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Androgenetic Alopecia in Women

      Androgenetic alopecia (AGA), also known in women as female pattern hair loss, is caused by androgens in genetically susceptible women and men. The thinning begins between ages 12 and 40 years, the inheritance pattern is polygenic, and the incidence is the same as in men. In susceptible hair follicles, dihydrotestosterone binds to the androgen receptor, and the hormone-receptor complex activates the genes responsible for the gradual transformation of large terminal follicles to miniaturized follicles. Both young women and young men with AGA have higher levels of 5α reductase and androgen receptor in frontal hair follicles compared to occipital follicles. At the same time, young women have much higher levels of cytochrome p-450 aromatase in frontal follicles than men who have minimal aromatase, and women have even higher aromatase levels in occipital follicles. The diagnosis of AGA in women is supported by early age of onset, the pattern of increased thinning over the frontal/parietal scalp with greater density over the occipital scalp, retention of the frontal hairline, and the presence of miniaturized hairs. Most women with AGA have normal menses and pregnancies. Extensive hormonal testing is usually not needed unless symptoms and signs of androgen excess are present such as hirsutism, severe unresponsive cystic acne, virilization, or galactorrhea. Topical minoxidil solution is the only drug available for promoting hair growth in women with AGA. Efficacy has been shown in double-blind studies using hair counts and hair weight.

      Keywords

      Abbreviations:

      AGA
      Androgenetic alopecia
      CTE
      Chronic telogen effluvium
      Androgenetic alopecia (AGA), also known in women as female pattern hair loss, is a common and distressing cause of hair loss in women and men. In spite of its prevalence, many clinicians and clinical investigators have difficulty making the diagnosis in women. The hair thinning begins between the ages of 12 and 40 years in both sexes (
      • Hamilton J.B.
      Patterned loss of hair in man: Types and incidence.
      ;
      • Trancik R.J.
      • Spindler J.R.
      • Cuddihy R.V.
      • et al.
      Clinician survey evaluating monovidil topical solution in the treatment of androgenetic alopecia in patients under 18 years of age.
      ;
      Trancik RJ, Spindler JR, Cuddihy RV, Doren P: Minoxidil topical solution in the treatment of androgenetic alopecia in patients under 18 years of age. Poster presentation at the 3rd Intercontinental Meeting of Hair Research Societies; June 13–15, 2001, Tokyo, Japan.
      ) and approximately half the population expresses this trait to some degree before the age of 50 years (
      • Venning V.A.
      • Dawber R.P.R.
      Patterned androgenic alopecia in women.
      ;
      • Olsen E.A.
      Androgenetic alopecia.
      ). Inheritance pattern of AGA is polygenic (complex inheritance) and is inherited from either or both sides of the family (
      • Kuster W.
      • Happle R.
      The inheritance of common baldness: Two B or not two B?.
      ;
      • Sreekumar G.P.
      • Pardinas J.
      • Wong C.Q.
      • et al.
      Serum androgens and genetic linkage. analysis in early onset androgenetic alopecia.
      ).
      1Trancik RJ, Spindler JR, Cuddihy RV, Doren P: Minoxidil topical solution in the treatment of androgenetic alopecia in patients under 18 years of age. Poster presentation at the 3rd Intercontinental Meeting of Hair Research Societies; June 13–15, 2001, Tokyo, Japan.

      Pathophysiology

      AGA is induced by androgens in genetically susceptible women and men. Hair follicles of women and men with AGA have increased 5α-reductase activity and increased levels of dihydrotestosterone (DHT) (
      • Schweikert H.U.
      • Wilson J.D.
      Regulation of human hair growth by steroid hormones. I. Testosterone metabolism in isolated hairs.
      ;
      • Dallob A.L.
      • Sadick N.S.
      • Unger W.
      • et al.
      The effect of finasteride, a 5α-reductase. inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness.
      ;
      • Kaufman K.
      Androgen metabolism as it affects hair growth in androgenetic alopecia.
      ;
      • Sawaya M.E.
      • Price V.H.
      Different levels of 5α-reductase type I and II, aromatase, and. androgen receptor in hair follicles of women and men with androgenetic alopecia.
      ). DHT, which is formed by the peripheral conversion of testosterone by 5α-reductase, is thought to be responsible for the characteristic miniaturization of scalp hair follicles in AGA. In genetically susceptible hair follicles, DHT binds to the androgen receptor, and the hormone-receptor complex then activates the genes responsible for the gradual transformation of large, terminal follicles to small, miniaturized follicles (
      • Price V.H.
      Testosterone metabolism in the skin. A review of its function in androgenetic alopecia, acne vulgaris, and idiopathic hirsutism including recent studies with antiandrogens.
      ;
      • Uno H.
      • Cappas A.
      • Schlagel C.
      Cyclic dynamics of hair follicles and the effect of minoxidil on the bald scalps of the stumptailed macaques.
      ;
      • Messenger A.G.
      The control of hair growth: An overview.
      ;
      • Kaufman K.
      Androgen metabolism as it affects hair growth in androgenetic alopecia.
      ). Over successive hair cycles in AGA, the duration of anagen shortens and matrix size decreases, resulting in smaller follicles that produce shorter, finer, miniaturized hairs that cover the scalp less and less well. These miniaturized hairs of various lengths and diameters are the hallmark of AGA (
      • Frieden I.J.
      • Price V.H.
      Androgenetic alopecia.
      ;
      • Whiting D.A.
      Diagnostic and predictive value of horizontal sections of scalp biopsy. Specimens in male pattern androgenetic alopecia.
      ;
      • Olsen E.A.
      Androgenetic alopecia.
      ). The number of follicles per unit area, however, remains the same (
      • Whiting D.A.
      Diagnostic and predictive value of horizontal sections of scalp biopsy. Specimens in male pattern androgenetic alopecia.
      ).
      In women with AGA, the extent of hair loss is generally less than in men. It has been assumed that the hormonal basis for AGA is similar in women as in men although earlier studies did not include female subjects (
      • Price V.H.
      Testosterone metabolism in the skin. A review of its function in androgenetic alopecia, acne vulgaris, and idiopathic hirsutism including recent studies with antiandrogens.
      ;
      • Frieden I.J.
      • Price V.H.
      Androgenetic alopecia.
      ). In order to compare and clarify the underlying hormonal basis, a study was conducted in 12 young women (ages 14–33) and 12 young men (ages 18–30) with AGA (
      • Sawaya M.E.
      • Price V.H.
      Different levels of 5α-reductase type I and II, aromatase, and. androgen receptor in hair follicles of women and men with androgenetic alopecia.
      ). Androgen receptor, type I and type II 5α reductase, and cytochrome p-450 aromatase, were measured in hair follicles from scalp biopsies of these young subjects. Both young women and young men had higher levels of type I and type II 5α-reductase and androgen receptors in frontal hair follicles compared to occipital hair follicles; however, the levels in women were approximately half the levels in men (
      • Sawaya M.E.
      • Price V.H.
      Different levels of 5α-reductase type I and II, aromatase, and. androgen receptor in hair follicles of women and men with androgenetic alopecia.
      ). At the same time, young women had much higher levels of cytochrome p-450 aromatase in frontal follicles than men who had minimal aromatase, and women had even higher aromatase levels in occipital follicles. The differences in aromatase, which is capable of converting testosterone to estradiol, are particularly notable. The findings of this study suggest that the milder expression of AGA in women may in part be the result of lower levels of 5α reductase and androgen receptors in frontal follicles of women compared to levels in men; additionally, higher levels of aromatase in women may result in increased local formation of estradiol from testosterone, and less formation of 5α-reduced products such as DHT.
      Although hair thinning in women with AGA may be diffuse, nevertheless there is a pattern in women as there is in men, with the frontal and parietal scalp generally showing the greatest thinning and the occipital scalp showing the greatest hair density. From a clinical perspective, hair follicles of the occipital scalp behave differently from frontal and parietal scalp follicles: in AGA, occipital follicles are typically spared by the hormonal influences; and in alopecia areata, occipital follicles affected by the ophiasis pattern are typically more resistant to regrowth. These different behaviors of occipital and frontal/parietal follicles may result from the embryological derivation of the dermis in these two regions. It is known from avian embryology that the dermis of the frontal/parietal scalp is of neural crest origin, whereas the dermis of the occipital scalp is of mesodermal origin (
      • Ziller C.
      Pattern formation in neural crest derivatives.
      ). Regulatory genes, growth factors, and cell–cell interactions may influence hair follicles differently in the two regions based on their dermal origin, and this may explain the patterning that is frequently seen in scalp hair loss.

      Clinical Features of Aga in Women

      Women first notice hair thinning over the frontal area, and gradually the scalp becomes more visible (Figure 1). Over time the thinning, although it is often diffuse and may involve most of the scalp, nevertheless is usually patterned with most marked thinning over the frontal and parietal scalp, and with greater density over the occipital scalp. Women typically retain a rim of hair along the frontal hairline (Figure 1, Figure 2), even when the scalp is visible behind the hairline (
      • Ludwig E.
      Classification of the types of androgenetic alopecia (common baldness) occuring in female sex.
      ). Miniaturized hairs, the shorter and finer hairs of various lengths and diameters, are the hallmark of AGA (
      • Frieden I.J.
      • Price V.H.
      Androgenetic alopecia.
      ;
      • Whiting D.A.
      Diagnostic and predictive value of horizontal sections of scalp biopsy. Specimens in male pattern androgenetic alopecia.
      ) and result from the shortening of anagen phase and reduction in matrix size. Increased spacing between hairs makes the central part appear wider over the frontal scalp compared to the occipital scalp.
      Figure thumbnail gr1
      Figure 1AGA in a 29-year-old woman. Note thinning in the frontal/parietal region and sparing of the frontal hairline.
      Figure thumbnail gr2
      Figure 2Drawing of scalp regions. The frontal hairline refers to the rim of hair at the anterior margin of the frontal scalp.
      Less commonly, hair density appears normal proximally, but the hair no longer grows to its previous length, resulting in wispy distal ends (Figure 3); in this case, the shortening of anagen progresses more rapidly than matrix reduction. The patient may note that her ‘pony tail’ is smaller in girth and the hair is cut to shorter lengths in order to give a fuller appearance. Rarely, advanced thinning occurs with loss of the frontal hairline, but this is invariably associated with markedly elevated circulating androgens (
      • Ludwig E.
      Classification of the types of androgenetic alopecia (common baldness) occuring in female sex.
      ).
      Figure thumbnail gr3
      Figure 3AGA showing the less common presentation of full proximal hair density and wispy distal density; in these cases, the shortening of anagen progresses more rapidly than matrix reduction.
      Androgenetic alopecia in women is not usually accompanied by increased shedding. However, in some instances, an episode of telogen effluvium following childbirth, major illness or other causes may uncover a latent predisposition to AGA. Sometimes the number of hairs shed is misleading in women who seldom comb their hair after shampooing, leave it to dry naturally; and later when their hands ‘comb’ through the hair many loose hairs appear on the fingers.

      Laboratory Evaluation

      Extensive hormonal testing is usually not needed unless symptoms and signs of androgen excess are present. Most women with AGA have normal menses and pregnancies. Women who require endocrine evaluation are identified in the office with careful inquiry regarding menses, history of infertility, and the presence of hirsutism, severe unresponsive cystic acne, virilization, or galactorrhoea. If any one of these is present, laboratory measurement of serum total or free tesosterone, dehydroepiandrosterone sulfate and prolactin are indicated. Other common causes of hair loss are ruled out by measurement of serum thyrotropin, iron studies including serum iron and ferritin, complete blood count, and RPR.

      Differential Diagnosis

      The diagnosis of AGA in women is supported by early age of onset, the pattern of increased hair thinning over the frontal/parietal scalp with greater hair density over the occipital scalp, retention of the frontal hairline, and the presence of miniaturized hairs.
      When these features are present, the diagnosis is not problematic. However, AGA is common and other causes of hair loss may coexist and need to be recognized or excluded. Scalp biopsy usually solves the differential diagnosis. Biopsies are taken from active, representative sites, and horizontal sectioning is preferred because of the larger number of follicular structures that can be studied (
      • Headington J.T.
      Transverse microscopic anatomy of the human scalp.
      ;
      • Whiting D.A.
      The value of horizontal sections of scalp biopsies.
      ). In AGA, biopsy shows increased numbers of miniaturized hairs, abundant and even enlarged sebaceous glands, and minimal inflammation though the latter is controversial (
      • Lattanand A.
      • Johnson W.C.
      Male pattern alopecia. A histopathologic and histochemical study.
      ;
      • Whiting D.A.
      Male pattern hair loss: Current understanding.
      ).
      Chronic telogen effluvium (CTE) may present a difficult differential diagnosis even though the features of CTE seem distinct. In CTE, women in the fourth to sixth decade, with above average hair density, describe sudden onset of marked shedding from the entire scalp. Hair pull test may extract increased numbers of telogen hairs easily, yet scalp hair density appears normal or minimally decreased even though the shedding may be prolonged. Miniaturized hairs are not seen. Horizontal sections of a scalp biopsy distinguish CTE from AGA: the ratio of terminal hairs to miniaturized hairs in CTE is 9: 1, in AGA is 2: 1, and in a normal scalp is 7: 1 (
      • Whiting D.A.
      Chronic telogen effluvium: Increased scalp hair shedding in middle aged women.
      ). Acute telogen effluvium may occur in a woman with long-standing AGA or unmask latent AGA. A careful history will usually identify the cause of profuse hair shedding such as high fever, severe dietary protein deficiency, or chronic blood loss as in women with prolonged heavy menses. Relevant laboratory tests are noted above. Categories of drugs that may cause hair loss include anticancer drugs, anticoagulants, anticonvulsants, antithyroid drugs, beta blockers, tricyclic antidepressants, and progestins with androgenic effects (
      • Mirmirani P.
      • Price V.H.
      Top 10 misconceptions about androgenetic alopecia in women.
      ). Both patchy and diffuse alopecia areata may coexist with AGA and sometimes present a challenging differential which is resolved by a scalp biopsy showing a peribulbar lymphocytic infiltrate around anagen hair bulbs. An adult with loose anagen syndrome has a history of decreased hair density since early childhood, and the pull test is strongly positive (
      • Price V.H.
      • Gummer C.L.
      Loose anagen syndrome.
      ). Low power microscopy of the easily extracted hairs shows misshapen anagen bulbs, a “ruffled” cuticle just distal to the bulb, and absent inner root sheath.

      Medical Treatment of Aga in Women

      Topical minoxidil solution is the only approved drug available for promoting hair growth in women with AGA (
      • Price V.H.
      Treatment of Hair Loss.
      ). Efficacy has been shown in double-blind, placebo-controlled studies using hair counts and hair weight as the primary end points (
      • Price V.H.
      Treatment of Hair Loss.
      ). Minoxidil-treated women had significantly higher hair counts and an increase in hair weight compared to women who received placebo. A double-blind study of women ages 22–41 years using 2% topical minoxidil solution showed a significant increase over placebo in mean change in hair weight at 16 weeks (
      • Price V.H.
      • Menefee E.
      Quantitative estimation of hair growth I. androgenetic alopecia in women: effect of minoxidil.
      ) (Figure 4). It should be noted that clinical perception of improved scalp coverage may take longer, up to 6–12 months, until hair length and mass are increased sufficiently (Figure 5). Minoxidil solution must be applied twice daily to a dry scalp.
      Figure thumbnail gr4
      Figure 4Mean change in hair weight in women using 2% topical minoxidil solution twice daily for 32 weeks.
      Figure thumbnail gr5
      Figure 5AGA in a 33-year-old woman before (top) and after (bottom) applying 2% topical minoxidil solution for 12 months.
      Finasteride is a competitive inhibitor of type II 5α-reductase, and is contraindicated in women who are or may become pregnant, because 5α-reductase inhibitors may cause abnormalities of the external genitalia of a male fetus. Finasteride was not effective in postmenopausal women in a placebo-controlled study (
      • Price V.H.
      • Roberts J.L.
      • Hordinsky M.
      • et al.
      Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia.
      ).
      Women are devastated by their thinning hair (
      • Cash T.F.
      • Price V.H.
      • Savin R.C.
      Psychological effects of androgenetic alopecia on women. Comparisons with balding men and with female control subjects.
      ), and need thoughtful evaluation and management, as well as reassurance that they may safely use hair cosmetics to make their hair appear fuller.

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        Different levels of 5α-reductase type I and II, aromatase, and. androgen receptor in hair follicles of women and men with androgenetic alopecia.
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        Diagnostic and predictive value of horizontal sections of scalp biopsy. Specimens in male pattern androgenetic alopecia.
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