adrenal androgenic female-pattern alopecia: sex hormones

Original Contr ibut ions

Adrenal androgenic female-pattern alopecia: sex hormones and the balding woman 1

James M. Kasick, M.D. Wilma F. Bergfeld, M.D. Willard D. Steck, M.D. Manjula K. Gupta, Ph.D.

Nineteen white women (age range, 18 -37 years) with a distinct pattern of d i f fuse alopecia, characterized by retention of the frontotemporal hairline and progressive loss of central scalp hair, were evaluated. The serum adrenal androgen dehydroepiandros-terone-sulfate (DHEAS) ranged from 2.2 to 5.8 fig/ml (mean, 3.9 ± 1 . 1 Mg/ml). The normal female range is 0.3 to 3.2 tig/ml (mean, 2.0 ± 0.7 fig/ml). All women had a normal total serum testosterone level. Of two women with elevated levels of serum prolactin, one had a pituitary adenoma as revealed by computed tomography. Apparently, DHEAS is hydrolyzed to dehydroepiandrosterone (DHEA) and subsequently converted to more potent androgens. In the hair follicle, DHEA will inhibit glucose-6-phosphate dehy-drogenase, a key enzyme of the pentose cycle that is essential for the synthesis of nucleic acids. T h e disruption of the growth of scalp hair may be due to this increased adrenal production as well as to the peripheral metabolism of DHEAS.

Index terms: Dehydroepiandrosterone-sulfate (DHEAS) • Hair loss • Hormones

Cleve Clin Q 50:111-122 , Summer 1983

T h e medical l i terature provides little assistance for the unders tanding and management of the balding woman. Counseling women with progressive alopecia using such terms as "diffuse hair loss of young women," "common baldness," and "male-pattern baldness" increases the pa-t ient 's anxiety and reflects the lack of scientific knowledge with regard to the pathogenesis of this condit ion. Most

1 Depar tments of Dermatology (J.M.K., w.F.B. , young women with chronic, diffuse, noncicatricial alopecia ^ S i c f o m X ^ are not properly evaluated or appropriately diagnosed. 1983; accepted March 1983. Particularly unfor tuna te is the woman who is advised that

111

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112 Cleveland Clinic Quarter ly Vol. 50, No. 2

this condit ion is male-pattern alopecia, which is genetically p r ede t e rmined and irreversible.

F rom Sep tember 1, 1981, to Sep tember 30, 1982, 578 women with nonscar r ing hair loss were seen for the first t ime in the Depar tmen t of Dermatology at the Cleveland Clinic. Of these, 105 women were diagnosed as having alopecia areata . For the others , a careful history was taken, and clinical and laboratory examinat ions were conduc ted to de t e rmine whe the r metabolic, endocr ine , connect ive tissue, o r o the r disorders were present . A distinct pa t tern of dif fuse central alopecia with re ten t ion of the f ron to t empora l hairl ine, not known to be associated with any specific d isorder , was observed repeatedly. A sim-ilar hair-loss pa t te rn was identif ied in the classi-fication of female androgene t ic alopecia by Ludwig1 as based on his observat ion of 468 pa-tients, but a review by Rook and Dawber 2 did not ment ion the association of any endocr ine abnormal i t ies with this type of alopecia.

O u r similar observations may be classified as follows:

Grade 1. T h i n n i n g of the central scalp hair with re tent ion of the f ron to t empora l hairl ine was percept ible (Figs. 1-3).

Grade 2. P r o n o u n c e d th inning of the central scalp hair and onset of hair loss f r o m the parietal and occipital scalp were noted (Figs. 4, 5).

Grade 3. Full baldness (few sparse hairs) of the central scalp and progressive hair loss f r o m the parietal and occipital scalp were apparen t .

Ludwig1 suggested that a relat ionship existed between the deg ree of androgen ic stimulation a n d the type of androgene t ic alopecia that devel-ops in genetically predisposed women. H e be-lieved that modera te ly increased levels of circu-lating androgens correla te with the female type of d i f fuse alopecia, whereas the male type of baldness with deep f ron to t empora l recession de-velops in women with tes tosterone levels compa-rable to those of normal men. T o de te rmine the validity of this concept , the androgen ic h o r m o n e s of 19 white women with grades 1 and 2 female-pa t t e rn alopecia were studied.

M e t h o d s Nine teen women had distinct, d i f fuse central

scalp alopecia with re tent ion of the f ron to t em-poral hairline. Based on clinical signs of and rogen stimulation, this g roup was divided into subgroups of 8 women with alopecia only and 11 women who had alopecia associated with hirsu-tism or acne. Simultaneous de te rmina t ion of total

Figu re 1. G r a d e 1 adrena l and rogen i c female-pat tern alopecia with percept ible th inn ing of the centra] scalp hair .

F igu re 2. Female-pat tern alopecia with re tent ion of the f ron-to temporal hairl ine.

serum tes tos terone (T), testosterone-estradiol b inding globulin (TeBG), and dehydroepiandros-terone-sulfate (DHEAS) was done by radioim-munoassay techniques (Table). As a control , the serum D H E A S levels were measured in 11 nor-mal women. In addi t ion, serum prolactin levels were de te rmined for 14 of the women studied. T h e T to T e B G rat io was calculated and named the "androgenic index" ( T / T e B G ) . A statistical analysis of the se rum D H E A S levels and the T / T e B G was p e r f o r m e d with Student ' s t test.

Resu l t s All 19 women had noted the progressive na-

tu re of their alopecia for at least one year be fo re obtaining a medical evaluation. T h r e e women had had their symptoms for 10 years be fo re seeking consultat ion. Al though the age r ange fo r the 19 patients was f r o m 18 to 37 years (mean, 25 years), the onset of symptoms occur red at a mean age of 23 years. No significant d i f fe rence in the mean age was apparen t between the



Summer 1983 Adrenal androgenic female-pattern alopecia 113

ÉKKV .

- ' ¡2 H& BMbIi.

wH . HrabSkaSr

% -T ̂ f j M^jky

Figu re 3. Progressive thinning of centra l scalp hair in g r ade 1 female-pat tern alopecia.

F igu re 4. G r a d e 2 androgenic alopecia with p r o n o u n c e d thin-ning of central scalp hair a n d onset of hair loss f r o m the parietal scalp.

subgroup with alopecia only and those with alo-pecia, hirsutism, and acne.

T h e serum DHEAS levels ranged f rom 2.2 to 5.8 ng/m\ (mean, 3.9 ± 1 . 1 /ug/ml); the normal female values range from 0.3 to 3.2 fig/ml. For those with alopecia only, the range was 2.2 to 5.4 Mg/ml (mean, 3.6 ± 0.9 ¡ig/mX). For those with alopecia, hirsutism, and acne, the range was 2.3 to 5.8 ng /n i l (mean, 4.2 ± 1.1 /zg/ml). T h e 11 normal women had a mean serum DHEAS level of 2.0 ± 0.7 /zg/ml. Therefore , the 19 women with alopecia had significant elevations of serum DHEAS (p < 0.001). No significant difference in the degree of elevation of serum DHEAS be-tween the 8 women with alopecia alone and the

Figu re 5. Scalp hair pluck, demons t ra t -ing thin and normal hair shaft d iameters in adrenal and rogen ic female-pat tern alopecia.

1 1 women with other signs of androgenic stimu-lation was noted.

For the 19 women with alopecia, T ranged from 45 to 147 n g / d l ; the normal female values range f rom 30 to 170 n g / d l . T h e TeBG ranged f rom 0.5 to 2.9 /xg dihydrotestosterone (DHT%); the normal female range is 0.6 to 2.4 /xg D H T % . No significant abnormality of the T and the TeBG levels in the two subgroups was apparent . Nevertheless, when the T / T e B G ratio of those with alopecia (0.0445 ± 0.0214) was compared to the ratio of those with alopecia, hirsutism, and acne (0.0823 ± 0.0385) a significant difference was observed (p < 0.025). T h e T / T e B G ratio for normal women ranges f rom 0.014 to 0.068.

Table. Abbreviations 3 /3-HSD 3 /3-hydroxy-steroid dehydrogenase 5 o - D H T 5 a -d ihydro tes tos te rone 17or-HD 17 «-hydroxylase 17 /3-HSD 17 /3-hydroxy-steroid dehydrogenase o r

17 /3-hydroxy-steroid ox idoreductase i7-KS 17-ketosteroids 21 -HD 21-hydroxylase DH F.A dehvdt oep iandros t e rone DHF.AS dehydroep iandros te rone-su l fa te Free T u n b o u n d se rum tes tos terone G-6-PDH glucose-6-phosphate dehydrogenase T total se rum tes tos terone T e B G testosterone-estradiol b inding globulin T / T e B G androgen ic index



114 Cleveland Clinic Quarterly Vol. 50, No. 2

Total Uri nary 17-Ketosteroids

CORTISOL

CORTISONE-

ANDROSTENEDIONE

45%-90% Fractionated 17-KS

Dehydroepiandrosterone

Androsterone

Etiocholanolone

lO%-55% Fractionated 17-KS

Nonspecific Chromogens

Figure 6. H o r m o n e s c o n t r i b u t i n g to t h e total u r inary 17-KS.

T h e serum prolactin levels of 12 of the 14 women tested (mean, 9.7 n g / m l ) were within the normal range of 0.8 to 19.7 n g / m l (mean, 10.2 ± 4.7 ng /ml ) . T h e other 2 women had elevated levels of 37.4 n g / m l and 24.9 n g / m l ; one underwent computed tomography, which revealed a small pituitary adenoma of the right lobe.

Discussion T h e diffuse pattern of central scalp alopecia in

young healthy women can be recognized clini-cally, and should be differentiated f rom the male pat tern of f rontotemporal recession and vertex thinning.2 Previous reviews have not associated elevated androgen levels with this female pattern of alopecia.2 '3

Dehydroepiandrosterone Sulfate

DHEAS

Figure 7. Molecular s t r u c t u r e of the Ci 9 ad rena l a n d r o g e n D H E A S .

Measurement of adrenal androgens: Usually, when evaluating the androgenic activity of women, the urinary 17-ketosteroids (17-KS) are measured, since this has been the only test avail-able for determining androgen production. Un-fortunately, this evaluation is limited since it measures androgen metabolites. Migeon4 shows that the excretory levels of these metabolites and the circulating levels of active androgens do not always correlate well. T h e total urinary 17-KS measure the unconjugated and conjugated neu-tral C19 steroids with 17-ketone (Zimmerman re-action), but do not quantitatively evaluate biolog-ically active androgenic hormones. Also, only a fraction of the metabolites are excreted as uri-nary 17-KS. Maroulis et al5 demonstrated that urinary 17-KS determinations do not reliably identify patients with elevated serum androgens. T h e more potent androgens, testosterone and 5 a-dihydrotestosterone (5 a -DHT) , contributed less than 1% to the total 17-KS. T h e major 17-KS being measured by the Zimmerman reaction consist of dehydroepiandrosterone (DHEA), an-drostenedione, androsterone, and etiocholano-lone (Fig. 6). Of these, DHEAS, a steroid with 19 carbon atoms (Fig. 7) which characterizes the hormones with androgenic activity capable of stimulating male secondary sex characteristics, is the peripheral androgen in greatest concentra-tion. DHEAS is only mildly androgenic.6

T h e large pool of circulating DHEAS has a slow turnover rate and is not subject to diurnal varia-tion.7"9 Although circadian variations are evi-dent , serum DHEA concentrations due to a long half-life show less synchrony with corticol secre-




Peripheral Interconversions Cjg Steroids

OHEAS

11 DHEA

33HSD

Androstenedione

J7&HSD

17BHSD

Androstenediol

'mso Testosterone

Androstenedione

J J 176HSD

Androsterone

5aR

Dihydrotestosterone

I t Androstenediol

Figure 8. Per iphera l metabol i sm of the Ci 9 ad rena l a n d r o g e n s .

tion.10 T h e adrenal cortex contributes 80% of the serum DHEA and over 90% of the serum DHEAS." There fo re , serum DHEAS is a useful marker for adrenal androgen secretion and can be measured by commercially available radioim-munoassay techniques requiring only 0.1 ml.6

Metabolism of DHEAS: Although the serum contains about 2 /ug/ml of DHEAS and only about 3 n g / m l of DHEA,9 the quantity of serum DHEA exceeds that of the T by at least 400 times.12 T h e concentration of serum DHEAS begins to rise before puberty and augments se-bum secretion.13 14 In the sebaceous gland, 3/3-hydroxy-steroid dehydrogenase A4 :1 isomerase converts DHEA to androstenedione or testoster-one through 5-androstene~3/3, 17/3-diol.11 T h e rise of serum DHEAS associated with adrenarche is followed several years later by the appearance of pubic and axillary hair.16-1 ' However, with aging, the events of adrenarche reverse, with decreasing serum concentrations of DHEA and DHEAS.

Although the adrenocorticotropic hormone partially controls adrenal secretion of DHEA and DHEAS, suppression of the serum prolactin with bromocript ine produces a corresponding decrease in the serum concentrations of DHEAS.19"21 Glickman et al22 noted that of 21 women with hyperprolactinemia, 40% had an

androgenic abnormality. Of these, 43% had an elevated unbound serum testosterone (free T ) level, al though the T was comparable. Depressed TeBG and high scrum DHEAS levels were found with lesser frequency (in 19% compared to 21%). These authors postulated that prolactin may ex-ert multiple effects on steroid secretion and me-tabolism.

T h e metabolism of DHEAS to DHEA proceeds via hydrolysis.23 T h e ratio of serum DHEA to DHEAS in women less than 50 years of age is considerably higher than that of men.1 8 Zumoff and Bradlow24 repor ted that the conversion of DHEAS to DHEA has a greater effect in women than in men.

Serum DHEA, through hydrolysis of DHEAS, becomes an abundant precursor for a more po-tent androgen, androstenediol (androst-5-ene-3(8, l7/?-diol).6 T h e production of androstenediol f rom DHEA is dependent upon the activity of 17/3-hydroxysteroid dehydrogenase (17 /?-HSD).25 Fur ther metabolism of androstenediol by 3j8-hydroxysteroid dehydrogenase (3/3-HSD) forms testosterone. T h r o u g h 5a-reductase (5a-R) testosterone is converted to 5a-dihydrotestos-terone (5«-DHT). There fore , the peripheral me-tabolism of DHEAS appears to be dependent upon the rate of hydrolysis to DHEA and subse-quent conversion to more potent androgens by




the activity of 17/3-HSD. In normal human facial skin, where 17/3-oxidation activity of 17/3-HSD predominates over 17/3-reduction, the 17-oxo-steroids andros tanedione and andros te rone a r e the main products . 2 5 In normal axillary skin and , to a lesser degree , in pubic skin, where 17/?-reduct ion predominates , 5 a - D H T and o the r 17/?-hydroxysteroids are the major metabolites of DHEAS." ' T h e r e f o r e , a metabolic pathway exists in axillary and pubic skin to allow female serum androgen levels of DHEAS to stimulate hair growth.

Normal female scalp skin minimally metabo-lizes DHEA, primarily to the weak androgens andros tenedione , androstanedione, and andros-terone.2"1 T h o m a s and Oake 2 6 studied the metab-olism of 7 s H-dehydroepiandros te rone in skin re-moved f rom the linea alba of hirsute and normal women. Af te r fou r hours of incubation, between 13% and 25% of the D H E A was utilized in 5 normal women (mean, 19 ± (SE) 2.1%), and between 40% and 65% was utilized in 5 hirsute women (mean, 52 ± (SE) 4.0%). They no ted increased peripheral metabolism of D H E A th rough testosterone and 5 a - D H T which f o r m e d androstanediol in hirsute women. Tes tos te rone metabolism was similar in the skin of hirsute a n d normal women, which suggested that the in-creased activity of 3/3-HSD did not occur as a result of any increase in testosterone product ion . T h e r e f o r e , the peripheral metabolism of D H E A varies with the site of the skin as well as with the enzymatic activity of 17/3-HSD and 3/3-HSD (Fig.

.

Hirsutism and DHEAS: T h e clinical associa-tion of abnormal growth of facial hair, hirsutism, and elevated serum DHEAS levels has been ob-served.2 7 Lobo et al6 de te rmined the mean serum DHEAS levels in 41 nonhirsute women with reg-ular menstrual cycles and with normal prolactin levels (<20 n g / m l ) to be 1.78 ± 0.1 /tig/ml (SE) with a range of 0 .3 to 2.8 ¡xg/m\. In 52 hirsute women, of whom 49 had ol igomenorrhea and 3 had regular ovulatory cycles, the mean serum DHEAS level was 3.36 ± 1.12 / ig /ml (SE); 31 of the 52 women (59%) had serum DHEAS levels exceeding two s tandard deviations above the nor-mal mean (>2.8 ¿ig/ml). Hirsutism has previously been a t t r ibuted to o ther gynecologic endo-crinopathies such as polycystic ovary syndrome (PCO). In 23 of the 52 hirsute women studied by Lobo et al,28 P C O was considered, based upon certain strict diagnostic criteria. Eight of these

23 women had serum DHEAS levels above 2.8 jug/ml, which suggests that adrenal hyperfunc-tion is a component of PCO.

Roy et al29 hypothesized that PCO was due to increased secretion of androgens like D H E A and androstenedione; in 42 female Sprague-Dawley rats given DHEA, 10 m g / k g body-weight, sub-cutaneously, cystic changes were p roduced in the ovaries of most of the animals. T h e r e f o r e , adre-nal androgen hypersecretion of DHEA and DHEAS might be a causative factor in polycystic ovarian changes and subsequent hirsutism.

Kirschner et al30 studied the role of DHEAS and other potential Ci 9 steroid p rehormones of testosterone. In 20 women, all considered to have idiopathic hirsutism, the urinary 17-hydroxy-cor-ticosteroid (17-OHCS) and basal serum Cortisol concentrat ions were normal . In 5 of the 20 women, the urinary 17-KS concentrat ions were greater than 15 m g / d a y . In 12 of the hirsute women, the average serum DHEA values were approximately twice those obtained in 5 normal women. Of these 12, the peripheral concentra-tions of androstenediol were elevated twofold over those found in the normal women. Yet, approximately 5% of the serum DHEA was pe-ripherally metabolized to androstenediol and 3% metabolized to andros tenedione. Only 0.6% of the serum DHEA was eventually metabolized to testosterone, account ing for only 8% of the total testosterone product ion in these hirsute women. Thus , a marked increase of serum DHEA may result in elevated tissue and follicular levels of D H E A without significant metabolism to testos-terone.

Hair follicles and DHEAS: Dehydroepiandros-te rone influences the funct ion and metabolism of scalp hair follicles.31 T h e principal metabolites of DHEA in scalp follicles are (in o rder of magni-tude): androstenediol , 7-hydroxy-dehydroepian-drosterone, 7-keto-dehydroepiandrosterone, 4-androstenedione, and 5-androstanedione. Fa-zekas and Sandor 3 ' r epor ted that normal female occipital scalp follicles pe r fo rmed the same met-abolic conversions as nonbalding male occipital follicles. However, four principal metabolites were fo rmed f r o m testosterone in male scalp hair follicles: androstenedione, 5 a - D H T , 5a-andro-stanedione, and androsterone. 3 2 T h e conversion of andros tenedione into testosterone and 5 a-D H T was very limited. In two normal men, the principal metabolite of testosterone which affects the beard , scalp, and pubic hair follicles was




androstenedione. 3 2 T h e format ion of andro-stenedione f r o m testosterone was three times greater than f r o m DHEA incubated at compa-rable concentrat ions in the male scalp hair folli-cle.31 These f indings suggest that androstenedi-one may be significant in the regulation of nor-mal hair growth. This compound , like 5 a - D H T , actively stimulates amino acid uptake and protein synthesis in intact human scalp hair follicles in vitro.33

In women who normally have reduced levels of T as compared to normal men, the role of o ther androgens may significantly affect the growth and distribution of scalp and body hair. In women, the serum concentrat ion of D H E A is much grea ter than that of T . 1 2 Hair follicles fo rm 100 times more androstenediol and 10 times more 7-hydroxy-DHEA f r o m DHEA than does human skin incubated unde r similar conditions.3 2

T h e r e f o r e , the hair follicle, ra ther than the skin, seems to be the pr imary site for per ipheral me-tabolism of DHEA.

A marked reduct ion in the format ion of 5-androstenediol f rom D H E A (an average of about 9% of the control values) was measured in a study of the metabolism of hair follicles f r o m the f ron-tal scalp of two balding men.3 1 T h e results sug-gested a decrease in the funct ion of 17/3-HSD, which resulted in decreased format ion of 5-an-drostenediol . Fazekas and Sandor3 2 examined the effect of D H E A and 5-androstenediol upon the activity of human hair follicle glucose-6-phos-phate dehydrogenase (G-6-PDH). DHEA and epiandrosterone were the most effective inhibi-tors of human hair follicle G-6-PDH activity. Androstenediol , androstenedione, androstane-dione, andros terone , and 5 a - D H T had only mar-ginal effects. T h e r e f o r e , DHEA has a s t rong inhibitory effect on the activity of this impor tant hair follicle enzyme. Adachi et al34 r epor ted that the activity of G-6-PDH increases most dramati-cally dur ing the growing phase of the human scalp hair follicle. G-6-PDH is a key enzyme of the pentose cycle, which supplies building blocks for the synthesis of nucleic acids and is an impor-tant source of nicotinamide adenine dinucleotide phosphate (NADPH). T h e hair follicle concen-trations of D H E A may be significant in regulat-ing the activity of follicular G-6-PDH. Increased intracellular concentrat ions of DHEA may de-crease the activity of G-6-PDH, in terfer ing with the follicular pentose cycle and inhibiting hair growth.

T h e concentrat ion of f r ee D H E A in the hair follicle has not been repor ted . Physiologic serum concentrat ions of DHEA in normal women are 0 .15 to 0 .75 n g / d l . 8 At these concentrat ions the inhibition of the enzyme G-6-PDH may be 5% to 10%.32 T h e actual intrafollicular concentrat ion of DHEA may be much grea ter than the serum concentrat ion, depend ing on the sulfatase activ-ity of the follicle and sur rounding tissue and the conversion of DHEAS to DHEA. More impor-tantly, abnormally elevated levels of serum DHEAS may increase hair follicle D H E A levels, resulting in grea ter inhibition of G-6-PDH. A defect in the funct ion of 17/3-HSD decreases for-mation of 5-androstenediol f r o m DHEA, thereby f u r t h e r increasing intracellular concentrat ions of DHEA. In summary, increased serum DHEAS concentrat ions and al tered metabolism of D H E A within the hair follicle may result in abnormal hair growth.

Androgenetic alopecia: T h e concept of a rela-tionship between the degree of androgenic stim-ulation and the type of androgenet ic alopecia in genetically predisposed females as r epor ted by Ludwig1 was based upon variations in the level of circulating testosterone. Price3 a t tempted to implicate increased local 5 a - D H T conversion in the affected hair follicles in the biochemical gen-esis of androgenet ic alopecia. Emphasis was di-rected toward the al tered androgen metabolism of frontal scalp hair follicles in genetically predis-posed individuals. These concepts of a l tered tes-tosterone metabolism and the role of 5 a - D H T in the pathophysiology of androgenet ic alopecia in young women requi re critical reevaluation.

Female-pattern alopecia: T h e progressive dif-fuse central scalp alopecia in healthy young women is a distinct clinical entity, and should not be confused with male-pattern baldness. T h e main differentiat ion is re tent ion of the normal hairline without f ron to tempora l recession in women. Jackson et al33 recognized that this con-dition di f fered f r o m heredi tary pa t te rn baldness. T h e i r observation was based upon mean anagen hair d iameter measurements in 58 women with diffuse hair th inning and without a detectable endocr ine abnormali ty. Male-pattern alopecia has been characterized by a gradual regression of the hair, with measurement of hair d iameter showing a gradual decrease.3 6 In contrast , women with this dif fuse alopecia showed a wide spread of anagen hair diameters, with two equal statis-tical peaks at 0 .04 m m and 0.06 mm. 3 5 This




suggests the existence of two d i f fe rent types of hair in diffuse female alopecia. In contrast , in 2 women with diffuse alopecia and hypothyroid-ism, 80% of the hairs were approximately 0 .04 mm thick, and virtually no hairs were of the normal average d iameter (0 .06-0 .08 mm). In ou r patients, microscopic examination of hair plucks showed a distribution of anagen hairs into thin and nearly normal shaft diameters (Fig. 5). T h e thin hairs were not the dystrophic anagen hairs characteristic of dif fuse alopecia areata.

Diffuse female-pat tern alopecia also differs f rom the diffuse thinning of hair limited to the vertex (skull-cap alopecia) observed by Ludwig1

in postmenopausal women. Female-pattern alo-pecia is not associated with any inf lammatory or cicatricial disorder of the scalp.

DHEAS and female-pattern alopecia: T h e 19 women in ou r study had a significant (p < 0.001) elevation of the serum adrenal androgen DHEAS compared to the 11 controls. T h e association of such an elevation level with a distinct pat tern of diffuse alopecia implicates the adrenal gland as the source of excess androgen h o r m o n e produc-tion. Serum D H E A S itself does not directly cause this type of alopecia; however, it is significant as a marker h o r m o n e fo r adrenal androgen hyper-excretion and as the p r e h o r m o n e to the periph-eral metabolism of more potent androgens . How-ever, all patients with clinical signs of androgenic stimulation should be carefully evaluated, be-cause serum DHEAS may not be abnormally elevated in all women with adrenal and rogen hyperproduct ion .

T h e serum pool of DHEAS is dependen t upon the ra te of format ion of DHEA, the ra te of sulfoconjugation of D H E A to DHEAS, and the metabolic clearance rate of serum DHEAS. In ou r study, a 19-year-old woman with diffuse cen-tral scalp alopecia, acne, and facial hirsutism had a normal serum DHEAS level of 2.3 /xg/ml. However , her ur inary 17-KS were 21.1 m g / 2 4 hours (normal range for females, 4 - 1 7 m g / 2 4 hr.). T h e increased excret ion of the urinary 17-KS may be the result of increased metabolic clearance of serum DHEAS. A normal serum DHEAS level alone is not a sufficient cri terion to rule out adrenal androgen metabolic abnormali-ties.

Testosterone and female-pattern alopecia: T h e el-evation of T was not identified by Ludwig1 in female androgenet ic alopecia. When women had elevations of T comparable to levels in normal

men, the male type of alopecia with f ron to tem-poral recession developed. All 19 women in our study had normal levels of T . No significant d i f ference in the T levels of the 8 women who had alopecia alone and the 11 women who had additional signs of androgenic stimulation, in-cluding acne and hirsutism, was noted. In the study by Lobo et al27 of 52 hirsute women, serum DHEAS alone was elevated in 33%, and T alone was elevated in 12%. However, 45% of the women had bo th elevated f ree T and serum DHEAS levels, while only 18% had both normal f r ee T and serum DHEAS concentrations. Lobo et al27 concluded that women with increased serum DHEAS levels tend to have elevated levels of f ree T .

T / TeBG ratio: T h e most significant sex ste-roid binding protein is the beta globulin TeBG. Hepatic product ion of T e B G may be al tered by pregnancy, hyperthyroidism, liver disease, and certain drugs, including conjugated estrogens and oral contraceptives. 8 40

Mathur et al41 evaluated 39 hirsute women and noted that 31 % had elevated serum DHEA levels, 41% had elevated androstenedione, 49% had elevated T levels, and 56% had elevated Free T . T h e y also repor ted that 72% of the patients had suppressed T e B G levels, and 77% had an ele-vated T / T e B G ratio. This g roup of hirsute women had mean Free T levels approximately 175%, T e B G levels approximately 50%, and T / T e B G ratios approximately 300% of those ob-served in normal subjects. Mathur et al41 con-cluded that both T e B G and T / T e B G provide bet ter indices of hyperandrogenici ty than does either T or f ree T .

In our study, 8 women with female-pattern alopecia only had a significantly lower T / T e B G (p < 0.025) than did the 11 women who had the signs of increased androgenic stimulation of acne and hirsutism. Fur the r study may correlate the level of T / T e B G with the serum levels of Free T , androstenedione, and the ratio of D H E A / DHEAS, especially in those patients with normal or border l ine increased T levels.

Prolactin and female-pattern alopecia: Ver-meulen et al20 recognized that serum DHEA and DHEAS levels were significantly higher than normal (p < 0.001) in women with elevated pro-lactin levels. This may be a t t r ibuted to pituitary hypersecretion, chronic t rea tment with psycho-tropic drugs, or to prolact inoma. Specific binding sites for prolactin have been identified in the




adrenal gland.4 2 Vermeulen et al20 suggested that prolactin can stimulate the secretion of adrenal androgens , such as DHEAS, by the adrenal cor-tex independent ly of the adrenocort icotropic ho rmone (ACTH) . Lobo et al21 no ted that a 60% reduct ion in serum prolactin p roduced an ap-proximately 30% decrease in serum DHEAS. Kandeel et al43 studied hyperprolact inemic women who were t rea ted with A C T H . They observed grea te r increases in circulating DHEAS than in A4 steroids such as testosterone and Cor-tisol and hypothesized that a dis turbance in the 3/3-HSD enzyme system increases the product ion of A:' steroids such as DHEA and 5-androstene-diol. T h r o u g h the enzymatic activity of 17/3-HSD, D H E A is der ived f r o m ^« -hyd roxy -p reg -nenolone, and 5-androstenediol is derived f r o m DHEA.

Serum prolactin levels were abnormally ele-vated in 2 of our 14 alopecia patients. Because pituitary adenoma was revealed by computed tomography in one of these 2 patients with hy-perprolact inemia, it is possible that a subset of women with female-pat tern alopecia due to adrenal androgen excess may have an acquired progressive fo rm of alopecia related to a prolac-tin-secreting adenoma. In an unselected autopsy series of 120 persons who did not have any clin-ical evidence of pituitary disease, 43 microaden-omas were found in 32 pituitaries (incidence, 27%); a n d 41% of the tumors , when stained, revealed the presence of prolactin.4 4 T h e inci-dence of prolactinomas did not di f fer between men and women. This indicates that more than one in 10 persons in the general population dies with a prolact inoma. Sherman et al studied 42 women with hyperprolact inemia due to pituitary adenomas, of whom 74% had onset of amenor-rhea following childbirth or took estrogen-con-taining oral contraceptives. Not ing that microad-enomas of the pituitary probably occur in 5% to 10% of the populat ion, Sherman et al4D postu-lated that in some women the estrogen of preg-nancy or of oral contraceptives may be enough to stimulate growth of a microadenoma to a critical size, which would lead to persistent hy-perprolact inemia. In the evaluation of andro-genic female-pat tern alopecia with or without hirsutism, the possibility of hyperprolact inemia due to a pituitary adenoma should not be over-looked.

Adrenal androgenic female-pattern alopecia: Elevation of serum DHEAS is a marker for a

clinically recognizable type of hair loss that is d u e to increased adrenal C ] 9 androgen product ion in young women. This type of alopecia may be associated with alteration of the hair shaft diam-eters, acne, and hirsutism. In young women, this disease is called adrenal androgenic female-pat-tern alopecia.

T h e pathogenesis of this pa t te rn is unclear, a l though it may be the result of several d i f ferent disorders of adrenal metabolism. A genetic basis for adrenal hyperproduct ion of D H E A or a de-ficiency of the 17/3-HSD or 3/3-HSD enzyme sys-tems in adrenal or per ipheral tissue cannot be ruled out . Acquired abnormali t ies of increased D H E A product ion th rough hyperprolact inemia secondary to pituitary adenomas, t h rough adre-nal cortical hyperplasia, or th rough adrenocort i -costeroid-producing tumors must also be consid-ered. T h e most significant abnormali ty may re-side within the hair follicle itself as a result of the intracellular metabolism of DHEA a n d inhibition of G-6-PDH of the pentose cycle. Hai r growth is dependen t upon shifts in glucose metabolic path-ways.34 Compared with that in rest ing follicles, glucose utilization in active anagen follicles in-creases 100%; glycolysis, 200%; activity of the pentose cycle, 800%; and metabolism by o ther pathways, 150%. Active anagen follicles genera te more nicotinamide adenine dinucleotide phos-phate (NADPH) th rough these metabolic path-ways than resting follicles. T h e r e f o r e , D H E A inhibition of G-6-PDH in the pentose cycle and reduced product ion of N A D P H may in ter fere with anagen follicle development and hair growth.

Milder forms of congenital adrenal hyperplasia (CAH) have been observed in adults. Lobo and Goebelsmann4 6 identif ied 5 women with partial 21-hydroxylase deficiency (21-HD) a f te r A C T H stimulation testing of 25 hirsute ol igomenorrheic women. Following a bolus of A C T H , 0.25 mg, administered intravenously, a much larger in-crease in serum 17-hydroxyprogesterone (17-HP) was noted in the 5 C A H patients than in the controls and the o ther hirsute women. These 5 C A H patients, clinically indistinguishable f r o m women with P C O and hirsutism, had basal serum measurements of DHEAS, andros tenedione , and T within the 95% confidence limits established for hirsute women, a l though 3 of the C A H pa-tients had serum C19 androgen steroid levels (DHEAS) above those seen in normal women.

T h e p roper evaluation of alopecia in young



120 Cleveland Clinic: Quarterly Vol. 50, No. 2

women is dependen t upon a complete history and clinical examinat ion in o rde r to identify eti-ologic factors. T h e hair pluck technique is useful fo r the examinat ion of anagen and telogen hairs, dysplastic hair shafts, and dystrophic hairs of diffuse alopecia areata.4 7 Laboratory evaluation for androgenic alopecia should initially include determinat ion of the serum DHEAS a n d T levels, T e B G (for the T / T e B G ratio), and serum pro-lactin amounts . An additional investigation would d e p e n d on the correlation of the initial clinical examinat ion and the laboratory results.

Treatment: T h e prospect of successfully treat-ing diffuse female-pat tern alopecia is improved by the identification of an adrenal androgen ab-normali ty. Several recent repor ts have indicated that spironolactone is a highly effective and safe agent fo r the t rea tment of hirsutism. Shapiro and Evron 4 8 gave 100 mg of spironolactone twice daily f r o m the fou r th to the 22 nd day of the menstrual cycle to each of 30 hirsute women. Improvement became evident in 23 of the 30 women, usually th ree to five months a f t e r the beginning of t rea tment . T h e tex ture of the hair became softer and less coarse. Al though a de-crease in hair density was an average of 64% of the initial value, the appearance of the hair was still abnormal compared to the nonhi rsu te con-trol women. Side effects repor ted in the first few weeks of spironolactone therapy included poly-uria a n d polydipsia in 8 women; headache in 2; weight gain in 2, increased appeti te in 2; and weakness, t iredness, and exhaustion in 6. Cum-mings et al49 studied 20 women t rea ted with spironolactone (200 m g / d a y ) for modera te to severe hirsutism. T h e y repor ted a reduct ion in the quanti ty and an improvement in the quality of facial hair growth in 19 of the patients. Nielsen5 0 evaluated the effect of spironolactone (50 m g / d a y ) on 21 hirsute women for an average period of seven months . T h e f requency of hair removal by mechanical and chemical methods was r educed by one half in 57% of these patients. Side effects no ted were tenderness of the breasts in 48% of patients and menstrual irregularities in 19%.

Based on these reports , we prescribed a low dose of 2 5 - 5 0 m g to be taken twice daily for 8 of the 19 patients with adrenal androgenic alo-pecia fo r periods ranging f rom 3 to 12 months . T h r e e of fou r women t rea ted for m o r e than nine months had an increased growth of scalp hair with a decrease in the amoun t of daily hair loss. T w o women t rea ted with spironolactone, 50 m g

twice daily for nine and 12 months , had a reduc-tion of serum DHEAS f r o m 4.3 to 2.3 ^ig/ml and 5.8 to 2.4 fig/ml, respectively. We have not prescribed spironolactone to p regnan t women, and have avoided its use in women with a familial history of breast carcinoma.

Menard et al51 s tudied the biochemical effect of spironolactone on the proges terone 21-HD and I 7 a - H D enzyme system, which is dependen t upon the adrenal microsomal cytochrome P-450. T h e i r findings show that the presence of the sulfur a tom at the carbon 1 -a position on the spironolactone molecule is requi red for the breakdown and loss of heme and apoproteins f r o m the adrenal cytochrome P-450, thereby de-creasing steroid hydroxylase activities in the adrenal gland. T h e reduct ion of I 7 a - H D paral-lels the destruction of cytochrome P-450 by spi-ronolactone. T h e loss of I 7 a - H D activity results in decreased product ion of 17a-hydroxy-preg-nenolone f r o m pregnenolone . Ultimately this leads to a decrease in concentrat ion of the serum Cj9 androgens D H E A S and testosterone as well as serum Cortisol. N o loss of cytochrome P-450 occurs in tissues in which steroid 17-a-HD activity is low o r absent. These studies suggest that the greater the activity of I 7 a - H D , the grea ter the effect of spironolactone on the loss of heme f rom the adrenal cytochrome P-450, resulting in de-creased adrenal androgen product ion.

Spironolactone also funct ions as an ant iandro-gen within the target organ. Corvol et al52 dem-onstrated that spironolactone is able to compete in vivo and in vitro with 5 a - D H T for intracellular androgen receptor sites. T h e affinity of spirono-lactone for the androgenic 8 S cytosolic receptor is about one twentieth that of 5 a - D H T .

Spironolactone appears to exer t its effect both centrally, by reducing adrenal C]9 androgen pro-duction, and peripherally, by in ter fer ing with androgen affinity to hair follicle cytosolic recep-tors.

Summary T h e association of increased levels of the serum

adrenal Ci 9 androgen D H E A S with a distinct pat tern of progressive central scalp alopecia in healthy young women is called adrenal andro-genic female-pat tern alopecia. A hypothesis for the pathogenesis of this alopecia is based on the inhibition of follicular G-6-PDH of the pentose cycle by intracellular DHEA, resulting in the alteration of the growth of anagen hair.

T h e T levels were normal in 19 women studied



Summer 1983

with this pat tern of alopecia. O t h e r manifesta-tions of androgenic stimulation, such as acne and hirsutism, were associated with an increased T / T e B G ratio.

T h e oral administrat ion of spironolactone is an effective t rea tment for hirsutism. This d r u g in-hibits adrenal C ] 9 androgen product ion by dis-rup t ing the l 7 a - H D - d e p e n d e n t adrenal micro-somal cytochrome P-450 enzyme system, is an androgen antagonist because it competitively binds with the androgen cytosolic receptor sites of the hair follicle, and may inhibit the effect of androgens in women with adrenal androgenic female-pat tern alopecia.

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Adrenal androgenic female-pattern alopecia 121

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Vol. 50, No. 2

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adrenal androgenic female-pattern alopecia: sex hormones

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