The paradoxical effects of androgens on human hair growth

6.3.1 Human hair growth before and after puberty

In utero the humanbodyiscoveredwith quite long, colourless lanugo hairs. These are shed before birth and at birth, or shortly after, babies normally exhibit pigmented, quite thick protective hairs on the eyebrows and eyelashes and variable amounts on the scalp; by the age of three or four the scalp hair is usually quite well developed, though it will not yet have reached its maximum length. These readily visible pigmented hairs are known as terminal hairs and are formed by large deep terminal follicles (Fig. 6.2). This emphasises that terminal hair growth on the scalp, eyelashes and eyebrows is not androgen-dependent. The rest of the body is often considered hairless but, except for the glabrous skin of the lips, palms and sole of the feet, is normally covered with fine, short almost colourless vellus hairs produced by small short vellus follicles (Fig. 6.2). The molecular mechanisms involved in the distribution and formation of the different types of follicles during embryogenesis are not

Vellus Hair

b NON-BALDING SCALP: Androgen independent

c SCALP: Androgen-sensitive

Terminal follicle long, thick pigmented

ANDROGENS

long, thick pigmented

ANDROGENS

short, fine unpigmented hair -

Vellus follicle

Terminal follicle

Vellus follicle

Fig. 6.2 Summary of various paradoxical effects of androgens on hair follicles

Androgens have no effects on some follicles (lower diagram), stimulate the gradual transformation of vellus follicles to terminal ones producing large pigmented hairs in many regions (upper diagram), while causing the reverse effect on the scalp in genetically-disposed individuals (middle diagram). The hair follicle undergoes several hair cycles (see Figure 6.1) between producing vellus and terminal hairs (modified from Randall 1996).

clear, but secreted signalling factors such as sonic hedgehog, Wnt and growth factors (e.g. the EGF and FGF families), nuclear factors including various homeobox genes and others such as Hairless and Tabby plus transmembrane molecules and extracellular matrix molecules have all been implicated (Wu-Kuo and Chuong 2000).

One of the first signs of puberty is the gradual appearance of a few larger and more pigmented intermediate hairs, firstly in the pubic region and later in the axillae. These are replaced by longer anddarker hairs (Fig. 6.2) and the area spreads. In boys, similar changes occur gradually on the face starting above the mouth and on the central chin, eventually generally spreading over the lower part of the face and parts of the neck, readily distinguishing the adult male (Marshall and Tanner 1969; 1970). The adult man's pubic hair distribution also differs from the woman, extending in a diamond shape up to the navel in contrast to the woman's inverted triangle. Terminal hair on the chest and sometimes the back is also normally restricted to men, though both sexes may also develop intermediate terminal hairs on their arms and legs, with terminal hairs normally restricted to the lower limbs in women (Fig. 6.3). In all areas the responses are gradual, often taking many years. Beard weight increases dramatically during puberty but continues to rise until the mid-thirties (Hamilton 1958), while terminal hair growth on the chest and in the external ear canal may first be seen many years after puberty (Hamilton 1946).

The amount ofbody hair is very variable and differs both between families within one race and between races, with Caucasians generally exhibiting more than Asians (Hamilton 1958). This implies a genetically-determined response to circulating triggers. The responses of the follicles themselves also vary, with female hormone levels being sufficient to stimulate terminal hair growth in the pubis and axillae, but male hormones being required for other areas, such as the beard and chest. Beard hair growth also remains high, right into a man's seventies, while axillary growth is maximal in the mid-twenties and falls quite rapidly then in both sexes (Fig. 6.4) (Hamilton 1958). This is a paradoxically different response in the two areas to apparent stimulation by the same hormones.

During early puberty the frontal hair line is usually straight across the top of the forehead. With increasing age there is a progressive regression of the frontal hair line in a prescribed manner (described below 6.3.3.1) accompanied by progressive thinning of terminal hair on the vertex. This is characterised by a gradual inhibition of terminal follicles to smaller vellus follicles (Fig. 6.2) with the length of anagen decreasing and that of telogen increasing. This is another example of a much more dramatic biological paradox. How does one hormone stimulate hair growth in many areas such as the face, have no effect in others e.g. eyelashes, while inhibiting follicles on the scalp? These contrasts are presumably due to differential gene expression within follicles from the various body sites. The intrinsic response of individual follicles is retained when follicles are transplanted to other skin sites

Normal Man Body

Normal Normal Normal Normal child woman man man with inherited body hair may body hair male pattern baldness increase after increases as normal male plus menopause with age gradual decrease in scalp hair

Hirsutism Pics
Androgen insufficiency syndromes

no androgen receptors

Child hair pattern only

XY,5a-reductase deficiency

Female hair distribution

Hirsutism

Male hair distribution

Female androgenetic alopecia gradual thinning on vertex -retention of frontal hairline

Fig. 6.3 Terminal hair distribution in people under differing endocrine conditions

Terminal hair with protective functions normally develops in children on the scalp, eyelashes and eyebrows. During, and after, puberty this is augmented by axillary and pubic hair in both sexes and beard, chest and greater body hair in men. In people with the appropriate genetic tendency, androgens may also stimulate hair loss from the scalp in a patterned manner causing androgenetic alopecia. None of this occurs without functional androgen receptors and only axillary and the lower pubic triangle hairs are formed in the absence of 5a-reductase type 2 (lower panel). Male pattern hair growth (hirsutism) may occur in women with circulating abnormalities of androgens or from idiopathic causes.

a Beard hair a Beard hair

b Axilliary hair

Age in years

Fig. 6.4 Paradoxically different patterns of hair growth in two androgen-dependent areas: the beard and the axilla

Both beard and axillary hair growth is stimulated by androgens during puberty in Caucasian (solid lines) and Japanese (dotted lines) men. However, while beard growth is maintained at high levels into old age in both races, axillary hair growth is maximal at 30 and decreases regularly to prepubertal levels. Reproduced from Randall 2000b showing data redrawn from Hamilton 1958.

Age in years

Fig. 6.4 Paradoxically different patterns of hair growth in two androgen-dependent areas: the beard and the axilla

Both beard and axillary hair growth is stimulated by androgens during puberty in Caucasian (solid lines) and Japanese (dotted lines) men. However, while beard growth is maintained at high levels into old age in both races, axillary hair growth is maximal at 30 and decreases regularly to prepubertal levels. Reproduced from Randall 2000b showing data redrawn from Hamilton 1958.

(Ebling and Johnson 1959); this is the basis of corrective hair follicle transplant surgery (Orentreich and Durr 1982).

6.3.2 Evidence for the role of androgens

Although androgens are the clearest regulators of human hair growth, unlike in most mammals (Ebling etal. 1991), various other circulating factors (reviewed in Randall 1994a) have an effect. These include adequate nutritional supplies, due to the follicles' high metabolic demands (Bradfield 1971), the hormones of pregnancy, which cause a prolonged anagen resulting in a synchronised shedding of a proportion of scalp hairs post-partum (Lynfield 1960), and lack of thyroid hormone which restricts hair growth (Jackson et al. 1972). Growth hormone is also necessary in combination with androgens for normal body hair development in boys (Zachmann and Prader 1970). There is a range of evidence supporting the importance of androgens which fits in well with the concept of much terminal hair growth being a secondary sexual characteristic. Terminal hair appearance in puberty parallels the rise in circulating androgen levels and occurs later in boys than girls (Marshall and Tanner 1969; 1970; Winter and Faiman 1972; 1973). Testosterone also stimulates beard growth in eunuchs and elderly men (Chieffi 1949) and increased beard growth noted by an isolated endocrinologist is ascribed to his rising androgens on anticipating his girlfriend's arrival (Anonymous 1970)! An extensive study in the USA also showed that castration before puberty prevented beard and axillary hair growth and after puberty reduced them (Hamilton 1951a; 1958). Nevertheless, the strongest evidence for the essential nature of androgens is the lack of anybody hair, even the female pubic and axillary pattern, or evidence of any male pattern baldness, in adult XY androgen insensitivity patients with absent or dysfunctional androgen receptors despite normal or raised circulating levels of androgens (see Chapter 3).

6.3.3 Androgen-dependent hair growth conditions

6.3.3.1 Androgenetic alopecia

A generalised loss of hair follicles from the scalp known as senescent balding has been reported in both sexes by the seventh or eighth decade (Courtois etal. 1995; Kligman 1988). This differs from the progressive baldness seen in androgenetic alopecia, also known as male pattern baldness, male pattern alopecia, common baldness or androgen-dependent alopecia. The connective tissue sheath left in the dermis when the follicle becomes miniaturisedduring androgenetic alopecia may become subject to chronic inflammation; this may prevent terminal hair regrowth in long-term baldness (Kligman 1988) although this is currently a matter of debate. Balding occurs in a precise pattern described by Hamilton (1951b), starting with regression of the frontal hairline in two wings and balding in the centre of the vertex. These areas gradually expand and coalesce, exposing large areas of scalp; generally the back and sides of the scalp retain terminal hair even in extreme cases (Fig. 6.3). Hamilton's scale was later modified by Norwood (1975) to includea wider range of patterns. The physiology and pathophysiology of androgenetic alopecia is reviewed more fully in Randall 2000a and 2001.

Male pattern baldness is androgen-dependent, since it does not occur in castrates, unless they are given testosterone (Hamilton 1942), nor in XY individuals with androgen insensitivity due to non-functional androgen receptors (Hiort this volume, Chapter 3). There is also a marked inherited tendency to develop it (Hamilton 1942), though the genetics are not yet established. Known dimorphic and polymorphic markers within the androgen receptor gene were recently investigated in Caucasian men (Ellis etal. 2001). The Stu I restriction fragment length polymorphism (RFLP) in exon 1 was present in 98% of 54 young balding men and 92% of392 older balding men, but was also found in 77% of their older, non-balding controls. When two triplet repeat polymorphisms were examined the distribution of neither short or long single triplet repeats of CAG or GAC differed significantly, but the incidence of short/short polymorphic CAG/GGC haplotypes were significantly higher (50% compared to 30%) in balding subjects and short/long were lower (7% rather than 22%) though no significance was stated in the paper. Interestingly, analysis of Spanish girls with precocious puberty i.e. appearance of pubic hair before 8 years of age showed the mean number of CAG repeats was shorter than controls (Ibanez etal. 2003). Shorter triplet repeat lengths have also been associated with another common androgen-dependent condition, prostate cancer (Stanford etal. 1997). Whether this has functional significance such as an increased androgen sensitivity or simply reflects linkage disequilibrium with a causative mutation is not clear. However, when the binding capacity for a range of steroids was compared between androgen receptors from balding and non-balding follicle dermal papilla cells no differences were detected (Hibberts etal. 1998).

The incidence of androgenetic alopecia in Caucasians is high with estimates varying widely but progression to stage type II being detected in 95% (Hamilton 1951b). Other races exhibit it to a lesser extent (Hamilton 1951b; Setty 1970) and it is also seen in other primates, being well studied in the stump-tailed macaque. This suggests a natural progression of a secondary sexual characteristic rather than the malfunction of a disease. Marked androgenetic alopecia would obviously highlight the surviving older man as a leader like the silver back ofthe chief male gorilla and the larger antlers of the mature deer stags. Others have speculated that the flushed bald skin would look aggressive to an opponent (Goodhart 1960) or mean there was less hair for the opposition to pull (Ebling 1985), giving the bald man important advantages. The lower incidence of androgenetic alopecia amongst men from African races (Setty 1970) suggests that any advantages did not outweigh the evolutionary survival advantages of the hairs' protection of the scalp from the hot tropical sun.

In the current youth-orientated culture of industrialised societies the association of increasing hair loss with age combined with the major role of hair in human communication means that androgenetic alopecia has strong negative connotations. It often causes psychological distress and reduction in the quality of life, even though it is not life-threatening or physically painful, in both men (Cash 1992; Franzoi etal. 1999; Girman etal. 1998;Maffei etal. 1990; Terry and Davis 1976; Wells etal. 1995) andwomen (Cash 1993; van der Dank etal. 1991). Other people perceive men with visible hair loss as older, less physically and socially attractive, weaker and duller. In parallel, people with androgenetic alopecia have a poor self-image, feel older and lacking in self-confidence, even those who seem accepting of their condition and have never sought treatment (Girman etal. 1998). Male pattern baldness primarily causes concern amongst those who develop marked loss before their forties and early balding has been linked to myocardial infarction (Lesko etal. 1993). Whether this indicates a dual end-organ sensitivity or reflects the psychological stress early balding induces in the youth-orientated American culture is unknown. No relationship between the incidence ofbalding and prostatic carcinoma was detected in men between fifty and seventy (Demark-Wahnefried et al. 1997).

Androgenetic alopecia has also been described in women, but the pattern of expression is normally different. Women generally do not show the frontal recession, but retain the frontal hairline and exhibit thinning on the vertex which may lead to balding (Ludwig 1977) (Fig. 6.3). Post-menopausal women may exhibit the masculine pattern (Venning and Dawber 1988). The progression of balding in women is normally slow and a full endocrinological investigation is recommended if a rapid onset is seen (Dawber and Van Neste 1995). Although female pattern hair loss is seen frequently in association with hyperandrogenism, other women frequently have no other symptoms of androgen abnormality. Therefore, there is some debate about whether androgen is essential for this hair loss in women (Birch etal. 2002) though this is still generally assumed. If, as occurs in men, the changes develop due to the genetically influenced, specific follicular responses within the scalp follicles themselves, it is not surprising that circulating androgen abnormalities are often absent.

6.3.3.2 Hirsutism

Hirsutism is the development of male pattern body hair growth in women. This also causes marked psychological distress because the person erroneously feels that they are changing sex. The extent of body hair growth which causes a problem varies and depends on the amount of normal body hair amongst her race or sub-group. Normally hirsutism would include terminal hair on the face, chest or back. Ferriman and Gallwey (1961) introduced a scale for grading hirsutism which is widely used, especially to monitor hirsutism progression with, or without, treatment.

Hirsutism is often associated with an endocrine abnormality of the adrenal or ovary causing raised androgens and is frequently associated with polycystic ovarian (PCO) syndrome. Some women have no obvious underlying disorder and are termed "idiopathic". The proportion of these is larger in older papers as modern methods increase the range of abnormalities that can be detected e.g. low sex hormone binding globulin. The assumption that idiopathic hirsutism is due to a greater sensitivity of the follicles to normal androgens is given credence by hirsutism occurring asymmetrically on only one side of a woman (Jenkins and Ash 1973).

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Responses

  • Mary
    Why nale and hair is increase in human body?
    2 years ago
  • Madihah Fesahaye
    Are eyebrows androgen dependent?
    9 months ago

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