the inflammatory aspect of androgenetic alopecia. A pilot study with an antimicrobial lotion. Journal of dermatological treatment7(3), pp.153-157.
  7. Plasma zinc levels in males with androgenetic alopecia as possible predictors of the subsequent conservative therapy’s effectiveness. Diagnostics10(5), p.336.
  8. Androgens are effective bronchodilators with anti-inflammatory properties: a potential alternative for asthma therapy. Steroids153, p.108509.
  9. Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. Hormone Molecular Biology and Clinical Investigation2(3): 293–9.