Hormones and hair loss
Hormones and hair loss

THE CONNECTION BETWEEN HORMONES AND THE HAIR GROWTH CYCLE

Hair grows in continuous cycles that are partially controlled by a number of steroid hormones produced in the hair follicle and other organs of the body.  Steroid hormones are a group of biologically active compounds that act as signalling molecules influencing the hair growth cycle.

Hair follicles undergo cyclical rounds between growth (anagen), transition to rest (catagen), rest (telogen) and shedding (exogen).

The longest phase in the cycle is anagen phase, this phase can last up to 7 years.  In anagen phase keratin cells are constantly multiplying, the increased number of keratin cells cause keratin cells to move up the hair shaft and emerge from the scalp.  Hair will continue to grow as long as keratin cells in the base of the hair follicle continue to multiply.

The catagen phase is a short transition period which is a type of regression from growth.  The keratin cells in the base of the hair follicle receive a signal to stop active growth, the hair fibre detaches from its blood supply and from the hair follicle stem cells in the epithelial column that promote new growth.  A ‘club hair’ is formed at the base of the hair fibre which features a bulb of keratin protein at the root tip of the hair strand.  The keratin bulb keeps the hair follicle embedded within the dermis until the hair sheds.

The telogen phase is the resting phase where hair the club hair sits in the dermis. This phase usually lasts around 3 months but the length of time a hair can remain in telogen is dependant on the thickness of the dermis and the size of the keratin bulb anchoring the resting hair fibre in the scalp.

The exogen phase is the point where the hair fibre completely detaches and is shed from the scalp.  This phase should occur when a new active follicle in early anagen phase is growing below the resting hair fibre.

Normally up to 10% of hairs are in resting phase and 90% of hairs are in growth phase.  When the percentage of hairs in telogen phase increase, there will be an increased rate of shedding.  Thinning tends to become noticeable when the number of hairs in anagen phase falls below 60%.

A number of hormones affect hair growth, the include: prolactin, melanocyte-stimulating hormone and thyroid hormones.  Four hormones that play a particularly important role in maintaining the balance between resting hairs and growing hairs are androgens, progesterone, estrogens and cortisol.

Hair cycle; growth and regression of the hair follicle

The hair growth cycle.  Each hair follicle goes through an independent cycle of growth and rest.

HORMONES PLAY A ROLE IN THE HAIR GROWTH CYCLE

Androgen, progesterone, estrogens and cortisol are biologically active steroids hormones synthesised from cholesterol, they play different roles in hair follicle development and cycling, some encourage hair growth others inhibit hair growth.

In females, a quarter of these steroid hormones can be produced in the ovary, a quarter is produced in the adrenal gland and half is produced in peripheral tissues such as adipose tissue, the skin and the hair follicle.

The synthesis of biologically active hormones from cholesterol is called steroidogenesis.  For the creation of androgens, estrogens, progesterone and cortisol a number of enzymes are needed to make modifications to cholesterol.

Cholesterol, hormones and hair loss

Cholesterol is used to create hormones essential for hair follicle growth.  Cells of the skin and hair fibre can independently synthesise androgens, cortisol, progesterone and estrogens from cholesterol using a process called steroidogenesis.

ANDROGENS TRIGGER ENTRY INTO THE HAIR GROWTH CYCLE

Androgens are the most important regulator of growth in the human hair follicle and facilitate development of keratin cells.  Cells in the hair follicle that control the regulation of hair growth are able to synthesise their own local supply of androgens from cholesterol or androstenedione.

Circulating androstenedione is a cholesterol derivative that is produced in the adrenal glands and the ovaries.

Androgens such as testosterone play a key role in maintaining the anagen phase.  Testosterone binds to androgen receptors in the dermal papilla cells and the outer root sheath of the hair follicle to regulate growth. Androgen receptors are activated by testosterone or the more potent androgen dihydrotestosterone (DHT), this activation induces an alteration in the expression and transcription of genes that code for proteins which instruct the cell to increase or decrease hair growth.

The binding of testosterone increases the production of a protein known as insulin-like growth factor, a key signal for hair growth stimulation.  Insulin-like growth factor stimulates early anagen phase which hastens the replacement of hair that is entering telogen phase, it also delays the switch from anagen to catagen which mean the hair follicle grows for a longer period of time [1].

Androgen dependant hair loss such as androgenic alopecia is due to altered androgen metabolism by the enzyme 5-alpha reductase.  5-alpha reductase converts testosterone to DHT, a more potent androgen than testosterone.

DHT leads to a reduced hair growth by enhancing the genetic expression and translation of genes that code for transforming growth factor, interleukin 6 and Dickkopf WNT signalling pathway inhibitor 1.

Transforming growth factor inhibits growth of most cells and can also increase the activity of local immune cells leading to micro-inflammation of the hair follicle.Interleukin 6 inhibits hair growth by suppressing keratin cell multiplication leading to premature entry into catagen phase.  The Dickkopf WNT signalling pathway inhibitor 1 inhibits the formation of a new hair fibre after exogen phase.  This means the hair cycle does not start a new anagen phase to replace lost hair.

Testosterone and DHT play opposing roles in the hair follicles on the scalp. DHT is considered more potent than testosterone as it binds to androgen receptors in the cell 2-3X more readily than testosterone so even if they are present in equal measure DHT will exert its influence on the cell.  Some people are slightly more sensitive to the DHT based on hereditary variations in genes that allows more damaged DNA to accumulate in the keratin cell.

Hair loss medication targeting the production of DHT show varying degrees of success in reducing the severity of androgenic hair loss.  Treatment success is increased when combined with zinc, a mineral shown to increase testosterone conversion and lower DHT.

Testosterone and the hair growth cycle

Testosterone is the main steroid hormone that increases hair growth.  Testosterone increases hair growth. DHT, a derivative of testosterone, leads to reduced hair growth.

PROGESTERONE SUPPORTS THE ANAGEN PHASE OF THE HAIR CYCLE

Progesterone belongs to a group of steroid hormones called progestogens and is the major progestogen in the body.  Progesterone maintains the hair follicle in anagen phase, increasing the multiplication of keratin cells [2] and blocking the action of 5-alpha reductase preventing the creation of DHT [3].

Progesterone raises levels of epidermal growth factor, a factor often used to induce the proliferation of keratin cells that make up the hair fibre.  Epidermal growth factor also stimulates stem cells that reside in the hair follicle niche.  The activation of stem cells are necessary for the survival and growth of keratin cells.

Cortisol is made from progesterone, therefore an increased cortisol need results in higher levels of progesterone synthesis [4] from available cholesterol.  If the need for cortisol is sustained over an extended period of time, eventually levels of progesterone in keratin cells will be substantially lowered.

Progesterone and hair loss

Progesterone regulates proliferation of hair follicle stem cells and lowers DHT.  Normal levels of progesterone are required for normal hair growth, a sustained cortisol need result in lower progesterone.

ESTROGEN RECEPTORS, GROWTH FACTORS AND INFLAMMATION

Estrogens are a category of steroid hormones responsible for the development and regulation of the female sex characteristics and reproductive health.  There are three major estrogens with estrogenic hormonal activity: Estrone, estradiol and estrone. Estradiol and estrone are the two estrogens that are involved in hair follicle cycling.

Estradiol is synthesised from from testosterone and estrone is synthesised from androstenedione (a weak androgen) by the enzyme aromatase.  Estradiol and estrone increases vascularisation and collagen production of the area surrounding the hair follicle and also raises the activity of pigment cells within the hair follicle whilst suppressing hair follicle sebaceous gland activity [5].

Estradiol is about 10X more potent than estrone about 100X more potent than estriol.  The potency of estradiol and estrone is measured by their ability to bind with estrogen receptors.

Like all steroid hormones, estrogens diffuse across cell membranes and bind to estrogen receptors inside the cell. Estrogen receptors α and β are involved in the regulation of genes that regulate entry into different phases of the hair growth cycle.

The binding of estrogen receptor α upregulates the expression of genes that code for insulin-like growth factor and epidermal growth factor, leading to a longer anagen phase in the hair cycle, and increasing the anagen to telogen ratio [6,7].  The binding of estrogen receptor β counteracts the activity of estrogen receptor α, promotes immune activity, induces the arrest of anagen and initiates telogen phase.

Estradiol and estrone target both estrogen receptors α and β but the binding area of estrogen receptor β is smaller and narrower than estrogen receptor α [8].  Androstenediol, a cholesterol derivative, preferentially binds to estrogen receptor β.  Androstenediol can be converted by an hydroxysteroid dehydrogenase enzyme to testosterone and then estradiol. Low activity of hydroxysteroid dehydrogenases that facilitate the conversion of androstenediol to testosterone will lead to increased activation of estrogen receptor β.

The binding of estrogen receptor β by androstenediol will counteract the activation of estrogen receptors α and lead to higher levels of inflammation and immune cell activity within the hair follicle.

Estrogen and hair growth

Cholesterol is used to create hormones essential for hair follicle growth.  Cells of the skin and hair fibre can independently synthesise androgens, cortisol, progesterone and estrogens from cholesterol using a process called steroidogenesis.

CORTISOL PREVENTS BINDING OF GROWTH FACTORS TO THE HAIR FOLLICLE

Cortisol, a steroid hormone produced from progesterone in the hair follicle, is known to affect the function and cyclic regulation of the hair follicle.  Cortisol regulates a wide range of processes in the hair follicle including inflammation response, blood sugar regulation and immune response.

Cortisol is essential for short-term metabolic management when there is low availability of elements needed for the hair follicle cycle.  To maintain metabolism cortisol is raised when we sleep and in-between meals When cortisol is present consistently at high levels it eventually breaks down important elements of the extracellular matrix in the dermis that are important for hair follicle development, namely hyaluronan and proteoglycans by approximately 40% [9].

The extracellular matrix is found in contact with most cells in the body.  It acts as a reservoir for growth factors (such as insulin-like growth factor and epidermal growth factor) and provides anchorage for the hair fibre.

Hyaluronan is a clear and gooey substance that acts as a scaffold within the extracellular matrix that surrounds the hair follicle.  Hyaluronan is considered similar to fertiliser as it supports hair growth and hydration in the dermis.  Hyaluronan plays a key role in tissue regeneration and lower levels of hyaluronan result in reduced anagen phase initiation after telogen phase is completed.

Proteoglycans are another major component of the extracellular matrix that plays a role in stabilising the hair follicle in the scalp.  Proteoglycans are also involved in binding calcium, potassium and water.  Evidence shows they can affect the activity and stability of proteins and signalling molecules necessary for the growth of the hair fibre matrix.

Cortisol also reduces the hair growth cycle by reducing the expression of proteins that bind with insulin-like growth factor, meaning even if this growth factor is present it can not encourage growth of the hair fibre.

Cortisol and hair loss

Cholesterol is used to create hormones essential for hair follicle growth.  Cells of the skin and hair fibre can independently synthesise androgens, cortisol, progesterone and estrogens from cholesterol using a process called steroidogenesis.

ENZYMES ARE ESSENTIAL FOR STEROID HORMONE SYNTHESIS

The synthesis of steroid hormones is initiated when cholesterol is delivered to cells from the liver.  Cholesterol needs to go through several enzymatic modifications before it becomes the final hormone product.

Enzymes are a type of protein found within a cell, they accelerate chemical reactions in the body by binding to molecules and creating specific alterations.  This process of modification to increase metabolism is known as enzyme catalysis.  The molecules that enzymes act on are called substrates and the enzyme converts the substrate into different molecules known as products.

A majority of biological functions require enzyme catalysis in order for molecules to be modified quickly enough to sustain life and normal metabolism.  Metabolic pathways are dependant on enzymes catalysis at individual steps.

Enzymes are usually much larger than their substrates ranging from 62 amino acids to 2,500 amino acids.  Two areas of an enzyme is responsible for enzymatic activity: the catalytic site and the binging site.  The catalytic site carries out the enzyme function (i.e hydrolysis or reduction) and the binding site binds tot eh substrate and holds it until the product is formed by catalysis.

Only a tiny portion of the enzyme structure is responsible for catalytic activity, around 2-4 amino acids make up the site of catalysis, the remaining enzyme structure serves to maintain the precise orientation and dynamics of the active site.  The catalytic site is located next to the binding site of the enzyme.

Some enzymes contain no amino acids that are involved in catalysis; instead the enzyme contains sites to bind catalytic cofactors.  Enzymes also contain allosteric sites where the binding of small molecules affect the functioning of an enzyme.  Allosteric sites are pockets in an enzyme that are entirely distinct from the binding site and the catalytic site and can be used to inhibit or accelerate the activity of an enzyme.

Enzymes convert cholesterol into the steroid hormones necessary for hair growth.  The hair follicle cycle is dependant on testosterone and estrogens for healthy hair growth whereas an overproduction of dihydrotestosterone and cortisol leads to hair loss.

ENZYME FUNCTION ALTERS STEROIDOGENESIS TO CONTROL HAIR GROWTH 

The synthesis of biologically active hormones from cholesterol is called steroidogenesis.  For the creation of androgens, estrogens, progesterone and cortisol a number of enzymes are needed to make modifications to cholesterol.

Enzyme activity can be altered by drugs that bind to allosteric sites: enzyme inhibitors that decrease enzyme activity and enzyme activators that increase activity.  Finasteride, an FDA approved hair loss medication is a 5-alpha reductase inhibitor that works by reducing the ability of the 5-alpha reductase enzymes to up-regulate testosterone to DHT.

Enzymes must first bind with their substrate before they can catalyse any type of chemical reaction and they are usually very specific about what substrates they will bind to though some enzymes have a broad selection of substrates they can work on.

The enzymes required for the steroidogenesis are located in tiny structures in cells known as organelles.

Cholesterol conversion into progesterone, androgens, estrogens and cortisol requires enzymes from two organelles in the cell: the mitochondria and the endoplasmic reticulum.

Finasteride for hair loss

Finasteride is an FDA approved hair loss medication works by inhibiting enzymes involved in steroidogenesis.  Finasteride inhibits 5-alpha reductase, an enzyme involved in the formation of DHT to testosterone.

THE MITOCHONDRIA AND ENDOPLASMIC RETICULUM ARE ESSENTIAL FOR STEROIDOGENESIS

The mitochondria and endoplasmic reticulum produce the key enzymes needed for the formation of steroid hormones from cholesterol.  The enzymes are from the cytochrome P450 family, a superfamily of enzymes containing heme as a cofactor that function as monooxygenases or they are hydroxysteroid dehydrogenases.

Cytochrome P450 is a generic term for a group of oxidative enzymes that contain a single heme group.

A P450 enzyme may be either type 1 (in the mitochondria) or type 2 (in the endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors such as heme.

Cholesterol is delivered to the mitochondria via LDL and transported to the inner mitochondrial membrane by the steroidogenic acute regulatory protein where the side chain cleavage enzyme (P450scc or CYP11A1) is responsible for the first catalytic step, generating pregnenolone.  This first step determines the capacity of the entire cell to produce steroid hormones.

Once pregnenolone is produced from cholesterol, it may undergo hydroxylation to yield 17α-hydroxypregnenolone, or it may be converted to progesterone.  Further enzymatic catalysis by hydroxysteroid dehydrogenase to produce androgens (testosterone and DHT), estrogens (estrone and estradiol) and cortisol.

Enzyme production involves the transcription and translation of the genes required for the creation of enzymes and can be increased or decreased in response to changes in the cells environment. These changes can be due to nutritional deficit, high blood sugar, low oxygen delivery to the cell. This is a form of regulation known as enzyme induction when there is an increase or enzyme repression when there is a decrease.

Flow chart of steroid hormones and their impact on hair growth

The mitochondria and endoplasmic reticulum are needed for the production of steroid hormones from cholesterol.  Cholesterol is converted to testosterone, dihydrotestosterone, estrone, estradiol, cortisol and progesterone via enzymes in the mitochondria and endoplasmic reticulum.

NUTRITIONAL AND ENVIRONMENTAL FACTORS IMPACT STEROIDOGENESIS

The steroid hormones produced from cholesterol determine the fate of the cell.  It will determine whether the cell will continue to grow or whether cell death should be induced.  Steroid hormones produced by the cell will also influence the cells inflammation response to circulating immune cells.

Given the role of the mitochondria in the consumption of oxygen and the regulation of cell death, any alterations in mitochondrial function will contribute to the progress of hair loss.  Mitochondria function can be disturbed by a number of factors including anemia, high glucose concentrations, cigarette smoke, pharmaceutical drugs, genetic abnormalities and alcohol.

The endoplasmic reticulum produces a larger number of enzymes responsible for steroid production in keratin cells, it also produces a small amount of cholesterol from circulating cholesterol precursors.  Endoplasmic reticulum can be stressed by high levels of cholesterol and low calcium levels.

A simplified approach to explaining steroidogenesis malfunction is to compare the keratin cells steroid machinery to a highway system.  Cholesterol as a precursor is travelling along a motorway with 4 lanes. Traffic flow is controlled by enzymes, a block at any junction (i.e, a specific decrease in one enzyme function), causes congestion on the motorway and traffic will spill into other lanes.  Eventually, traffic will accumulate and and try to find a way out through other junctions.

Dihydrotestorone (DHT) will be present in higher  percentage levels in the hair follicle in the hair follicle when disturbed metabolism leads to low free testosterone.  DHT can not be aromatised to estradiol, thus causing an imbalance that will lead to a reduction of growth phase and an increase of hair in telogen phase.  Eventually the terminal hairs will regress to vellus hair due to a reduction of keratinocyte differentiation.

The tight control of enzyme activity is essential for normal hair growth.  any malfunction including mutation, overproduction, underproduction or deletion of a single enzyme involved in the formation of androgens, progesterone, estrogens and cortisol can lead to an under or overproduction of these steroid hormones and lead to hair loss.

Flow chart of steroid hormones and their impact on hair growth

Steroid hormone synthesis is disturbed by factors such as alcohol intake or poor nutrition.  When external factors impact enzyme function this will lead to an increase in steroid hormones that negatively effect the hair growth cycle.

MINERALS, COFACTORS AND COENZYMES SUPPORT STEROID HORMONES NEEDED FOR HAIR GROWTH

A number of factors contribute to appropriate formation of the correct production of steroid hormones.  Some enzymes need additional components known as cofactors and coenzymes to show full activity.  Cofactors serve many purposes such as active site stabilisation.  Coenzymes are small molecules that are bound to an enzyme and transport chemical groups from one enzyme to another.

Examples include NADH, NADPH and ATP, other coenzymes such as thiamine pyrophosphate and tetrahydrofolate are derived from B complex vitamins thiamine and folate  An essential consideration for maintaining steroidogenesis in the keratin cells that make up the hair fibre is maintaining coenzyme and cofactor concentration.

Cofactors and coenzymes that are particularly important include:

Zinc is important for the function of hydroxysteroid dehydrogenase that convert androstenediol, dehydroepiandrosterone and androstenedione to testosterone.  Zinc has also been shown to work similarly to Finasteride in that it is able to reduce the activity of 5-alpha reductase resulting in inhbited DHT production.  Clinical trials have demonstrated that zinc levels also inhibit the production of cortisol and increase the activity of aromatase for the increase of estradiol production.

Iron is required for heme formation, an essential component of enzymes from the cytochrome P450 enzymes needed for the introduction of cholesterol into the mitochondria for the initiation of steroid hormone synthesis.  Heme acts as an essential cofactor and increases enzyme catalysis when present.

Sulphur is required for the formation of iron-sulphur proteins called ferredoxins.  Ferredoxins are required for the cholesterol side chain cleavage enzyme which catalysis the first step in cholesterol metabolism.

Thiamine pyrophosphate is a cofactor that plays an essential role in cholesterol metabolism.

Maintaining adequate levels of zinc, iron, sulphur and thiamine will support the production of the necessary steroid hormone in keratin cells.

Flow chart of steroid hormones and their impact on hair growth

Minerals, coenzymes and cofactors support steroidogenesis and hair growth.  A number of nutritional factors are neccessary for the production of the steroid hormones that are required for hair growth.

BALANCING STEROID HORMONES FOR HAIR GROWTH

Human hair follicles have their own reserve of sex steroid-metabolising and synthesising enzymes.  This accounts for the lack of abnormal testosterone or estrogen in blood tests in most women experiencing female pattern hair loss (androgenic alopecia).

Estrogens and anti-androgen therapies are generally used as topical treatment when hair growth is reduced. Studies have reported an increased anagen and decreased telogen rate after treatment with estrogens, compared with a placebo [10].  For the treatment of androgenenic alopecia in women, solutions containing estradiol benzoate, estradiol valerate, or 17α-estradiol have a high success rate when testosterone levels are manipulated pharmacologically or with nutritional therapy.

The best way to balance your steroid hormones is to exercise regularly, reduce alcohol intake and lower stress levels.  It is important to address any irregular eating habits and ensure you eat breakfast everyday as cortisol peaks in the morning.

Some women find nutritional therapy very helpful when nutritional deficiencies lower steroidogenesis potential.

Nutritional factors that may impact steroid hormones production include low iron, low zinc, low vitamin D and high blood sugar.

Blood tests can also help pinpoint any systemic irregularities with steroid hormone synthesis, but cannot determine the level of steroid production in the hair follicle.

REFERENCES

  1. Castela, M., Linay, F., Roy, E., Moguelet, P., Xu, J., Holzenberger, M., Khosrotehrani, K. and Aractingi, S., 2017. Igf1r signalling acts on the anagen‐to‐catagen transition in the hair cycle. Experimental dermatology, 26(9), pp.785-791.
  2. Urano, R., Sakabe, K., Seiki, K. and Ohkido, M., 1995. Female sex hormone stimulates cultured human keratinocyte proliferation and its RNA-and protein-synthetic activities. Journal of dermatological science, 9(3), pp.176-184.
  3. Dean, H.J. and Winter, J.S.D., 1984. The effect of five synthetic progestational compounds on 5α-reductase activity in genital skin fibroblast monolayers. Steroids, 43(1), pp.13-24.
  4. Herrera, A.Y., Nielsen, S.E. and Mather, M., 2016. Stress-induced increases in progesterone and cortisol in naturally cycling women. Neurobiology of Stress, 3, pp.96-104.
  5. Shahrad, P. and Marks, R., 1977. A pharmacological effect of oestrone on human epidermis. British Journal of Dermatology, 97(4), pp.383-386.
  6. Levin, E.R., 2003. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Molecular endocrinology, 17(3), pp.309-317.
  7. Munive, V., Santi, A. and Torres-Aleman, I., 2016. A concerted action of estradiol and insulin like growth factor I underlies sex differences in mood regulation by exercise. Scientific reports, 6(1), pp.1-10.
  8. Brzozowski AM, Pike ACW, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson JÅ, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–758.
  9. Thom, E., 2016. Stress and the Hair Growth Cycle: Cortisol-Induced Hair Growth Disruption. Journal of drugs in dermatology: JDD, 15(8), pp.1001-1004.
  10. Eohnemus U, Uenalan M, Inzunza J, Gustafsson JA, Paus R. The hair follicle as an estrogen target and source. Endocrine reviews. 2006 Oct 1;27(6):677-706.

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