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Virilizing Syndromes Ivor H I76 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from VIRILIZING SYNDROMES IVOR H. MILLS, PH.D., M.D., M.R.C.P. Departments of Medicine and Chemical Pathology, St. Thomas's Hospital Aledical School, London, S.E.' Common Androgen Pathway Adrenal Acetate Pregnenolone - 17OH prognnolon ProgesteroneI 170H-progesteronl 1707H-11 deooxycorticosterOnf Testosterone Androstenedione - 1 OH androstenedione Protected by copyright. 19-Oi androstenedione Oestradiol-17l Ovary FIG. I.-Biosynthetic pathways of steroids in adrenal, ovary and testis. Virilization implies that a person has been this gland.26 The biosynthetic pathway to andro- influenced by an excess of androgen. Although stenedione is shown in Fig. i. In the adrenal the this may be comparatively easily recognized in dominant pathway is to hydrocortisone (cortisol) children and women, it is extremely difficult to (Fig. 2) and this is controlled by the pituitary detect in men. hormone, ACTH (corticotrophin). In its turn The naturally occurring substances which are ACTH is depressed by cortisol; by this feed- known to have androgenic activity and which are back mechanism the production of cortisol is con- http://pmj.bmj.com/ of importance in man are, in decreasing order of trolled at the appropriate level. activity: testosterone, androstenedione, dehydro- By administration of ACTH production of epiandrosterone and i i -hydroxyandrostenedione. cortisol can be greatly increased. In younger Androsterone has also been suggested as arising children this treatment produces only a very small in the adrenal, but the evidence for its production increase in androgen excretion. With the onset of by this gland is limited to two observations with puberty the adrenal response to corticotrophin incomplete identification.'7, 8 changes towards the adult pattern and appreciable Apart from androsterone, all these substances androgen production is found. After loss of the on September 29, 2021 by guest. have been isolated from adrenal glands, though in pituitary in the adult the adrenal androgen response the case of testosterone it was from an adrenal to ACTH reverts to that of a young child. In tumour. contrast to this, some women with simple hir- sutism have an exaggerated androgen response to The Origin of Androgens ACTH. It has been suggested by Prunty22 and Androgenic substances are produced by three Mills20 that these data might be explained by the glands, the adrenal, testis and ovary. One sub- existence of a second pituitary hormone which stance is common to all three glands, namely, comes into play at puberty and which acts syner- androstenedione (Fig. i). In the testis this is gistically with ACTH to increase adrenal androgen converted to testosterone, in the ovary it is on the secretion. This hormone might reasonably be pathway to oestradiol and in the adrenal it appears called the androgen-stimulating hormone. to be one of the definitive androgens produced by The qualitative similarity of the steroid path- March i)6b MILLS: Virilizing Syndromes if Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from 120K1 0 0 HYDROCORT ISONE ANDROSTENEDIONE AETICHOLANOLONE 0 ON OEHYDRDE.PIANDROSTERONf- T ESTOST ERONE ANDROSTERONE- FIG. 2.-Structures of steroids. ways in the gonads and adrenals was first sug- presence of an enzyme system for attaching a gested by Samuels,23 and it is quite possible that hydroxyl group on carbon atom i i of the steroid the increased androgen production by all three at nucleus (see Fig. 2). This enzyme system may the time of puberty might be controlled by the operate as the last stage in cortisol synthesis or it same pituitary hormone. may work after removal of the side chain and con- In young animals approaching puberty andro- vert androstenedione to i i-hydroxyandrostene- stenedione appears in spermatic vein blood before dione. In so doing it would decrease the andro- testosterone does and is increased by treatment genicity of the androstenedione. The i i-hydroxy- Protected by copyright. with chorionic gonadotrophin. However, the latter lating enzyme system has only rarely been demon- trophic hormone will not effect the conversion of strated in gonadal tissues.24 androstenedione to testosterone.18 After puberty chorionic gonadotrophin in male animals and man Metabolism of Androgen increases the secretion of testosterone and not The similarity in the steroid pathways in adrenal that of androstenedione. This evidence is in and gonads complicates the problem of detecting support of the view that one pituitary hormone the source of excess androgen secretion in the stimulates androgen synthesis as far as andro- various virilizing syndromes. Androstenedione and stenedione, but another is necessary to convert the testosterone are interconvertible in some tissues androstenedione to testosterone. One of these and both are excreted in the urine as the 17-keto- hormones is interstitial cell-stimulating hormone steroids androsterone and aetiocholanolone (Figs. (ICSH). The pathway from progesterone to 2 and 3). The presence of these i7-ketosteroids in androgen in human ovarian tumour tissue has the urine (and they are the major ones) gives no been demonstrated by Savard et al.25 and Mills information as to the gland secreting the parent http://pmj.bmj.com/ et al.2' It was found by Meyer'9 that both andro- compound. However, DHA and the i i-oxygenated stenedione and Ig-hydroxyandrostenedione are 17-ketosteroids (Fig. 3) are characteristic of the converted to oestrogen and it seems probable, adrenal and the ratio of these to the androsterone therefore, that Ig-hydroxyandrostenedione is an and aetiocholanolone may well give an indication intermediate between androgen and oestrogen. In as to which gland is secreting the excess androgen. the ovary the administration of FSH either in If either the testis or the ovary is producing vivo or in vitrol5 stimulates the conversion of testosterone or androstenedione excessively the on September 29, 2021 by guest. androgen to oestradiol. proportion of the total 17-ketosteroids that is DHA Adrenal androgen production differs in certain would be expected to be abnormally small. In important ways from ovarian or testicular androgen practice this ratio is found to be very variable in secretion. The compound dehydroepiandro- normal people, probably because DHA may be sterone (DHA) is characteristic of the adrenal (see converted to androstenedione and appear in the Fig. i). What part it plays as an androgen'is urine as androsterone or 'aetiocholanolone. The obscure. In adrenal vein blood Short26 found it is reverse situation, however, gives valuable infornia- sometimes present to a greater extent than andro- tion, i.e. a markedly raised DHA exctetion stenedione and sometimes t'o a lesser extent. How- definitely indicates that the adrenals are secr&ig ever, the greater androgenicity of androstenedione excess androgen. tmade it always the dominant androgen. Another Study of the II-oxygenated I7-ketosteroids is; important characteristic of' the adrenal is the complicated by the fact that some arise from the X.78 POSTGRADUATE MEDICAL JOURNAL Aftirch. I96Q Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from Androstenedione Testosterone D.H.A. Androsterone Astiooholanolone D.N.A. (5') (5P) 11 P OH And r o*t enedi one Cort i*o I .. .1.1 0lOH Ill-ke9to 11 0 OH Androsterone Aetiocholanolone Aetiooholanolone FIG. 3.-Androgens and their urinary excretion products. I-DEOXY 17-KETO STEROIDS ~RATI:1' I l-OXYGENATED AETIOCHOLANOLONES Protected by copyright. 2 4 6 8 10 12 14 C * .0 H - PS-L * http://pmj.bmj.com/ S-L -* * 0 0 A-G * FiG. 4.-The ratio i hydroxy androsterone in the urine of normal on September 29, 2021 by guest. i i-oxygenated aetiocholanolones individuals and patients with virilism. C = normal controls, H = idio- pathic hirsutism, S-L = Stein-Leventhal syndrome, A-G = adrenogenital syndrome.7 metabolism of ii-f3-hydroxyandrostenedione and i i-hydroxy or i i-keto-aetiocholanolone.10 If, some from cortisol (Fig. 3). However, if the iI- therefore, adrenal secretion is directed more to- oygenated ketosteroids are separated into the three wards androgen secretion thanto cortisol secretion, com.pounds, one finds that i i-hydroxyandro- one would expect the androsterone and aetio- stnedione leads mainly to i i-hydroxyandro- cholanolone or the ii-hydroxyandrosterone to be serone,5 but the small fraction of cortisol which is highrelative to the i i-oxygenated aetiocholanolones excreted as 17-ketosteroid is found mainly as which arise mainly from cortisol. This divergence March I966 MILLS: Virilizrng Syndromes Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from RATO *- ANDROSTERONE Il-OXYGENATEDt1-HYDROXYAETIOCHOLANOLONES 2 3 4 H -@: * * PS-L S-L 00 0 *-- A-G - * FIG. 5.-The ratio ii-deoxy I7-ketosteroids in the urine of no l Protected by copyright. I I -oxvyenated aetiocholanolones individuals and patients with virilism. Symbols as for Fig. 4.7 co0 Coo ACETATE OHOLESTEFtOL PREGNENOLONE PROGESTERONE HC CHeOH CHtoH http://pmj.bmj.com/ CIO C-O CGO Ho OH - OH o CORTISOL 11- CESOXYCORTISOL IT-HYOROXYPROGESTERONE on September 29, 2021 by guest. OH3 C-O CHOH -OH Os-H 17KS Ho- 40 17- HYMOXYPRENANOLDNE PREGNANETRIOL BIOSYNTHESIS OF CORTICOIDS IN CONGENITAL ADRENAL HYPERPLASIA FIG. 6.-The biosynthetic pathway in patients with the adrenogenital syndrome. POSTGRADUATE, MEDICAL JOURNAL March 1960 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from 90 x NORMAL 80 * HIRSUTE O CHILDREN o HYPOPITUITARISM 70 60 500 *0. KETO- 50 STEROIDS 40 . 0 x MG/DAY |x X 30 00. X x 0x 2020 xX. .0 0 x Xx X X X 10 x x 0 0 20 30 40 50 60 70 80 90 100 HO KETOGENIC STEROIDS MG/ DAY FIG.
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