THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 60, No.6 Copyright© 1973 by The Willia ms & Wilkins Co. Printed in U.S.A.

HIRSUTISM: A REVIEW OF THE GENETIC AND EXPERIMENTAL ASPECTS* SIGFRID A. MULLER, M.D.

INTRODUCTION to be under hormonal control, whereas both axil­ The genetic and environmental factors, which lary hair and lower pubic hair were pubertal together are responsible for our lack or abundance events, similar in both sexes and related to adrenal of hair, are little understood. Especially noticeable androgens. The upper pubic hair, the beard, hair in is the paucity of knowledge about the regional the external auditory canals and nasal vestibula, variations in hair growth or the different sensitivi­ and increased hairiness of the trunk and extremi­ ties to pilary stimulation. Nevertheless, because of ties were thought to be secondary sexual character­ the easy applicability of investigational techniques istics of the true male (Danforth, 1939; Flesch, and the availability of large amounts of experimen­ 1954; Porter and Lobitz, 1970). Major differences tal tissue, our knowledge of hair phenotypes and between the sexes are quantitative rather than growth is considerable and significant. qualitative; therefore classification becomes dif­ Although disorders of the hair may have no ficult. For example, hair on the scalp or extremities practical or medical significance, involving little or can be assigned to one of several categories, and n.o interference with the general physical condi­ certain variations are normal in familial and racial tiOn, they are commonly important to the patient strains but abnormal in others; thus comparisons because of psychological factors. They may be an between individuals are often impossible. It is also early warning of a serious underlying medical likely that hair growth is never completely free of disorder, such as a congenital abnormality, or a hormonal control. cl.ue to correct medical diagnosis. Explanations of Knowledge about the endocrine control of hair d1sordered pilary metabolism could well provide growth is deficient, but three points seem incon­ t he necessary insight whereby rational therapy trovertible. (1) The androgens, particularly tes­ could be applied to various diseases. tosterone, are the principal stimuli for the growth The ideal state of "hairiness" is not a character­ of terminal hair. Their secretion by the gonads and istic of many men or women, nor can normal the adrenals must be genetically determined by a subjects be absolutely separated according to sex variety of mechanisms; examples of abnormal by their hair patterns. In fact, it is difficult to androgen function are found in the heritable syn­ decide nowadays which is considered less esthetic dromes of congenital adrenal hyperplasia, familial in our society, too little or too much hair; but it is multiple endocrine adenomas, and certain intersex certain that as civilization changes so do "ideal" problems. (2) The various responses of hair to amounts and distribution of hair. Although I will androgenic stimulation are governed by genetically discuss hirsutism and alopecia separately, the determined intrinsic qualities unique to a particu­ distinction is arbitrary in a sense, since regional lar hairy region and especially to the individual differences in end-organ sensitivities often result in follicle. New information that may explain this hairiness in one area and hairlessness in another in seeming paradox will be discussed later. (3) In res ponse to similar pilary stimuli. If more than one most cases, aging is a prerequisite for the expres­ di sorder is present, the result is also a mixed sion of the hair-stimulating effects of androgens (or picture. The treatment of these conditions will not for the loss of hair in the temporal and vertex be considered here. regions of the scalp). However, aging is only a In this paper, the term hirsutism is used in its relative factor since hirsutism and baldness can traditional sense to denote only hypertrichosis. develop rapidly in cases of precocious puberty or Some physicians, however, use the term to denote severe endocrinologic disease. Hairiness on the excessive growth of hair in a characteristic mascu­ trunk and extremities frequently increases for line fashion (Brooksbank, 1961; Wilkins et al., several years after maximal levels of androgens 1965) . I have chosen not to do so because of the have been attained in the plasma of normal men co nsiderable overlap between normal men and and women, an effect probably genetically in­ women in the amounts and distribution of terminal fluenced , though little information is available on hair. The overwhelming majority of women who this subject. Conversely, the loss of androgens as a consult physicians because of excessive hair on the result of castration or the removal of a n androgen­ trunk, extremities, or face are completely feminine secreting tumor rarely reverses hirsutism and com­ by every other measurement and should not be mon baldness rapidly; more commonly many considered masculine. months or years are required for normal patterns of hair growth to reassert themselves. ENDOCRINE CONTROL OF HAIR GROWTH Baulieu (1970) pointed out that steroid hor­ Traditionally, lanugo and vellus hair, eye hair, mones penetrate the cells which they affect, unlik.e and some hair on the extremities were not thought peptide hormones which act at the level of the * From the Department of Dermatology, Mayo Clinic, external membrane. Several studies have in­ Rochester, Minnesota 55901. dicated that the potent androgen, dihydrotestos-

457 458 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY terone (D HT), which is the in t racellular effector of (1970) pointed out that in creased clearance of tes­ testosterone action in the target tissue may reenter tosterone by extrahepatic target tissues could ex­ t he blood from t he tissue in which it is produced plain the paradox of normal pl asma testosterone a nd cause androgeni c effects on other tissues o f levels occurring with in creased rates of testoster­ the body. Larger amounts of DHT are more likely one production in so me v iri li zed women. to originate fr om go nadal sources (Bardin and Ma­ In considering mechanisms whereby t he in­ houdeau, 1970; Bashi re la hi and Vi ll ee, 1970). In cre ased stimulation of target t issues such as hair prostatic cell s, DHT was bound mostly in nuclei might be controll ed geneticall y, I wou ld a lso point (Bruchovsky a nd Wilso n, 1968). Although t he to t he possible role of t he testosterone-binding reductase necessary for co nverting testosterone to ,6-globulin (TeBG), which binds testosterone in DHT was found to be present in both nuclei a nd hi gh affinity in some ways ana logous to cortisol­ cytoplasm, o nly t he latter contained the e nzyme binding g lobulin . Al though t he control of the needed to reduce DHT to t he relatively inactive metaboli c cl earance rate of steroids is not com­ androstanediol. Anderso n and Liao ( 1968) pro­ pletely understood, several studies suggest th at posed a specific receptor for DHT at its site of TeBG retards t he metabolism of testosterone (Ver­ action from which it ca n b e dislodged on ly with meulen et a l. , 1969; Bardin a nd Mahoudeau, 1970; difficul ty. Probably only a limited number of Mercier-Bodard et a l. , 1970) . According to Ito and "androphilic receptors" (Hansson et al., 1971) are Horton (1970) , TeBG has a g reater affinity for soluble protein macromolecules; at least in pros­ DHT t ha n for testosterone. DHT arises principally tatic nuclei, t he a ndrophilic macromolecul es a re from t he ovarian secretions in the female a nd from acidic proteins associated with nuclear chromatin. the peripheral conversion of testosterone in t h e T he function of t he androgen-binding nuclea r male. T hus, numerous factors influence the meta­ protein s is unknow n, but t hey could affect gene bolic clearance rate of testosterone, including transcription by inactivating repressor substances plasma g lobulin bin ding, t he nuclear a ndrophilic (Fang eta!., 1969), an effect in agreement with t he receptors, and the activity of steroid metaboli zing immediate activation of ribonucleic acid a nd pro­ enzy mes in target tissues. The suggestion by Ismail tein synthesis by a ndrogens (Willia ms-Ashman, and Loraine ( 1969) that hirsutism results from a 1965; Liao and Lin, 1967; Bashirela hi eta!. , 1969). lac k of antiandroge ni c s ubstances has not been Recent studies indicate t hat normal human skin investigated. actively meta boli zes androgenic hormones in vivo Sansone a nd Reisner's (1971) report of signifi­ as well as in vitro (Wotiz et a l. , 1956; Baulieu, cant regional variations in the ability of skin to 1970; Faredin et al. , 1970). Most of t hese studies co nvert testosterone to DHT confirms t hat varia­ provide substantial data on t hese effects in acces­ tion in end-orga n sensitivity. T hey observed that sory sex ual tissues, such as t he prostate or semina l the conversion of DHT was 2 to 20 times greater in vesicles, but only a few studies have been done on acne-bearing skin t ha n in normal skin from a t he skin. Several hydroxysteroid dehydrogenases corresponding area a nd that normal facia l skin have been found in human skin (Baillie et al. , showed more conversion tha n norma l back skin. 1966; Ron gone, 1966), principall y in t he sebaceous The rates of conversion to DHT were hi gher in glands, though steroid dehydrogenases also have male skin than in female skin from t he same sites. been found in fibroblasts growin g in tissue cult ure. Human ha ir follicles have not been studied in In a ddition, a ndrogenic steroids have· been found in t his manner, but Takashima et a l. (1970) pub­ a nd on t he surface of t he s kin and hair, a nd li shed results on the in vit ro metabolism of testos­ dehydroepiandrosterone can be metaboli zed by terone in the hair fo llicles of stumptailed ma ­ skin in vitro with the formation of testosterone as caques, showing that the hair fo llicle itself is a n ac­ we ll as of other steroids (Cameron et a l. , 1966) . In tively meta boli zin g a ndrogeni c s ite and that scalp summa rizing t he li terature on androgen metabo­ ha ir, both from bald and from nonbalding a reas is li sm in the skin , Stra uss a nd Pochi (1969) pointed more active t han back hair. The greatest activity out t hat, although t he specifi c site for such metab­ was in the ha ir bulb, a nd anagen fo llicles were oli sm remains unknown, t he sebaceous g lands are more active than telogen. Utili zing thin-layer chro­ implicated m ost clearl y. Wilson a nd Walker matographic methods, t hey observe d that the (1969), however, fou nd t hat even skin devoid of metabolism of testosterone was less active in pilosebaceous structures had at least a limited follicles from t he balding scalp than from the hairy ability to co nvert testosterone to DHT. scalp a nd t hat t he production of its metabolite , Human skin was shown by Faredin et al. (1970) mainly androstenedione, was much greater in t he to be an active metabolic s ite fo r androgenic bald areas. T hus, t hey showed, fo r the first time, a steroids. They demonstrated t hat both normal and biochemical difference between follicles in bald hirsute fema le s kin synthesized testosterone, 5a­ and ha iry regions. androstane-3 , 17-dione, and androsterone from In a n extension of t his study, Adachi and Kano [4 -C "]a ndrost-4-ene-3, 17-dione and confirmed (1970) showed that in ha ir follicles of the human the latter co mpound as a precursor of testosterone scalp adenyl cyclase was greatly inhibited by DHT and the presence of 17 ,6- hydroxysteroid dehydro­ but not by testosterone. They proposed a molecu­ genase in the s kin as we ll. Bardin a nd Mahoudeau lar mechanism whereby DHT causes inhibition of HIRSUTISM 459

aden y l cyclase in t he follicles, a decrease of t he Jewish immigrants are frequently more hirsute intracellular cycl ic-AMP level, and consequent tha n dark-skinned groups despite their li ght pig­ inhibit ion of energy production and protein syn­ mentation and hair color (Danforth and Trotter, thesis in the ha ir. T his inhibit ion causes premature 1922; Schwartz, 1942; McKnight, 1964) . termination of the growth cycles of term in al h a irs Detailed reports on English, Welsh, American, and their transformation into vellus ha irs . Danish, Dutch, and Indian women have indicated These tentative insights into t he mechanisms of much diversity in t he distribution of hair (Dan­ hair growth still leave many questions unanswered. forth and Trotter, 1922 ; Pedersen, 1942- 1943; For example, what are the regional differences in Beek, 1950; Shah, 1957; Thomas and Ferriman, the response to similar pilary stimulation? Never­ 1957). These studies, suggested that termina l h ai r theless, an understanding of the enzymatic con­ was commoner on the arms and legs of Welsh trols responsible for such differences in follicular women than on t hose of Danish, American, and metabolic activity a ppears to be within reach. An Indian women. On the other hand, t he incidence of important avenue for t he analysis of the genetic facial hail in Welsh women was similar to t hat in transmission of common baldness as well as of American women but higher than that in Swedish certain forms of hirsutism may have been pro­ and Indian women. Beek (1950) analyzed the vided. distribution and extent of ha ir in 1,000 healthy women in Holland, noting the incidence of ha iri ­ CLASSIFI CATION OF HIRSUTISM ness by decades. He reemphasized t hat the inci­ dence of hairiness is strongly age-related and that From a c linical point of view, my previous comparison of similar population groups is crucial. classif ication of hirsutism (1969) is still reasonably Among his more interesting res ul ts was the age­ satisfactory t hough a few a lterations and addit ions related increase in the number of women with have been made (Table). Genetic factors, though moustache and beard hairs, from a relative zero still undetermined, a re operative in various degrees incidence in the first two decades to approximately· in almost every category. Even in drug-induced 90 percent in cidence at age 65 and older. The hirsutism, differences in individual susceptibilities incidence of hirsutism elsewhere was otherwise are clearly evident. gen erally similar to that of Danish and American women. Racial and Familial Hirsutism McKnight's study (1964) of 400 women students Normal distribution of hair. Orientals, Eskimos, at the University of Wales illustrates fully the American Indians, and Negroes are much l ess difficul ties of assigning medical significance to hirsute than Caucasians. This is especially true of hirsutis m. Eighty-four percent of these students Orientals who rarely have facial or body hair had terminal hair on the lower part of the legs and except in the pubic and axill ary regions and of 70 percent on the upper part of the arms and legs; American Indians who, in addition, rarely ever 26 percent had terminal hair on the face, usuall y have common baldness in either sex. Lee and the moustache area, whereas 1 percent had hair on associates (1963) noted that East Asian Arctic the c hest or breasts; 35 percent had abdom inal Mongol oid women frequently have li ttle o r n o hair usuall y concentrated on the linea alba. The pubic hair and Japanese women reportedly have more severely hirsute we re more li kely to have much less axillary hair than white American terminal h air on the breasts, lumbosacral regions, women (Hamilton a nd Terada, 1963). At t he other and upper part of the back, such involvement extreme, t he Ainu, a n abori gina l people who popu­ indicating the need for medical study. Only two late a northern Japanese island, are said to be t he women showed additional signs of masculinization most hirsute (Cockayne, 1933) . To my knowledge, and subsequently were found to have adrenal detailed comparative studies of hirsutism and virilism; one additional patient was found to be a common baldness have not been carried out in pseudohermaphrodite. non-Caucasoid women except by Hamilton (1958) A familial tendency to hirsutism in white sub­ who compared Japanese and white American wo­ jects is not an uncommon clinical observation men. Setty (1970, 1971) has also provided data of (Hamil ton, 1964) . Hamilton et al. (1969) noted hair patterns in Caucasoid and Negroid men. similar patterns and amounts of sternal and beard Despite the considerable diversity that exists ha irs in identical twins, but fraterna l twins a nd among Caucasians, several major studies of hirsut­ siblings did not resemble their parents and differed ism in healthy subjects have been reported. It is as much from one another as from a n unrelated gener ally agreed that dark-haired , darkly pig­ control group. Lorenzo (1970) recently reported mented Caucasians of eit her sex tend to be more n ew evidence to support genetic etiology for famil­ hirsute t han light- haired ones. I have found t hat ial hirsutism, probably based on a multifactorial persons of Mediterranean and Middle Eastern pattern of inheritance. The familia l incidence and ancestry accept their hirsute tendencies as being distribut ion of hirsutism were ascertained in 90 inherited more readily than do others. Blond, subjects seen at t he Endocrinology Clinic of the fair-skinned, Nord ic groups are less hairy; but University of Michigan, in t heir first-degree rela­ decendents of Irish, English, Welsh, and Russian t iv es (mothers and sisters), and in a control group. 460 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE Classification of hirsutism

I. In normal subjects A. Intrinsic factors 1. Racial and familial: generali zed and localized forms including midphalangeal hair, hairy ears, and rare localized types 2. Physiologic: premature pubarche, adolescent development, precocious sexual development, pregnancy, menopause, neural and emotional factors 3. Idiopathic B. Extrinsic factors 1. Local trauma 2. Drugs a. Without virilization Dilantin Diazoxide Hexachlorobenzene Corticosteroids; ACTH b. With potential virili zation Progestogens Anabolic agents Androgen therapy C. Hamartomas or nevi 1. Pigmented nevi with hair, especially bathing-trunk type 2. Nevus pilosus 3. Pigmented hairy epidermal nevus (Becker) II. In pathologic conditions A. Endocrinologic disorders 1. Ovarian origin a. Stein-Leventhal syndrome; familial hyperthecosis b. Virilizing ovarian tumors: arrhenoblastoma, granulosa theca-cell tumor, hilus-cell tumor, pseudomuci­ nous cystadenoma, cystoadenocarcinoma, Brenner tumor c. Metastatic carcinoma to ovary (Krukenberg's tumor) 2. Pituitary origin a. Cushing's syndrome b. Acromegaly 3. Secretion of hormones by nonendocrine tumors a. Ectopic ACTH syndrome: mainly bronchogenic, thymic, and pancreatic carcinomas causing Cushing's syndrome b. Multiple endocrine adenomatosis: Cushing's syndrome and acromegaly 4. Adrenal origin a. Syndromes of congenital adrenal hyperplasia b. Adult adrenogenital syndrome c. Adrenal adenoma or carcinoma; adrenal rest tumors 5. Intersex problems other than congenital adrenal hyperplasia a. P ure gonadal dysgenesis and Turner's syndrome: with or without androgen-secreting tumors such as hilus-cell tumors or gonadoblastomas b. Male pseudohermaphroditism including incomplete testicular feminization and testicular masculini­ zation- feminization syndromes B. Congenital anomalies 1. Hypertrichosis lanuginosa; idiopathic gingival fibromatosis and hypertrichosis 2. Corneli a de Lange syndrome 3. Congenital generalized lipodystrophy 4. Leprechaunism 5. Congenital hemihypertrophy 6. Cowden's syndrome 7. Mucopolysaccharidoses HIRSUTISM 461

T ABLE-Co ntinued

8. Bird-headed dwarfism of Seckel 9. T risomy 18 10. Rubinstein- Taybi syndrome ill. Miscell aneous A _ Starva tion; a norexia nervosa B . Acquired h ypert ri chosis la nuginosa ( mali gnant down ) C. Juvenile hypothyroidism D. Acrodynia E. Porphyria cutanea tarda; va riegate porphyri a; congenita l porphyria

T h e r e were 20 wo men wi th associated ovari a n English wo men than a mong w hite Ameri can wo­ dysfunction, 27 with adrenal cortical hyperfunc­ men. tion , a nd 43 grouped as " idiopathi c" with n o Dupertuis a nd associates (1945) and Bee k (1950) app a r e nt e ndocrine a bnormali ties. T he severi ty of confirmed the presence of a disperse type of pubic t h e hirsut ism co uld not be correlated wi th any hair in which a heavy growth extends up the d iagn osis. The degree and extent of hairiness in the abdom in al skin and occurs o nly in men, never in relat i ves were intermedi ate between those of the normal wo men. T he o nly other types of hair index cases and the controls. Because of the distribution that are co nsidered truly masculine pa r a lle l association of ·hirsutism and androgonic are coarse ear h air reported b y Ha mil ton (1947) in equivalents which h e ident ified as acne, common 75 percent of Caucasian m en but not in wo men or baldness, and cli toral h ypertrophy, Lorenzo ques­ eunuchs a nd by Beek (1950) in 59 p ercent of men tion e d the existence of a distinct idiopathic type 25 to 34 years of age but only in 1 percent of wo men of h irs u tism. He p roposed that the ge netic co ntrol of a s imilar age. Ha milton et a!. (1969) also of a ll t hree entities was exerted at the hormonal indicated coarse sternal hair to be a similar but less level. I agree that in most cases t he s imilarit ies dependable s ign of masculinization. amon g racial, fa milial, and idiopathic types of Localized f orm s of h ypertrichosis. Most of the hirs u t is m are too great to permit t heir clinical numerous observations on the heritability of local­ recogn ition wi th r easona ble certainty. ized areas of h ypertrichosis deal with h air on the I know of no fa mily pedigrees supporting a n midphalangea l skin of the fin gers. Danfo rth (1921) inherited p attern for the adult a drenogenital syn­ first suggested that the complete absence of hair at drom e _ H owever, t he Stein- Leventhal syndrome this site was due to a single recessive gene. Later, does a ppear to have signifi cant heritability. Cooper Bernstein (1949) postulated fi ve diffe rent a lleles to et a l. (1968) investigated 1 8 fa milies in which the account for i t. Reports of several affected children Stein- Leventhal syndrome had appeared and con­ born to parents who lacked the t rait indicated that e! ude d that the disorder was inherited, proba bly as the inheri tance of mid-digital hair was not due to a an a u tosomal dominant c hanicteristic. Support for single mendeli an gene ( Beckman and Book, 1959) . th is p ossibility is p rovided b y t he report of Givens Salda nha a nd Guinsburg (1961), who reviewed the et al. ( 1971 ) in which 41 members of two families li terature a nd presented additional d ata of their were affected b y a broad phenotypic s pectrum of own, noted that the t rait is virtually a bsent a mong hirs u t is m and oli go menorrhea, thought to be t rans­ Eskimos and present in a fr equency of 10 to 30 m itted as an a utosomal dominant t rait. The occur­ percent a mong J a panese, Ameri can India n, a nd ren ce of hypogonadism in a fe w of the men and Negro s ubjects, and of 50 to 80 percent a mong the gr e ater frequency of the condition in the Europeans. Similari ties between this t rait a nd the offspring of m ale fa mily members suggest tha t this racial occurrence of hirsutism are immediately may b e a sepa rate rare e ntity. a pparent; this type of hairiness is proba bly in­ Just as the a mounts and distribut ion of terminal f1uenced b y androgens (Garn, 1951). Of particular hair s h ow considera ble o verl ap b etween n ormal interest was the order of frequency of the affected men a nd women, patterns of growth of pubic hair fin gers-fourth, third, fifth, and second; the action also vary greatly. Al though h ori zo ntal p atterns o f of d ifferent a ll elic ge nes is s uggested . The inheri ­ growth a re commoner in white American wo men tance of middle phalangeal h air has not yet been and a c uminate distribution i s commoner in men, determined ; a lthough i t may have so me an­ significant numbers of n ormal m en and women thropologic importance, it is not an ideal subject have e it her type o r intermediate types. Major for genetic investigation. racia l differences have a lready been m entioned, as Hairy ears (hypertri chosis pinnae auris) are well as minor differences indicated by the report of important only because geneti c s tudies in Indian T h om as and Ferriman (1957) who noted a lower and Israeli pedigrees have indicated the likelihood incidence of a n acuminate p attern and a higher of h olandric o r Y- linked inheri tance (S iatis and incide n ce of the sagittal p attern among whi te Apelba um, 1963; Dronamraju, 1964) . Stern et a!. 462 THE JOURNAL OF INVESTIGATIVE DERMAT OLOGY

(1964) summarized t he li terature a nd presented the li terature. Alt hough n o evidence suggests t h at data which, however, do not prove beyond a doubt premature pubarche in an otherwise healt hy c hild t hat t his characteristic is inherited. Its incidence heralds t he o nset of organic disease of t he nervous a mong Israeli men was 25 .8 percent; a mong two system, it does occur rather commonly in children groups of Indian m en fr om M adras and West wit h severe organi c b rain disease. Bengal, it was 70 percent and 30 percent, respec­ The cause of t he disorder is not known, b ut t ively. T he tra it, t he severi ty of whi ch vari ed according to several postulates it refl ects prema­ widely, was never seen before puberty and usually t ure activity of t he a drenal gla nds i n t he p roduc­ did not reach full expression until much l ater in tion of androgens a nd thus a nticipates puberty, life. Unless t he hairs are suffi ciently coarse, t here increased end-organ sensitivi ty of t he pubic a nd may be a question as to whether t he t rait is axillary hair, or h ypothala mi c abnormali ty (Conly actua lly present. T he true condit ion includes only et al. , 1967; Sigurjonsdottir and Hayles, 1968b). ha ir growing on or adjacent to t he pinna of the ears Fa milial occurrence of t his condition is uncom­ a nd does not include hair growing on the lobule or mon . Perloff and Nodine ( 1950) reported an af­ in the external ear cana l', another m ale t rait t hat is fected brother and sister; of the 24 patients re­ related to androgen stimulation but is an unrelated ported from the Mayo Cli nic (S igu rj onsdottir and phenomenon already discussed . H ayles, 1968b), all but two we re fe males and three In each of the other striking o bservations of had a fa mily history of premature pubarche. A locali zed hypertrichosis, a mendelian inheritance young woman wi th onset of the co ndition at 5. has been suggested . Examples are hairy e lbows weeks · of age and two brothers sim il arl y affected (Beighton, 1970b) in an Amish kindred, inherited ex perienced a normal adolescence and subse­ probably as an a utosomal r ecessive trait, a nd quently gave birth to two unaffected children . A hypertri chosis of t he medial left eyebrow n ear the second patient in t he series reported the history of root of t he nose in 9 members of three ge nerations an affected paternal grandmother, and a third pa­ of a family observed b y Ludwig a nd discussed by tient had a fe male fi rst cousin aid to be affected. Cockayne (1933). Beek (1950) likewise reported None of these relatives, however, were examined symmetri cal extensions of t he eyebrows to t he by the authors. Thus, wh ereas we ll over 100 cases midline, equally common among men and women, of this cond it ion h ave been reported, only a few in up to 22 percent of a Dutch population. Cock­ mention affected r elatives. Adequate genetic ayne ( 1933) also reviewed briefly t he details o f studies have not been carried out, but t here does vari ous locali zed f orms of hypertrichosis presuma­ seem to be a small degree of h eri tability. bly related to dominant inheritance; evaluation of A dolescent development . Puberty greatly stimu­ his data, however, is not possible. Persons we re lates t he growt h of hair, particul arly of sexual h air. included who had excessive eyebrows and eye­ Adolescence begins wi t h increased secretions of lashes and locali zed h ypertrichosis of t he forehead gonadotropic hormones by the a nterior l obe of t he and neck. Mention should also be made of T rotter pit uitary gland conco mitant w ith increased secre­ and Danfo rth's (1922) unlikely suggestion t hat hair tions of adrenal androgens in girls indicated b y the in the moustache area is inheri ted by women as a development of sexual h air and increased urinary dominant c ha racteristic. 17 -ketosteroids. Wilkins et al. (1 965) stated t hat puberty begins a ny time between the ages of 9 a nd Physiologic Factors 17 years, a li ttle earlier in girls t han in boys. T his is a n artific ial category t hat cannot reall y Ax illary hair begins to grow about 2 years after be separated from the racial and fa milial factors pubic hair (Ha milton, 1958) and reaches a m ax­ sin ce genetic mechanisms are s ignificantly o pera­ imum in the t hird decade. Adolescence is a lso the t ive in a ll of t hem. Nevertheless, it provides a time of the g reatest growth of terminal hair in conveni ent focus fo r a di scussion of some of t he other a reas, especially o n t he extremit ies a nd the normal and important changes in adolescence and t runk in geneticall y predisposed w om en . aging. The information about t he ge netics of these Little is known about t he complex interaction of events is Jess conclusive. ge netic a nd environmental factors t hat infl uence Premature pubarche. T his term refers to the t he o nset of puberty. Where t he e nvironment is unexplained development o f pubic hair a nd, less good, most of t he vari a bility in t he age when commonly, axillary hair in children who show n o mena rche begins is due to ge netic differences. In other signs of sexual maturation . Commoner France the mean diffe rence in menarchial age for among g irls t han boys, it is seen in children as identical twin s was 2 months compared wit h 8 young as 4 or 5 years of age, t he youngest affected m ont hs fo r n onident ical twins (Tisserand-Perrier patient reported b eing 5 weeks o f age. Puberty 1953). According to M otulsky a nd E pstein (1968) fo llows norma lly in these children . S igurjonsdottir t he time w hen m enarche begins in mothers and and Hayles (1968b) reported 24 such cases; only daughters as we ll as in sisters shows a significant one patient had organi c disease of the central correlation and in dicates control by multiple nervous system , whi ch was attributabl e to neurofi ­ genes. Tanner (1962, 1969) , who reviewed the bromatosis. H owever, associated organic neural literature on m enarchial age, concluded that disease was noted i n a t hird of the cases reported in during t he last 100 years menarche has been oc- HIRSUTISM 463

curring in European girls 3 to 4 months earlier per delivery. That predisposing genetic factors are decade. Hong Kong Chinese girls and Cuban girls significant was suggested by Bissell and Williams experience menarche t he earliest. The Bundi of (1945), who reported tra nsient hirsutism during New Guinea are the o nl y known group in which the pregnancies of a woman and her daughter. An menarche is as late nowadays as it was in Europe a increase in adrenal androgens caused by increased century ago. stimulation of the adrenal glands during preg­ P recocious sexual development. S uch develop­ nancy has been postulated as the etiologic factor; ment accompani ed by adult patterns of hair however, the androgeni c activity of progesterone is growth occurs more frequent ly in girls than in boys not thought to be reponsible (Brooksbank, 1961). at exceedingly young ages. In a Danish p opulation M enopause . Beek's study (1950) of women in the of about 4.5 million from 1938 to 1946, the in ci­ Netherl ands confirmed the long-standing clinical dence of constitutional or idiopathic precocious fin ding t hat menopause heralds t he o nset of in­ puberty was estimated b y T hamdrup (1961) as 4 creased loss of hair in the pubes, axillae, chest, and girls a year and 1 boy every other year. extremit ies. In contrast, growth of hair on the chin In 80 to 90 percent of the cases of precocious and on the moustache area increases with age in puberty, no abnormality in the endocrin e or ner­ postmenopausal wo men. Thomas and Ferriman vou s system is found. Infrequently associated pa­ (1957) corroborated t hese findings. Ha milton thologic disorders have included brain tumors, (1958) noted an abrupt decline in the g rowth of encephali tis, a nd ovarian a nd adrenal neoplasms axillary hair coinci ding with the menopause, which (Seckel, 1946; Thamdrup, 1961; Sigurjonsdottir was accentuated in a study of Japanese women: in and Hayles, 1968a; Hung et al., 1971). In T ham­ a group of women over 60, not a single axillary hair drup's study among the patients with idiopathi c was found in 98 percent. precocious puberty, there was a distinct prepon­ Although the decrease in axill ary a nd pubic hair derance of close female relatives with unusually in older women can be explained b y t he decline in early p ubertal development but no distinct pattern ovaria n androgenic secretion, the paradoxical in­ of inheritance. Wilkins et a!. (1965) also noted a crease in facial h air cannot be attributed to in­ familial tendency to sexual precocity; in one fami ly creased adrenal androgens (Hamilton and Terada, both sexes were affected. J acobsen and Macklin 1963). Brooksbank (1961) s ummarized the various (1952) reported four generations of a family in theories implicating an altered ratio of androgen to which 27 males but no females we re affected . estroge n after the reduction of ovari a n function. Precocious puberty in both a male and a female What role estrogens play in mitigating the effects sibling with normal parents also has been reported of androgens on h air growth is largely unexplained; (Ferrier et al. , 1961). Sexual precocity in gi rls, the fact remains that reasonably near physiologic accompanied by macular areas of hyperpigmenta­ concent rations o f exogenous estrogens do not re­ tion of irregular outline, polyostotic fibrous dys­ verse the rapid rate of growth of sexual h air. plasia, and sometimes other endocrine abnorma li ­ Hamilton and Terada (1963) suggested that the ties, is a rare nonfamili al disorder call ed Albright's seeming increase in facial hair after the menopause syndrome (Albright et al. , 1938). is actually coarsened h air produced by inherent Hirs utism in normal children. The evaluation of changes within the follicles themselves which are hirsutism in children can be rather complex, de­ age dependent but unrelated to hormonal stimula­ pending on the extent and severity of the involve­ tions. I.a m n ot aware of any recent fa milial studies ment, a nd requires a total evaluation of the pa­ on the extent and severity of postmenopausal tients . This latter task is made even more difficul t mo ustache a nd chin hairs. by the lack, except for Holzel's study (1951) , of Neural and emotional factors. In previous re­ systematic invest igations of normal children; views of the evidence fo r n eural co ntrol of hair many more studies are needed. Small to moderate growth, I h ave concluded that there are no experi­ amounts of lanugo hair widaly distributed in the mental or objective c linical observations to sub­ newborn are not rare but usua lly disappear during stantiate such control (1969). Quite the contrary, the first year or two of life (Wilkins et al. , 1965). in most cases, hirsutism is usua lly related to Occasionally, t he lanugo hair persists and forms hormonal mechanisms medi ated t hrough the hy­ terminal hair, most commonly in the lumbosacral pothalamic- pi tui tary-adrenal- ovarian axis or is a region a nd longitudinally a long t he spinal column fortui tous relationship. Emotional stress has been and on the extremities. Many of the generali za­ implicated as a ·factor in hirsutism. Bush and tion s about familial adult hirsutism can b e made Mahesh (1959) emphasized the e nvironmental as­ abou t t h e con dition in children. Occasionally no pects in their report of the rapid development of etiologic factors will be found (Fig. 1A). hirsutism in one of identical twins after severe Pregnancy. Women in their first trimester of emo tional stress. When ACTH was given to both pregnancy co mmonly experience increased hairi­ twins, the urinary excretion of 17 -ketosteroids ness, especiall y on the face, extremities, and about increased much more in the hirsute twin than in the breasts (Bissell and Williams, 1945; Stoddard, t he nonhirsute twin. Meyer and Zerssen (1960) 1945). In most cases the hypertrichosis is s light to reported a high l evel of a nxiety in hirsute women. moderate and disappears after or even before Lloyd (1963) believes that intense and prolonged 464 HIRSUTISM 465

emotional stress alters the patterns of secretion of occurrence of hirsutism and arteriovenous aneu­ adrenal steroids. Cortisol may augment the re­ rysms in the same areas (Allen, 1954) . However, sponse to androgens, and epinephrine can increase induced hyperemia of the skin had no therapeutic the production of cortisol (Lloyd, 1968). Neverthe­ effect on alopecia, and hair is apparently not easily less, clinical observations of the relationship be­ affected by external forces. tween hirsutism and psychologic stress are only Drug-induced hirsutism, either a simple, gener­ rarely substantiated by adequate experimental alized hypertrichosis or part of a virilizing syn­ data. As Lloyd (1963) pointed out, psychologically drome, is an increasingly frequent complication of depressed patients may only be more conscious of modern therapy (Fig. 3A). The types of drugs that excess hair. cause this type of reaction vary considerably (Ta­ ble). This complication should suggest major Idiopathic Hirsutism investigational avenues for study, but little prog­ ress has been made. The most interesting findings This term, which represents a poorly defined and involve those forms of hirsutism caused by Dilan­ heterogeneous category, is most commonly used to tin (Bray, 1959; Livingston et al., 1955), diazox ide describe a type of hypertrichosis with android (Baker eta!., 1967), and hexachlorobenzene (Turk­ distribution that obviously excludes ovarian or ish porphyria) (Cam and Nigogosyan, 1963) , which adrenal lesions (Fig. 2) . Usually it is accompanied are probably mediated by other influences than by acne, irregular menses or amenorrhea, obesity, steroidal hormones. On the other hand, if steroidal and even common baldness. This clinical syn­ drugs capable of inducing virilization are adminis­ drome blends so imperceptibly with the following tered, hirsutism is an expected complication. Pro­ three other main categories that it is often difficult gestogens, anabolic steroids, and testosterone and to separate them with certainty: (1) the racial or its derivatives are in this category. Genetic differ­ familial type of hirsutism in which the menstrua l ences in individual susceptibility to the develop­ cycle and fertility are co~pletely normal, (2) the ment of hirsutism and virilization are apparent in acquired adult adrenogenital syndrome, and (3) the variable doses of testosterone required to the Stein-Leventhal syndrome. Except for Lo­ produce this effect. Some women are susceptible to renzo' s study (1970), little information is available exceedingly small doses of androgens (Hamblen, on the genetic influence of these conditions. I 1957), and brunettes are said to be more suscepti­ previously summarized the arguments (1969) for relating the idiopathic type to one or another type ble than blonds (Geist, 1941). of hirsutism, but until more information and pre.­ Hirsutism Associated With Nevi or Hamartomas cise evaluation are available, this category should probably be maintained. Severe hypertrichosis sometimes occurs in com­ pound or dermal nevi, an association referred to as Extrinsic Influences on Hair Growth nevus pigmentosus et pilosus. A familial occur­ rence has been postulated for the inheritance of Several investigators have suggested important moles, with dominant transmission reported in environmental effects on hirsutism, especially of some pedigrees (Denaro, 1944; McKusick, 1971). sun and wind on increased amounts of hair on Moles are also a feature of Turner's syndrome. sun-exposed areas, but this influence has never Nevertheless, in most people, multifactorial in­ been proved (Castellani, 1938). Probably only herita nce is the more likely mechanism. When severe and repeated cutaneous stimulation, like pigment cells are not present, as happens occasion­ that reported in retarded patients who chew and ally, such localized areas of hairiness in normal bite their skin repeatedly (Ressmann and Butter­ skin are called "nevus pilosus" (Fig. 1B). They worth , 1952) , will cause localized hypertrichosis. occur most commonly on the back, especially in Occupational types of localized hairiness of the the lumbosacral region; occasionally they are as­ shoulders and adjacent areas, like those of sack sociated with abnormalities of the spinal column. bearers (Csillag, 1921) and of porters carrying Special mention should be made of the giant heavy loads on straps (Naus, 1961), have been bathing trunk nevi that frequently have luxuriant reported. An excessive amount of hair has been growths of pigmented hair (Reed and Becker, noted about the peripheral areas of lichenified 1964) . Reed et al. (1965a) pointed out the derma to­ plaques (Ressmann and Butterworth, 1952) and mal distribution, the asymmetry sharply delimited hair neogenesis was postulated in stimulated acan­ at the midline or the symmetry of the lesions, as thotic skin (Muller, 1971) . Several investigators well as occasional association with neurfibromato­ (Becker and Obermayer, 1940; Ressmann and sis. Crowe and associates (1956) reported extensive Butterworth, 1952; Flesch, 1954) have suggested bathing trunk nevi in three of their 223 patients that hyperemia of the skin increases the growth of with neurofibromatosis. Nevertheless, except for hair, basing their hypothesis on the simultaneous two possible cases involving a boy and his sister

FIG. 1. Hirsutism of unknown cause. A. In 7-year-old girl who had had dumbbell-type neuroblastoma resected from posterior mediastinum at 13 months of age, onset of hirsutism at 5 years. B. Nevus pilosis of right shoulder, present since infancy without change in 56-year-old man. C. Facial hirsutism in 54-year-old woman who had noted excessive hair growth 1 year before diagnosis of porphyria cutanea tarda. 466 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

F IG. 2. Idiopathic hirsutism in a 22-year-old healthy woman. First noted at 14 years of age; endocrine studies and menstruation were normal. A a nd B. Hypertrichosis of face and breasts; C. mild female-type common baldness; D. acuminate pattern of pubic hair.

(Cockayne, 1933), familial giant nev i h ave not co nstitute t he largest number of patients referred been reported. Neurofibromatosis is transm itted as to endocrinologic c linics (Deller et al. , 1965). The a mendelian a utosomal dominant t ra it. main conditions with easily recognizable genetic Copeman and Jones (1965) reported 24 cases, aspects are the syndromes of congenital adrenal two of them women, with a distinctive type of hyperplasia and other intersex disorders. Cooper et hypertrichosis associated with nevus unius later­ a l. (1968) and Givens eta!. (1971) s uggest that the a li s previously described by Becker (1949) ; t he Stein- Leventhal sy ndrome be included in this incidence of t he lesions was estimated to be at least category; but we need more information about the one in 4,000 patients. The lesions occurred most male members of such families before we can often on the upper part of the trunk and were accept an a utosomal dominant mode of inheri­ considered a maldevelopment or hamartoma of t he tance. epidermis. Some areas were extensively involved, Cushing's syndrome and acromegaly. T hese con­ but epidermal t hickening was not apparent in all ditions have been reported infrequently in the cases. familial syndromes of multiple endocrine adeno­ mas (Ball ard et a!. , 1964; Steiner et a l. , 1968) . Hirsutism Associated With Endocrinologic Eight examples of acromegaly in affected members Disorders of two successive generations included four fathers The causes of hirsutism associated with known and one or more affected sons (Koch a nd Tiwisina endocrinologic abnorma li t ies are listed in the Ta­ 1959). Daughaday (1968) reported t hat hypertri­ ble. It s hould be emphasized that t hese syndromes chosis develops in 53 percent of patients with probably affect only 1 percent or less of patients acromegaly a nd is usually detected early. Hirsut­ with hypertrichosis (Fig. 3B and C). Known endo­ ism in acromegaly has been related to excess crinologic disease is more prevalent in extremely pituitary trophic factors other t han growth hor­ hirsute women, especiall y in t hose who show signs mone. Late in the disease, loss of hair occurs when of defeminization or questionable virilization and pituitary insufficiency develops. The incidence of

FIG . 3. A. Facial hirsutism in 55-year-old woman. First noted 4 months after daily application of an androgen cream to the vulvar region; hypertrichosis also present on extremities and pubic area. Band C. Signifi cant hirsutism in 75-year-old woman. Hirsutism had been present 6 months in beard a rea, extremities, and pubic area, associated with adrenal carcinoma. Mild psoriasis also noted in C. 467 468 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

hirsutism in Cushing's syndrome has been esti­ Except for increased somatic growth, patients mated to be as low as 25 percent and as high as S4 with the simple virilizing fo rm of congenital adre­ percent (Soffer et a!. , I96I) . Full-blown Cushing's nal hyperplasia do well in infancy. In females syndrome is easy to recognize, a nd hirsutism is not virilization is usua lly evident at birth with variabl~ an important diagnostic sign since other clinical degrees of masculinization of t he external geni­ features are so pronounced. Mild forms of the talia. If the patient remains untreated, increased disease have been n oted with obesity of a nonde­ somatic g rowth and secondary sexual characteris­ script type and mild hirsutism (Goldzieher, I964). tics appear, including pubic hair at the age of 2 Mention should be made of an increasingly years. Both male a nd female patients have a common type of Cushing's syndrome associated growth of beard, common baldness (if genetically with the autonomous production of an A CTH-like disposed), and masculine habitus. Excessive pro­ substance by nonendocrine tumors. Almost SO duction of testosterone from androstenedione has percent of these neoplasms have been one of three been demonstrated (Rivarola et a!. , I967). Mild cell types-bronchogenic carcinoma, thymic car­ degrees of the defect may not become evident in cinoma, and pancreatic carcinoma (Liddle et al. , females until adolescence or early a dulthood (Ca­ I965) . A cure of Cushing's disease with hirsutism thro, I969) . has been reported following removal of an argentaf­ The common form of congenital adrenal hyper­ finoma of the appendix (Bernstein et al. , I970). plasia affects both sexes equally and is inherited as Upton a nd Amatruda (I971) found tumor peptides an autosomal recessive trait. Its incidence has been with corticotropin-releasing factor-like activity. estimated to be 1 in 67,000 persons in Maryland Congenital adrenal hyperplasia. At least six a nd 1 in 5,000 in Switzerland, the esti mates of the types of congenital adrenal hyperplasia have been frequency in heterozygotes being 1 in I2S a nd 1 in thoroughly described and the biochemical defects 35, respectively. Usually more females than males investigated. The abnormali ty in the common are ~e ported, since the condition is more easily varieties is a defective biosynthesis of cortisol observed and diagnosed in females than in males. which results in increased secretion of ACTH a nd In patients with the s imple, common virilizing adrenal h yperplasia. Concomitantly an increased forms, the onset of vi rilization occurs at different production of a ndrogen causes premature viriliza­ ages in different pedigrees; in the virilizing and tion in the male and masculinization of the female salt-losing forms, the o nset of electrolyte loss with a consequent stimulation of sexual hair. This begins either neonatall y o r l ater in life. Sotos abnormality is t he most common cause of female (1970) has pointed out t hat some of the cases of pseudohermaphroditism or of a mbiguous genitalia what seem to be mixed forms of congenital adrenal in the newborn . Bongiovanni and Root (I963) have hyperplasia are not easily explained. reviewed the subject extensively. Large amounts of Therapy for all forms of congenital adrenal pregnanetriol are regularly found in the urine of hyperplasia is usually complex, depending on the about 95 percent of all patients, a finding consist­ extent of the cortisol or mineralocorticoid defi­ ent with the block in the conversion of I7-hydroxy­ ciency. Surgical correction of the external geni­ progesterone to cortisol. However, different en­ talia is sometimes indicated; in such cases, special zymatic deficiencies in cortisol biosynthesis a re consideration must be given to the sex of rearing now recognized. Except in congeni tal lipoid adre­ and the psycholog ic adjustment. Such therapeutic nal h yperplasia and in complete I7-hydroxylase measures are thoroughl y discussed in most stan­ deficiency (and the rare IS-hydroxylase and IS­ dard textbooks on endocrinology (Hubble, I969) . dehydrogenase deficiencies that are solely salt-los­ Rare form s of congenital adrenal hyperplasia: ing forms and hence will not be discussed further), Adrenal hyperplasia II is a rare, virilizing, hyper­ excessive androgens are produced in all forms of tensive type caused b y 11 -hydroxylase deficiency congenital adrenal hyperplasia (Sotos, I970). that results in the retention of a potent salt-retain­ Common virilization type of co ngenital adrenal ing steroid and hypertension. About 5 percent of hy perplasia: Ninety-five percent of t he cases of the cases of conge nital adrenal h yperplasia a re of congenital adrenal hyperplasia are of this type, this type (Cathro, I969) . Affected patients mani­ which is pue to a deficiency of 21 -hydroxylase that fest a progressive virilization si milar to that in the results in a block of C-21 hydroxylation of 17- other forms described. Sometimes the enzymatic hydroxyprogesterone. Of the two common forms, defect is mild, and hypertension either is absent the milder, simple virilizing form constitutes two­ altogether or commences later in childhood or thirds of the cases, a nd the virilizing, salt-losing adulthood (Sotos, 1970). form t he other one-third. In the latter type, the Other rare genetic types include forms caused by production of aldosterone is decreased, and aldos­ deficiencies of 3-,8-hydroxysteroid dehydrogenase terone antagonists accumulate and lead to severe or by 17-hydroxylase deficiency. Complete defi­ wasting and addison ian crises. Degenhart and col­ ciency of the former results in severe loss of salt leagues (I965) postulated that these forms were and death. Females have variable degrees of virili­ dependent upon different genetic defects; it is zation of the external ge nitalia and males have usually true that only one form or the other is seen defective virilization of the external ge nitalia since in affected members of a kindred. the enzyme deficiency is a lso present in the Leydig HIRSUTISM 469

cells of t he testis. In such cases, virilization does nal ge ni tali a. Feminization is less adequate at not occur; instead sexual underdevelopment and a puberty than in patients affected with the com­ deficient synthesis of estrogens and androgens as plete form. Some have scanty sexual hair, whereas well as of cortisol, plus excessive production of others are hirsute. The inheritance is similar to progesterone, 11-desoxycorticosterone, and cor­ that of the complete form , but whether it is a ticosterone, are present. The biochemical error in separate genetic entity is not clear (Sotos, 1970). the ovaries accounts for the defective production of Patients with the testicular masculinization- fem­ estrogen. The inheritance of this form appears to ini zation syndrome resemble those with the in­ be more complex, and there may be different complete form of testicular feminization and are genetic forms. Thus, a father and son have been distinguishable mainly by the hereditary pattern, reported to be involved; in another case, an X­ which suggests an a utosomal recessive trait with linked recessive inheritance was thought to be consanguinity in the family background (Philip implicated (McKusick, 1971; Sotos, 1970). and Trolle, 1965; Sotos, 1970). In lipoid adrenal hyperplasia, the biosynthetic defect occurs between cholesterol and pregnene­ Hirsutism Associated With CongenitaL AnomaLies lone. Infants of both sexes have normal external Many congenital syndromes, in which hirsutism genitali a since the production of estrogens and is of variable significance, are included here. In androgens is affected. All known subjects have lost some cases, such as hypertrichosis lanuginosa, salt, have had recurrent infections, and have died Cornelia de Lange syndrome, congenital general­ in infancy. ized lipodystrophy, and leprechaunism, hypertri­ Intersex probLems other than congenitaL adrenaL chosis is a prominent feature; it has also been hy perpLasia. Five to 10 percent of patients with associated with congeni tal hemihypertrophy (Hur­ P~re gonadal dysgenesis have had associated witz and Klaus, 1971) . Cowden's syndrome, a rare hirsutism or virilism, the causes of which were not disorder of which the genetics are not known, always known. Recently Judd and associates consists principally of congenital macrogingivae, (1970) demonstrated the production of testosterone large fibroadenomas of the breast which may by rudimentary gonadal streaks in a young woman become malignant, and papillomas of the mouth. with progressive hirsutism. Hirsutism and virilism According to Witkop (1971), hypertrichosis is have a lso been described in patients with Turner's sometimes a feature. In t he mucopolysac­ syndrome. In both conditions, explanations fre­ charidoses, the trisomy 18 (E) syndrome, and the quently have not been apparent; but in some cases Rubinstein- Taybi syndrome, hypertrichosis is of androgen -secreting tumors, particularly hilus cell less clinical importance and will not be discussed tumors and gonadoblastomas developing in the further (Bartok et a !. , 1968; Smith, 1970). I have dysgenetic go nads, may have been responsible. In deleted Bloom's syndrome from my previous list male pseudohermaphrodites reared as gi rl s, hirsut­ (1969) on the advice of German (personal com­ ism sometimes develops during adolescence as a munication), who has seen almost all the reported functional consequence of testicular remnants, and patients. The occurrence of hirsutism in t he Seckel a fami lial occurrence has been noted in some syndrome is also in doubt. Seckel (1960) reported patients (McK usick, 1971). However, about a third t hat generali zed hypertrichosis occurred in 4 of 15 of the patients with male pseudohermaphroditism, patients who were bird-headed dwarfs, but no who are classified as having the complete fo rm of mention of this was made by other authors. On the testicular feminization and are frequently particu­ contrary, McKusick eta!. (1967) noted occasional larly feminine in appearance, do not have axillary a lopecia in t he Seckel syndrome. The various or pubic hair; the remainder have sparse amounts mechanisms leading to increased hairiness have of hair despite the normal concentration of plasma not yet been explained. Undoubtedly other con­ and urinary testosterone. Furthermore, testoster­ genital anomalies will be added to t he list, but one does not cause a n increased growth of hair in confirmatory information on the relative frequency t hese patients. Karsznia and associates (1969} and and importance of this characteristic is needed. Wilson and Walker (1969) suggested that t he Hypertrichosis lanuginosa. In t his extremely occurrence of decreased end-organ sensitivity in­ rare hereditary di order of autosomal dominant volves a deficiency in the conversion of testosterone inheritance, t he generalized growth of lanugo hair to dihydrotestosterone in· the skin, but this has not persists (Cockayne, 1933; Flesch, 1954). The degree been definitively confirmed. This form of testicular of hirsutism varies and the lanugo hair does not feminization is transmitted through apparently develop into terminal hair. Hirsutism may be normal females a nd affects about half of their present at birth or may not become apparent until genetic sons. It is not known, however, whether this as late as the seventh year. Dental abnormali ties, is an X-linked recessive or an autosomal dominant especiall y anodontia and gingival fibromatosis, trait without effect in the female. It has a lso been have been reported in several patients. Gor\in and suggested that the disorder results from a regulator Pindborg (1964) have referred to this condition as a gene abnormali ty. syndrome of "idiopathi c gingival fibromatosis and Patients with the incomplete form of testicula r hypertrichosis." The development of normal ter­ feminization usually have ambiguous male exter- minal ha ir in some patients seen by Gorlin a nd 470 THE JOURNAL OF INVESTIGATIVE DERMAT OLOGY

Pindborg s uggests different forms o f t he disorder finding. Hensley and Glynn (1969) reported such a since in t he classic form termina l ha ir is said never case and revi ewed 5 other si milar cases in t h e to replace lanugo ha ir. This is best illustrated b y literature, noting t hat epitheli al m aligna ncies (two Cockayne's (1 933 ) separation of the condition af­ of which were s mall cell anaplastic carcinomas of fecting Julia Pastrana a nd her son into a separate the bronchi) were reported in each case. No steroi­ syndrome termed b y him " hypertrichos is termi­ da l abnorma lities in these patients have been nalis w it h Simian characteri stics" because of the reported to date, and t he sexual ha ir is not termina l appearance of t he ha ir, which was in ­ affected. T his syndrome of " maligna nt down," as tensely pigmented, a nd of certain facia l character­ Fretzin (1967) has called i t, is completely differen t istics. In reviewing t he literature from t he 16th from t he rare cases of hirsutism in women as­ cent ury to t he present, Felgenha uer (1969) grouped sociated wi t h m etastatic carcin oma of the ovary all these cases into one syndrome, as did Beighton (Krukenberg's t umor), whi ch i s sometimes as­ (1970a). Whether or not they are separate e nt it ies sociated wit h virilization or m ay result from t h e or constitute o nly varia ble e xpressions of an a uto­ secretion of a ndrogen b y a n ovari an stroma ( Scully soma l dominant t ra it rema ins to be seen. a nd Ri chardson, 1961; Ober et a!. , 1962). Cornelia de Lange sy ndrome. Failure to grow, Important a lso is t he hirsutism associated with mental retardation, a n a bnormal distinctive cry, a ll the forms of porphyria, es pec iall y porphyria and a cluster of relatively minor congenital malfor­ cutanea tarda ( Fig. 1C), variegate p orphyri a, a nd mations a re characteristic of this syndrome, which co n ge ~i ta l porphyri a ( Dean, 1963 ; Zeligm an, is of uncertain genetic etiology. Both autosomal 1963) . However, t he severest hirsutism was t hat of recessive inheri tance and a c hromosomal a berra­ t he so-called m onkey children seen during t h e t ion have been suggested (J ervis a nd Stimson, epidemi c o f p orphyria in Turkey caused b y t he 1963; Hart et al. , 1965; Schuster a nd J ohnson, in gestion of hexachl orobenze ne. 1966; M cKusick, 1971 ). Hirsutism is invaria bly Hypothyroid children frequently have a noticea­ present. T he eyebrows are long, thick, a nd darkly ble unexplained increase in lightly p igmented fine pigmented and may meet in t he midline a nd t he ha ir on the t runk and extremi t ies t hat is never seen eyelashes are long a nd deli cate. The a nteri or wi t h signs o f virilism . T reatment with t hyroid ha irline of t he scalp is set low on t he forehead . An extract causes co mplete in vo lution of t he hair. The increased growth of h air o n t he back is common, cause of the hirsutism or t he reason fo r t he and occasionally o ther areas of t he t runk and susceptibility of children has not b een explained, extre mit ies are a lso hirsute. but increased conve rsion of testosterone to urinary Co ngenital generalized lipodystrophy ( Berar­ metaboli tes wit h greater a ndrogenic activity dinelli's or Seip's sy ndrome). The syndrome con­ (Goldzieher, 1964) or alterations in t he metabolic sists of co ngenital genera li zed lipodystrophy as­ clearance rate of testosterone o r in t he testoster­ sociated wi t h accelerated somatic g rowth, acan­ one- binding globulin are possibilities (Bardin and t hosis nigri cans, diabetes melli t us, and a number Mahoudeau, 1970). of other abnorma li t ies. T here is hi rsut ism of t he CO M MENTS face, nec k, a rms, and legs and frequently a low anterior h a irline. The hypertri chosis does not in ­ The management o f a patient wi t h hi rs utism clude pubic or axill ary hair although enlargement need n ot be complicated even t hough t he as­ of t he pha llus s uggests an androgen effect. How­ sociated disorders a re n umerous (Forbes, 1965; ever, Gordon and colleagues ( 1971 ) have related Muller, 1969). Endocrinologic a bnormali ties are this to the increased secretion of growth hormone seen in a bout 1 percent of t he wo men who consul t a or to t he impaired p eriphera l breakdown of the physician about hypert richosis b ut a re co mmoner hormone. Autosoma l recessive inheri tance is in­ in severe degrees of hirsutism. New techniques will di cated ; many cases have been of Portuguese­ probably identify a dditiona l cases of a bnormal Spanish ancestry. Leprechaunism (Donohu e a nd endocrine fun ction, like t hose shown b y Bardin Uc hida, 1954; Smit h, 1970; Kaloustian et al. , 1971) a nd Ma houdeau (1970) in some virili zed women has been r egarded as a possible vari ant o f congeni­ who had in creased testo terone-prod uction rates tal genera li zed lipodystrophy. However, g rowth but, paradox icall y, norm al pl asma testosterone retardation and the leprechaun facies a re com­ levels because of the increased clea ra nce of hor­ pl etely different, a nd probably t he syndromes are mone by extrahepatic t issues. also diffe rent. Facia l a nd body hirsutism similar to However, explanations for t he extraordinary the Seip syndrome is sometimes seen, a nd t he vari abili ty normall y fo und in m an and fo r t he mode of inheritance is similar (Reed eta!., 1965 b) . numerous c ases of hypert ric hos is t hat ari se from M iscellaneo us causes. A number of other condi­ nonendocrinologic causes will probably co me from tions associated wit h hirsutism (Ta ble) form a n additiona l investigations of the e nd-o rgan respon­ interesting g roup of disorders in whi ch h ypert ri ­ siveness of t he pilosebaceous structures t hemselves chosis is not easil y e xplained . S pec ial mention to androgenic s timulation . Studies in t hese area should be ma de of acquired h ypertri chosis lanugi­ have only j ust b egun, but a lready tangible results nosa in adults (Lyell and Whit tle, 1951; Fretzin , can be seen in t he reports of Bruchovsky a nd 1967) in whi ch metastatic cancer was an associated Wilson ( 1968), Ad achi and Kano ( 1970), Faredin et HIRSUTISM 471

al. (1970), Takashima et a!. (1970) , and Sansone tosterone. Biochem. Biophys. Res. Commun., a nd Reisner (1971), all having to do with vari ations 4 1:884-890. ess of pilosebaceous Albright, F., Scoville, B. , and Sulkowitch, H. W. (1938) . in t he end-organ r esponsiven Syndrome characteri zed b y osteitis fibrosa dis­ follicles in t he skin. semin ata, areas of pigmentation, and a gonadal New avenues of investigation of hair biology dysfunction: further observations including t he re­ have been opened by Freedberg (1970), who re­ port of two more cases. Endocrin ology, 22:411- 421. ncorporating system Allen, A. C. (1954). The Skin: A Clinicopathologic ported a cell-free amino acid-i Treatise. C. V. Mosby Company, St. Loui s, p. 606. prepared from ma mmalian h a ir root cell s t hat Anderson, K. M ., and Liao, S. (1968). Selective retention could provide important information about t he of dihydrotestosterone by prostatic nu clei. Nature regulatory mechanisms and biochemical pathways (Lond.), 219:277- 279 . Baillie, A. H., T homson, J., and Milne, J. A. (1966). The involved in the synthesis of ha ir protein. Should distribution of hydroxysteroid dehydrogenase in t h e system prove to be sufficient ly active and human se baceous g lands. Br. J. Dermatol. , repro ducible, then hair bulbs should become a 78:451- 457 . prime t issue where th" anormali t ies in severa l Baker, L., Kaye, R., Root, A. W. , and Prasad, A. L. N. ( 1967). Diazoxide treatment of idiopathic hypo­ genetic and drug-induced disorders could be deter­ glycemia of infancy. J. Pediatr., 71:494 - 505 . mined. Already avail able is a more direct applica­ Ba ll ard , H. S., Frame, B. , and Hartsock, R. J. (1964). tion of plucked ha ir bulbs for t he d iagnosis of Familial mult iple e ndocrine a denoma-peptic ulcer genet ic disorders and the ident ification of heter­ complex. Medici ne (Baltimore) , 43:481- 516. ozygotes reported by S il vers a nd associates (1971) Ba rdin, C. W. , and Mahoudeau, J . A. (1970). Dynamics of androgen m etaboli sm in women wi t h hirsutism. in the Lesch- Nyhan syndrome. These workers Ann. Clin . Res., 2:251- 262. sh owed the absence of hypoxanthine-guanine­ Bartok, W. R. , Reed, W. B. , and Fish, C. (1968). phosphoribosyl-transferase by usin g hypoxan­ Rubinstein- T aybi syndrome. Cut is, 4: 1350- 1353 . t hine-C 14 as substrate and measuring the conver ­ Bashirelahi, N. , Chader, G. J., and Villee, C. A. (1969). Effects of dihydrotestosterone o n the synthesis of sion to radioactive nucleotide in affected patients nucleic acid and ATP in prostatic nuclei. Biochem. a nd t he mosaicism in hair folli cles of obligate Biophys. Res. Commun., 37:976- 981. heterozygotes in which 25 percent of hair roots Bashirelahi, N. , and Villee, C. A. (1970). Synthesis of lacked t he enzyme. These results, which are a n nucleic acids by isolated nuclei: Effect of testoster­ one a nd dihydrotestosterone. Biochim. Biophys. a ddit ional confirmation of the Lyon hypothesis, Acta, 202:192- 194. strengthen the expectation that similar studies wi ll Baulieu, E. E. (1970). T he action of h ormone metabo­ confirm t he usefulness of hair roots in the study of li tes: a new concept in endocrinology: A review of the metabolism and the activity of testosterone . Ann. numerous genetic disorders. Clin . Res., 2:246- 250. Little is known about environmental influences Becker, S. W. (1949). Concurrent melanosis a nd hyper­ on hair growth, but t he possibilit ies of Freed berg's trichos is in distribution of nevus unius lateral is. Arch . model system (1970) as well as the use of follicle Dermatol. , 60: 155- 160. kinetics and Becker, S. W. , and Obermayer, M. E . (1940 ). Modern squash preparations for studies of cell Dermatology and Syphilology. J . B. Lippincott Com­ response to irradiation (Malkinson et a!. , 1971) pany, Philadelphia. su ggest that much additional information will be Beckman, L., and Bi:ii:ik, J. A. (1959 ). Distribution and for t hcoming shortly. It has previously been shown inheritance of mid-digital ha ir in Sweden. Hereditas. that protein deprivation (Bradfield et a!. , 1967 ; 45:215- 220. Beek, C. H. ( 1950). Study on extension and distribution Bradfield eta!. , 1968) causes significant atrophy of of human body-hair. Dermatologica, J0 /:317- 33 1. t he hair root; such information has been used to Beighton, P . (1970a). Congenital hypertri chosis lanugi­ survey protein malnutrition in a population group. nosa. Arch. Dermatol. , /0/:669- 672. The hair roots, t herefore, are an important biologic Beighton, P. (1970 b) . Familia l hypertrichosis cubit i: hairy e lbows syndrome. J. Med. Genet., 7:158- 160. t issue, easily available for investigation (Muller Bernstein, J ., Herle, A. V., J acobson, S., and Brown , J. and W inkelmann, 1969), whose versatili ty has not (1970). Cushing's syndrome c ured b y a ppendectomy been generally appreciated by t he scient ifi c com­ (a bstract). Clin . Res., 18: 120. munity. Bernstein, M. E. (1949). The middigital h air genes: Their inheri tance and distribution among the white A number of fundamental clinical problems race. J. Hered., 40:127- 131. relating to hirsut ism need to be resolved. What Bissell , G. W., and Willia ms, R. H. (1945). Hirsut ism in causes the hirsutism induced by Dilantin, diazox­ fema les: A clinical study of its etiology, co urse and Why does hirsut ism treatment . Ann. Intern . Med., 22:773-806. ide, or hexachlorobenzene? Bongiovann i, A. M. , and Root, A. W. (1963). The occur in patients with porphyri a? Finally, and adrenoge nita l syndrome. N. Engl. J. Med., most importantly, why is hypertrichosis of the 268:1283- 1289. moustache a nd chin areas seen in many post­ Bradfield , R. B. , Bailey, M. A. , and Cordano, A. (1968) . Ha ir-root changes in Andean Indian children during menopausal women in spite of declining levels of marasmic kwashiorkor. Lancet, 2: 1169- 1170. all sex hormones? Answers to t hese complex ques­ Bradfield, R. B., Ba il ey, M. A. , and Marge n, S. (1967). tions will no doubt be difficult, but t hey should Morphological changes in human scalp hair roots provide abundant biologic information applicable during deprivation of protein. Science, /57:438- 439. . Bray, P. F. (1959). Diphenylhydantoin (Dil antin®) after to numerous medical problems 20 years: A review with re-emphasis by treatment of REFERENCES 84 patients. Pediatrics, 23:151- 161. Brooksbank, B. W. L. (1961) . Endocrinological aspects of Adachi, K., and Kano, M. (1970). Adenyl cycl ase in hirsutism. Phys iol. Rev. , 41:623-676. human hair follicles: Its inhibit ion by dihydrotes- Bruchovsky, N., and Wil son, J . D. (1968). The co nversion 472 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

of testosterone to 5 a-androstan-17{j-o1-3-one by rat Faredin , I., Toth, I., Fazekas! A. G. , Kokai, K., and prostate in vivo and in vitro. J. Bioi. Chern., Julesz, M. (1970). The m v1tro metabolism of (4- "C) 243:2012- 2021. androst-4-ene- 3 , 17 -dwne by normal and hirsute fe ­ Bush, I. E ., and Mahesh, V. B. (1959). Adrenocortical male skin . Int. J. Dermatol., 9:147- 152. hyperfunction with sudden onset of hirsutism. J. Felgenhauer, W. R. (1969). Hypertrichosis lanuginosa Endocrinol., 18:1- 25 . uni versalis. J. Genet. Hum., 17:1- 44. Cam, C., and Nigogosya n, G. (1963). Acqu ired tox ic Ferrier, P., Shepard, T. H ., fl, and Smith, E . K. (1961). porphyria cutanea tarda due to hexachlorobenzene: Growth disturbances and valu es for h ormone excre­ Report of 348 cases caused by this fun gicide. tion in various forms of precocious sexual develop­ J.A.M.A., 183:88- 91. ment . Pediatrics, 28:258- 275. Cameron, E. H. D., Baillie, A. H ., Grant, J. K., Milne, J. Flesch, P. (1954). Hair growth. ln: Physiology and A. , and Thomson, J . (1966). Transformation in vitro Biochemistry of the Skin (ed. by Rothman S.). of [7 a -' H ]dehydroepiandrosterone to [' H] testoster­ Uni versity of Chi cago Press, Chicago, pp. 601-'661. one by skin from men (abstract). J . Endocrinol. , Forbes, A. P. (1965) . Hypertrichosis (co ncluded). 35:XTX - XX. Engl. J. Med., 273:646- 648. Castell ani, A. (1938). Note on some li ttle-k nown condi­ Freedberg, I. M. (1970). Hair root cell -free protein tions of the lanugo hair. J. Trop. Med. Hyg., 41 :400. synthesis. J. Invest. Derma to!. , 54:108- 120. Cathro, D. M. (1969). Adrenal cortex and medulla. ln: Fretzin, D. F. (1967). Malignant down. Arch. Dermatol., Paediatric Endocrinology (ed . by Hubble, D.). F. A. 95:294- 297 . Davis Company, Philadelphia, pp. 187- 327 . Garn, S. B. (1951) . The use of middle-phalangeal hair in Cockayne, E. A. (1933). Inherited Abnormalities of the population stud ies. Am. J. Phys. Anthropol., Skin and Its Appendages. Oxford Uni versity P ress, 9:325- 333. London. Geist, S. H . (1941). Androgen therapy in the hu man Conly, P. W., Sandberg, D. H., and Cleveland, W. W. fema le. J. Clin. Endocrinol., /:154- 161. (1967). Steroid metabolism in premature pubarche Givens, J. R., Wiser, W. L., Coleman, S. A., Wilroy, R. and virilizing adrenal h yperplasia. J . Pediatr. , S ., Andersen, R.N., a nd Fish, S. A. (1971). Familial 71:506-511. ovari an h yperthecosis: a study o f two families. Am. Cooper, H. E., Spell acy, W. N. , Prem, K. A., and Cohen, J. Obstet. Gynecol. , 1/0:959-972. W. D. (1968). Hereditary factors in the Stein- Leven­ Goldzieher, J. W. (1964). Adrenal cortical dysfunction. t ha l syndrome. Am. J . Obstet. Gynecol., Clin. Obstet. Gynecol. , 7:11 36- 1159. 100:371 - 387. Gordon, H. , Pimstone, B. L. , Leary, P.M., and Gordon , Copeman, P. W. M., and J ones, E. W. (1965) . Pigmented W. (1971). Congeni tal generali zed lipodystrophy ha iry epidermal n evus (Becker). Arch . Dermatol., with abnormal growth hormone homeostasis. Arch. 92:249- 251. Dermatol., 104:551- 599. Crowe, F. W., Schull, W. J., and Nee!, J. V. (1956). A Go rlin, R. J ., and Pindborg, J . J. (1964). Syndromes of Clinical, Pathological, and Genetic Study of Mul­ the Head and Neck. McGraw- Hill Book Company, tiple Neurofibromatosis. Charles C Thomas, Pub­ New York. lisher, Springfield, Tll inois, p. 47. H amblen, E. C. (1957). Androgenic therapy of woman. Cs ill ag, J. (1921). Ober Berufshypertrichose. Arch. Der­ Sout h. Med. J., 50:743- 752 . matol. Syphil., /34:147- 150. Ham il ton, J. B. (1947) . A secondary sexual character that Danforth, C. H. (1921). Distribution of hair on the digits develops in an organ common to both sexes but in man. Am. J. P hys. Anthropol. , 4:189- 204 . norma lly o nly in men: With a discussion of the Danforth, C. H. (1939). Physiology of human hair . relation of this c haracter to endocrin e stimulation Physiol. Rev. , 19:94 _: 111. (abstract) . J. Clin. Endocrinol., 7:465. Danforth, C. H ., and T rotter, M. (1922). The distribution Hamilton, J. B. (1958). Age, sex, and genetic factors in of body hair in white subjects. Am. J . P hys. An ­ the regulation of hair growth in man: A comparison thropol. , 5:259- 265. of Caucasian and Japanese populations. In: Th e Daughaday, W. H. (1968). T he adenohypophysis. In : Biology of Hair Growth (ed. by Montagna, W. , and Textbook of Endocrinology (ed. by Williams, R. H.) Ellis, R. A.). Academic Press, New York, pp. (4th edition). W. B . ..Saunders Company, Philadel­ 399- 433. phia, p. 73. Hamilton, J . B. (1964). Racial and genetic predisposi­ Dean, G. (1963). The Porphyrias: A Story of Inheritance tion. Ciin. Obstet. Gynecol. , 7:1075- 1084. and Environment. J. B. Lippincott Company, P hila­ Hamil ton, J. B. , and Terada, H. (1963). Interdependence delphia. of ge netic, aging, and endocrine factors in hirsutism. Degenhart, H. J., Visser, H. K. A. , Wilmink, R. , and In : The Hirsute Female (ed. by Greenblatt, R. B.). Croughs, W. (1965). Aldosterone and cortisol secre­ Charl es C Thomas, Publisher, Springfield , Illinois, tion rates in infants and children with conge ni tal pp. 20- 47. adrena l hyperplasia s uggesting d ifferent Hamilton, J. B. , Terada, H., Mestler, G. E., and Tirman, 21- hydroxylation defects in "salt-losers" and "non­ W. ( 1969). Coarse sternal ha irs, a male secondary sex salt-losers." Acta Endocrinol. (Kbh.) , 48:587- 601. character that can be measured quantitatively: the Dell er, J. J., Jr., Wegienka, L. C., Conte, N. F., Rosner, influence of sex, age, and genetic factors. 11 . Other J . M., a nd Forsham, P . H. (1965). Testosterone sex-differing c haracters: relationship to age, to one metaboli sm in idiopathic hirsutism. Ann. Intern. another, and to values for coarse sternal h airs. In: Med., 63:369- 376. Advances in Biology of Skin: Hair Growth (ed. by Denaro, S. J. (1944). The inheritance of nevi. J. Hered., Montagna, W., and Dobson, R. L.). Vo l. IX . Perga ­ 35:215- 218. mon Press, New York , pp. 129- 151. Donohue, W. L., and Uch id a, I. (1954). Leprechaunism: Hansson, V., Tveter, K. J., and Attramadal, A. (1971). a euphemism for a rare familial disorder. J. Pediatr. , Uptake a nd binding of 5a-dihydrotestosterone in rat 45:505- 519. ventral prostate in vivo. Acta Endocrinol. (Kbh.) . Dronamraju, }(. R. (1964) . Y- linkage in man. Nature 67:384- 392. (Lond.) , 201:424- 425. Hart, Z. H., Jaslow, R. I., and Go mez, M. R. (1965). T he Dupertuis, C. W., Atkinson, W. B., and Elftman, H . de Lange syndrome. Am . J. Dis. Child ., /09:325-332. (1945) . Se){ differences in pubic hair distribution. Hensley, G. T ., a nd Glynn, K. P. (1969). Hypertrichosis Hum . Bioi. , 77:137- 142. lanuginosa as a s ign of in terna l malignancy. Cancer. Fang, S., Anderson, K. M., and Liao, S. (1969). Receptor 24:1051-1056. proteins for androgens. J . Bioi. Chern., 244:6584- Holzel, A. (1951) . Hypertri chosis in chi ldhood: a c linical 6595. study. Acta Paediatr. Scand ., 40:59-69. HIRSUTISM 473

Hubble, D. (1969). Paediatric Endocrinology. F. A. Davis (1970) . Sex steroid binding plasma protein (SBP). H Company, Philadelphia. Acta Endocrinol. [Suppl.] (Kbh.), /47:204- 221. ung, W. , Milhorat, T. H., Nelson, K. B., a nd August, Meyer, A. E., and Zerssen, D. vo n (1960). A psychological G. P. (1971) . Sexual precocity as the only s ign of a investigation of women with so-called idiopathic brain tumor in a 9-year-old boy. Am. J. Dis. Child. , hirsutism. J . Psychosom. Res ., 4:206- 235 . 12/:524- 527. Motulsky, A. G. , and Epstein, C. J . (1968). Genetics and Hurwitz, S., a nd K laus, S. N. (1971). Congeni tal hemihy­ endocrinology. In : Textbook of Endocrinology (ed. pertrophy with hypertri chosis. Arch. Dermatol., by Williams, R. H.) (4th edition). W. B. Saunders 103:98- 100. Company, Philadelphia, pp. 1131- 1159. lsmai~. A. A. , and Lorain e, J. A. (1969). Hirsutism: A Muller, S. A. (1969) . Hirsutism . Am. J . Med., disorder fr equent ly associated with menstrual abnor­ 46:803- 817. malities. Clin. Obstet. Gynecol., / 2:800- 827. Muller, S. A. (1971). Ha ir neogenesis. J. In vest. Der­ Ito, T ., and Horton, R. (1970). A new androgen in human matol. , 56:1 -9. plasma (abstract). Clin . Res. , /8:1 22. Muller, S. A., and Winkelmann, R. K. (1969). Oxidative Jacobsen, A. W., and Macklin, M. T. (1952). Heredi tary enzymes in plucked human scalp h airs (abstract). J. sexual precocity: Report of a family wi th 27 affected Invest. Dermatol. , 52:400. .members. Pediatrics, 9:682- 694. Naus, A. (196 1). Occupational hypertrichosis in porters Jerv is , G. A., and Stimson, C. W. (1963) . De Lange carryin g heavy loads on straps. Cesk. Dermatol. , syndrome: The "Amsterdam type" of mental defect 36:479:.481. with co ngeni tal m a lformation. J. Pediatr., Ober, W. B., Pollak, A. , Gerstmann, K. E., and Kupper­ 63:634- 645 . man, H. S. (1962). Krukenberg tumor with andro­ Judd , H . L., Scully, R. E., Atkins, L., Neer, R. M., a nd ge nic a nd progestational activity. Am. J. Obstet. Kliman, B. (1970) . Pure gonadal dysgenesis with Gynecol. , 84:739-744. progressive hirsutism: Demonstration of testosterone Pedersen, J. (1942- 1943). Hypertrichosis in women: On production by go nadal streaks. N. Engl. J . Med. , certain regularities in the distribution of hypertri ­ 282:881- 885. chosis over the body regions, and on the importance Kaloustian, D. M. D. , Kronfol, N . M., Takla, R. , of age to its frequency in so me a reas. Acta Derm . H abash, A. , Khaz in, A. , and Najjar, S. S. (1971) . Venereal. (Stockh.), 23:1- 13. Leprechaunism: A report of two new cases. Am. J. Perloft·, W. H., and Nodin e, J. H. (1950) . The association D is. Child ., / 22:442- 445 . of congen ital spastic quadriplegia and androgenic Karsznia, R., Wyss, R. H. , Hei nrichs, W. L. , and Herr­ precocity in four patients. J. Clin. Endocrin ol. , mann, W. L. ( 1969). Testicular feminization: An /0:721- 728. apparent enzyme defect. Gynecologica, 167: 197- Philip, J., and Trolle, D. (1965) . Famili al male her­ 204. maphroditism with delayed and partial masculiniza­ Koch , G. , and Tiwisina, T. (1959). Beitrag Erblichkeit tion. Am . J. Obstet. Gynecol. , 93:1076- 1083. d er Akromegalie und der Hyperostosis generalisata Porter, P. S., and Lobitz, W. C., Jr. (1970). Human h air: mit pachydermie. Aerztl. Forsch., 13:489- 504. A genetic marker. Br. J. Dermatol., 83:225-241. Lee, M . M. C. , Chang, I<. S. F., and Chan, M. M. C. Reed, W. B. , and Becker, S. W. (1964). Extensive hairy (1963) . Sexual maturation of Chinese girls in Hong pigmented nevus (abstract). Arch. Dermatol., . Kong. Pediatrics, 32:389- 398. 90:344. L1ao, S ., and Lin; A. H. (1967). Prostatic nuclear Reed, W. B., Becker, S. W., Sr. , Becker, S. W., Jr., a nd c hromatin : a n effect of testosterone on the synthesis Nickel, W. R. (1965a). Giant pigmented nevi, mela­ of ribonucleic ac id rich in cytidylyl (3 ', 5') guanos in e. noma, and leptomeningeal melanocytosis: A clinical . Proc. Nat!. Acad. Sci. U.S.A., 57:379-386. a nd histopathological study. Arch. Dermatol. , Liddle , G. W., Givens, J. R. , Nicholson, W. E., and 91 :100-119. Island, D. P. (1965). The ectopic ACTH syndrome. Reed, W. B. , Dexter, R. , Corley, C., and Fish, C. (1965b). Can cer Res., 25:1057- 1061. Conge ni tal lipodystrophic diabetes with acanthosis Livingston, S., Petersen, D., and Boks, L. L. (1955). ni gricans: The Seip- Lawrence syndrome. Arch. H y pertri chosis occurring in association with Dilantin Dermatol. . .9/:326-334. t h e rapy. J . Pediatr., 47:351-352. Ressmann, A. C. , and Butterworth, T. (1952). Localized Lloyd, C. W. (1963). Studies of adrenal function of acq·uired hypertrichosis . Arch . Dermatol., hirs ute women. In: The Hirsute Female (ed. by 65:458- 463 . Greenblatt, R. B.). Charles C Thomas, Publisher, Rivarola, M.A., Saez, J . M., and Migeon, C. J . ( 19 Springfield, Illinois, pp. 67). 88- 100. Studies of androgens in patients wi t h congenita Lloyd, C. W. (1968). The l ovari es. In: Textbook of adrenal h yperplasia. J. Clin. Endocrinol., J<;ndocrinology (ed. by Williams, R. H.) (4th Edi­ 27:624-630. tion). W. B. Saunders Company, Philadelphia, pp. 459- 536. Rongone, E. L. (1966). Testosterone metabolism by human m ale mamm Lorenzo , E. M. (1970). Familia l study o f hirsutism. J. ary s kin. Steroids, 7:489- 504. C lin. Endocrinol., 31:556- 564. Saldanha, P. H., and Guinsburg, S. (1961) . Distribution Lyell, A., and Whittle, C. H. (195 1). H ypertric hosis and inheritance of middle phalangeal hair in a white l an ugin osa, acquired type. Br. J. Dermatol. , population of Sao Paulo, Brazil. Hum. Bioi. 63:411-413. 33:237- 249. Malkinson, F. D. , Griem, M. L., and Marianovic, R. Sansone, G. , and Reisner, R. M. (1971). Differential rates ( 1971). Follicle. squash preparations: Uses in studies of conversion of testosterone to dihydrotestosterone of cell kinetics (abstract). J. Invest. Dermatol., in acne a nd in normal human skin-a possible 56:252. pathogenic factor in acne. J. Invest. Dermatol., McKnight, E. (1964). The prevalence of " hirsutism" in 56:366- 372. young women. Lancet, 1:410- 413. Schuster, D. S., and Johnson, S. A.M. (1966). Cutaneous McKu sick, V. A. (1971) . Mendelian Inheritance in Man: manifestations of the Corneli a de Lange syndrome. Catalogs of Autosomal Dominant, Autosomal Reces­ Arch. Dermatol., 93:702- 707. sive, and X-Linked Phenotypes. (3rd edition) . Johns Schwartz, J. H . (1942). Hirsut ism. Psychiat. Q. , Hopkins Press, Baltimore. /6:281- 294. McKu sick, V. A., Mahloudji, M ., Abbot, M. H ., Linden­ Scully, R. E ., and Richardson, G. S. (1961). Luteiniza­ berg, R., and Kepas, D. (1967). Seckel's bird-headed tion of the stroma of metastatic cancer involving t he dwarfism. N. Engl. J. Med., 277:279- 286. ovary a nd its endocrine significance. Cancer, Mercier-Bodard, C. , Alfsen, A. , and Baulieu, E. E . 14:827- 840. 474 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Seckel, H. P . G. (1946). Precoc ious sexual deve lopment Ta nner, J. M . ( 1962). Grow th at Adolescence: With a in children. Med . Clin . North Am ., 30:183- 209. General Co nsidera tion of the Effects of H ereditary Seckel, H. P . G. (1960). Bird-Hea ded Dwarfs: Studies in and Environmental Fa ctors Upon Growth and M atu­ Developmental Anthropology Including Human ration From Birth to Maturity (2nd Edi tion). Black­ Proportions. Charl es C Thomas, P ublisher, Spring­ well Scientifi c Publications, Oxford. fi eld, Illinois. Tanner, J . M . (1969). Growth and endocrinology of the Setty, L. R. (1970). Hair patterns o f the scalp of whi te adolescent. In: Endocrine and Genetic Diseases of and Negro males. Am. J . Phys. Anthropol. , 33:49- 55. Childhood (ed . by Gardner, L. !.). W. B. Saunders Setty, L. R. (197 1). Ha ir patterns of the face of white and Company, Philadelphia, pp. 19-60. Negro ma les. J. NaU. Med. Assoc., 63: 128- 131. Tha mdrup, E. (1961 ). Precocious Sexual Development: A S ha h, P . N. (1 957). Human b ody hair: A quant itative Clinical S tudy of 100 Children. Charles C Thomas study. Am . J. Obstet. Gynecol. , 73: 1255- 1265. Publisher, Springfi eld , lliinois. ' Sigurjonsdottir, T . J ., and Hayles, A. B. (1 968a) . Preco­ T homas, P. K., and Ferriman, D. G. (1957). Va ri ation in cious puberty: A report o f 96 cases. Am. J . Dis. facial and pubic hair growth in white women. Am . J. Child., I 15: 309- 32 1. Phys. Anthropol. , 15: 171- 180. Sigurjonsdottir, T . J ., and Hayles, A. B. (1968b) . Prema ­ Tisserand-Perrier, M . (1 953). Etude co mparative de ture pubarche. Clin . Pediatr., 7:29- 33 . certains processus de croissance chez les jumeaux. J . S il vers, D. N., Balis, M. E ., and Dancis, J . ( 1971) . I. Genet. Hum., 2:87- 102 . Identification of t he heterozygote of Lesch- Nyhan T rotter, M ., and Danforth, C. H. ( 1922). The incidence disease using hair roo ts (a bstract). J . Invest. Der­ and heredity of facial hypertri chos is in whi te wo men . matol. , 56:252. Am . J. Phys. Anthropol. , 5:391 - 397. Slatis, H. M ., and Apelb aum, A. (1963). Ha iry pinna o f Upton, G. V., and Amatruda, T . T., Jr. (197 1). Evidence the ear in Israeli popul ations. Am . J . Hum. Genet. , for the presence of tumor p ept id es wit h cort ico­ 15:74- 85. tropin-releasing-factor-like activity in t he ectopic S mith, D. W. (1 970 ). Recognizable Patterns of H uman ACTH syndrome. N. Engl. J. Med ., 285:4 19-424. Malformation: Genetic , Embryologic, and Clinica l Vermeul en, A., Verdonck, 1., Va nder Straeten, M., and Aspects (vol. 7). W. B. Saunders Company, Phila­ Orie, N. ( 1969). Capacity of the testosterone-bindina delphia . globulin in human pl asma a nd influence of s p ec i f i ~ Soffer, L. J ., Iannaccone, A. , and Gabrilove, J . L. (1 961). binding o f testosterone o n i ts metaboli c c learance Cushing's syndrome: A study of fifty patients. Am . rate. J . Clin . Endocrinol. , 29:1470- 1480. J . Med ., 30:129- 146. Wilkins, L., Blizzard, R. M., and Migeon, C. J . ( 1965) . Sotos, J . F. (1970) . The e ndocrine system. In : Genetic The Diagnosis and Treatment of Endocrine Dis­ Disorders o f M an (ed . by Goodman, R. M .). Little, orders i n Childhood and Adolescence (3rd Edition). Brown & Company, Boston, pp. 625-828. Charl es C Thomas, Publisher, Springfield, lllinois. Steiner, A. 1 ., Goodman, A. D. , and Powers, S. R. (1968). Williams- Ashman, H . G. (1965) . Androgenic control of Study of a kindred with pheochromocytoma, medul­ nucleic acid and protein synthesis in ma le accessory lary thyroid carcinoma, hyperparathyroidism and genital organs . J . Cell. Physiol. , 66 (Suppl. Cushing's disease: Multiple e ndocrine neo plasia, 1):1 11 - 124. type 2. Medicine ( Baltimore), 47:371- 409. Wilson, J . D., and Walker, J . D. (1969) . The conversion of Stern, C., Centerwa ll , W. R., and Sarkar, S. S. (1964). testosterone to 5 a lpha-androstan-1 7 beta-o1-3-one New d ata on the probl em of Y-linkage of h a iry (dihydrotestosterone) by s kin sli ces of m an. J . Clin. pinnae. Am. J. Hum . Genet., 16:455- 47 1. Invest. , 48:371 - 379. Stoddard, F . J . ( 194 5). Hirsut ism in pregnancy. Am . J . Wi tkop, C. J ., Jr. (1971 ). Heterogeneity in inheri ted Obstet. Gynecol. , 49:417- 422. dental tra its, gin gival fibromatosis a nd amelogenesis Strauss, J . S., and Pochi , P. E . (1969) . Recent a dvances imperfecta. South. Med . J ., 64 (Suppl. 1): 16- 25. in androgen m etaboli sm and t heir relation to the Wotiz, H. H., Mescon, H. , Doppei, H., and Lemon, H . M . skin. Arch. Dermatoi. , 100:62 1- 636. (1 956). T he in vitro meta bolism of testosterone by T a kashima, 1., Adachi , K. , and Montagna, W. (1970) . human skin. J . Invest. Dermatol. , 26:113- 119. Studies of common baldness in the stumptailed Zeligman, I. ( 1963). P atterns o f p orphyria in the Ameri­ macaque. IV. In vitro metabolism of testosterone in can Negro. Arch. Dermatoi. , 88:616- 626. the ha ir follicles. J. In vest. Derm atoi. , 55: 329-334.