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.