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 hirsutism 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 = idiopathic 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. 7.-The relation between 17-ketosteroids and 17-ketogenic steroids.

Data for control days and the first, third and fourth days of ACTH gel Protected by copyright. 20 u. b.d. I.M. are plotted. is exaggerated during ACTH administration.7 The The response is best assessed in relation to the ratios are abnormal in congenital adrenal hyper- corticoid response. In children and patients with plasia and idiopathic hirsutism (Fig. 4). They are hypopituitarism the 17-ketosteroid response is also abnormal in some patients with the Stein- poor (Fig. 7). In some patients with idiopathic Leventhal syndrome (Figs. 4 and 5),7 which sug- hirsutism it is greater than normal (Fig. 7). When gests that the adrenal as well as the ovaries may be the testes are removed the androgen-stimulating a6bnormal in this condition. hormone apparently rises because the i7-keto- In congenital adrenal hyperplasia (the adreno- steroid response to ACTH is unusually good genital syndrome) the primary defect, as first (Table i). shown by Bartter et al.,2 is that there is inter- Conversely, if there is a tumour producing excess ference with cortisol synthesis (Fig. 6) and ACTH androgen, this appears to suppress the androgen- secretion rises and stimulates the adrenal to secrete stimulating hormone so that the 17-ketosteroids http://pmj.bmj.com/ more androgen. The hold-up in cortisol synthesis rise very poorly when ACTH is given (Table z). is at the stage of. 17-hydroxyprogesterone.'6 This The response to ACTH, therefore, is a very useful steroid is then metabolized to give rise to preg- test in patients with virilizing conditions. nanetriol and 17-hydroxypregnanolone (Fig. 6). In normal individuals only very small amounts of Clinical Assessment pregnanetriol are excreted (except during preg- Virilization may become apparent in three dif- nancy, when it is 'not of adrenal origin14). The ferent ways: (a) at birth, (b) as precocious ketogenic steroid technique11 measures preg- puberty, (c) in adults. on September 29, 2021 by guest. nanetriol as well as cortisol and its metabolites in the urine. The ratio of ketogenic steroids to preg- (a) At Birth nanetriol is therefore a measure of the efficiency of Female infants may be born with partial mascu- cortisol synthesis. This ratio is very low in the linization of the external genitalia (female pseudo- adrenogenital syndrome. hermaphrodites). This may include enlargement of In one other respect adrenal androgen differs the clitoris or labial fusion or both. It may be so from gonadal and that is in its response to ACTH. severe that the vagina and urethra open into a Only adrenal androgen is increased in response to common urogenital sinus or the child may appear ACTH. However, the rise in 17-ketosteroid ex- like a male with hypospadias. The corresponding cretion when ACTH is administered depends upon condition in the male (macrogenitosomia) consists tfhe amount of androgen-stimulating hormone. of enlargement of the genitalia, especially the March I96C) MILLS: Virilizing Syndromes I8I Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from TABLE I TABLE 3 RESPONSE TO ACTH IN A MAN SOME YEARS AFTER THE INCIDENCE OF THE VARIOUS CAUSES OF PRECOCIOUS BILATERAL ORCHIDECTOMY AND WITHOUT REPLACEMENT PUBERTY* THERAPY % (both 17-keto- 17-ketogenic Cause Females Males sexes) Therapy steroids steroids mg./day mg./day Idiopathic .. 401 III 62 Congenital adrenal None ...... 11.0 9.8 hyperplasia . 58 42 12 . .. 1, 0.9 9.I Ovarian tumours .. 78 9 ACTH gel 20U. b.d. I.M. 27.2 29.4 Intracranial lesions i 8 51 8 ,,, ,, 30 35 Albright's syndrome 33 2 4.2 36 44 Adrenal tumours .. 4 i6 2.4 36 39 Testicular tumours i8 2.2 *Based on Wilkins.27 TABLE 2 RESPONSE TO ACTH IN A WOMAN WITH AN ANDROGEN- tion of ACTH usually causes increased i7-keto- SECRETING OVARIAN TUMOUR steroid excretion in contrast to the response in normal children. This also suggests that there I 7-keto- 17-ketogenic Therapy steroids steroids must be some other factor besides the defect in mg./dav mg./day cortisol synthesis. Girls with enlargement of the clitoris should not be rashly subjected to amputa- None ...... 1.3 5.8 8.4 8.2 tion unless the enlargement is really gross. With ACTH gel 20 u. b.d. I.M. 8. I 17.3 control of the excessive androgen secretion and 10.1 14.5 normal growth of the rest of the body, the clitoris ,, a, , ,, ,, I 3.2 I2.7 may not be out of proportion some 20 years later.

I4.2 38.6 Protected by copyright. ANDROGENS DURING PREGNANCY penis, and this may easily be overlooked. There Partial virilization of females has been reported are three causes of these conditions: (i) Congenital not only after administration of methyl test- adrenal hyperplasia (the adrenogenital syndrome). osterone,3 but also when certain' synthetic pro- (ii) Congenital abnormalities without hormonal gestational agents have been given for threatened disturbance. (iii) Administration of androgenic abortion. Some of these progestational agents are substances to the mother during pregnancy. The androgenic, especially i7-ethinyl testosterone second can only be diagnosed by excluding the (' Ethisterone ') and 17-ethinyl Ig-nortestosterone other two, but even if the third is suspected it is ('Norlutin'), as reported by Grumbach et al.'3 still essential to exclude congenital adrenal hyper- Two mothers given progesterone have had virilized plasia. infants, but this may have been coincidence con- sidering the number of women given progesterone CONGENITAL ADRENAL HYPERPLASIA during pregnancy who have had normal infants. The age of presentation depends upon the The children are in all hormonal respects normal http://pmj.bmj.com/ severity of the condition. The most severely and the only treatment required is minor surgery affected have genital abnormalities at birth. It is if the labia are fused. The same applies to infants difficult to explain these just on the basis of a with non-hormonal congenital abnormalities. defect in cortisol synthesis. Diagnosis. It is important to diagnose the con- (b) Precocious Puberty dition as early as possible so that treatment with In children virilization may present as precocious

cortisone may be started. This will prevent further puberty. In girls there is usually enlargement of on September 29, 2021 by guest. virilization and completely normal development the clitoris first, followed by appearance of pubic will then ensue. Fertility in the female then hair. In boys the penis is usually first affected: appears to be unimpaired and children born to it increases in size and pigmentation. Erections such mothers have been normal, although re- become more frequent, the scrotum darkens and latives of patients with the adrenogenital syndrome pubic hair appears. In both sexes acne may do seem to have minor defects in cortisol synthesis.9 develop. Much later axillary hair appears and The diagnosis is confirmed firstly by persistence then the voice deepens. Only rarely does facial of raised i7-ketosteroid excretion after the first hirsutism appear in children. The bone age few weeks of life and secondly by excretion of increases and growth has the typical puberty spurt. pregnanetriol of more than a few hundred micro- Early on, therefore, the children are taller than grammes per day. Both these abnormalities are others of the same age, but epiphyseal closure suppressed by cortisone treatment. Administra- comes early and the final stature is shorter than 1i82 POSTGRADUATE MEDICAL JOURNAL Marrch I960 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from normal. Mental age is unaffected and usually gest that the presence of one need not be tooth development is not advanced. postulated.' The incidence of the various causes of precocious puberty is shown in Table 3 (based on OVARIAN TUMOURS Wilkins27). The commonest ovarian tumour in childhood is the granulosa cell tumour. It may cause precocious IDIOPATHIC (CONSTITUTIONAL) sexual development at any age from five months The changes are those of normal puberty. The upwards. Uterine bleeding is almost invariable excretion of i7-ketosteroids, oestrogens and and this excludes an adrenal cause for the sexual gonadotrophins are as found at adolescence. It development. The I7-ketosteroid excretion is occurs predominantly in girls and may begin as normal or only slightly raised (i.6 to 3.5 mg./day early as the time of birth, but most commonly in the reported cases), but, on the other hand, arises about four or five years of age. It may be urinary oestrogen levels are usually high. In every necessary to exclude the other causes (see below). case there has been a palpable pelvic tumour by the time the child presented with obvious symptoms CONGENITAL ADRENAL HYPERPLASIA and signs. If the children do not have genital abnormalities Other ovarian tumours in childhood are ex- at birth, they usually present about the age of two ceedingly rare. A few cases of teratoma have been or three years, either with enlargement of the described and clinically resemble granulosa cell clitoris or penis or with development of pubic hair. tumour. Chorionepithelioma is even rarer. The By this time they will show more rapid growth patients have marked wasting associated with than normal and, in particular, advanced bone age. sexual precocity and sometimes menstruate. As as above. The might be expected, there is a high titre of chorionic The diagnosis is made mentioned gonadotrophin in the urine. pregnanetriol excretion becomes increasingly valu- Protected by copyright. able and especially its relationship to the total INTRACRANIAL LESIONS ketogenic steroids when ACTH is given. In These form a surprisingly high proportion of the normal individuals the ratio total ketogenic steroids cases of precocious puberty when it is not con- pregnanetriol stitutional. Clinically they resemble exactly idio- is between 9 and 30 during ACTH administration pathic precocity unless neurological signs are and in congenital adrenal hyperplasia it is usually present. The hormonal changes that occur are under two.7 Treatment with normal replacement precisely those of normal puberty. The intra- doses of cortisone should be started as soon as the cranial lesions have all been in the region of the diagnosis is confirmed. Without this the females hypothalamus or if they originate in surrounding will rarely menstruate and boys will not develop structures, e.g. pineal, they encroach upon the active spermatogenesis. Both will occur regardless hypothalamus. The tumours have mostly been of chronological age if cortisone therapy is com- gliomas or astrocytomas. Sometimes they are menced after the bone age has reached I2 years.

associated with other hypothalamic disturbances http://pmj.bmj.com/ A few children with the adrenogenital syndrome e.g. polydipsia, polyphagia, obesity, sleep dis- are hypertensive, and in two of these it has been turbance. The same syndrome may arise after shown that the metabolic block is in the conversion encephalitis or miliary tuberculosis or in associa- of i i-deoxycortisol to cortisol (see Fig. 6). The tion with congenital brain defects. If there is a corticosterone which is made in small amounts history of encephalitis in a child presenting with by the normal adrenal also fails to undergo iii- precocious puberty further investigations should hydroxylation and so desoxycorticosterone is be carried out to confirm or exclude, if possible, formed. It is thought that this compound is hypothalamic damage. on September 29, 2021 by guest. responsible for the hypertension. Treatment with cortisone in the early stages gradually allows the ALBRIGHT'S SYNDROME blood pressure to return to normal. Precocious puberty is one aspect of this syn- Another small group of patients with the adreno- drome. Puberty is in all respects similar to the genital syndrome includes those who are ' salt- normal, but may occur at any age from a few losing'. They present as in adrenal crisis and are months upwards. The other features of the con- very likely to die undiagnosed. They need ex- dition are brownish areas of skin pigmentation cessive amounts of sodium-retaining steroid and which are present from birth and patchy areas of added salt as well. Some have defective aldo- rarefaction in the bones ('polyostotic fibrous sterone synthesis.4 Extensive search for a sodium- dysplasia'). There may be sclerosis of the base of losing steroid in them has failed to reveal one and the skull, but there are no abnormalities of calcium recent studies on renal handling of sodium sug- or phosphorus metabolism. March I960 MILLS: Virilzing Syndromes I.83 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from TABLE 4 suppression test is essential to distinguish the two REsPONSE TO ACTH IN A Boy AGED TBEn WITH AN conditions. ANDROGEN-SECRETING ADRENAL TUMOUR CUSHING'S SYNDROME I7-keto- 17-ketogenic Therapy steroids steroids In children this is not usually associated with mg./day mg./day virilization, whereas the features of cortisol excess are quite obvious. None ...... 35 8.3 28 5.2 ACTH gel20u. b.d. I.M. 36 I I (c) Adults 23 62 The differential diagnosis here is somewhat 39 62 more difficult. Causes of virilization in the adult 26 129 include the following (in approximate order of frequency): ADRENAL TUMOURS (i) Idiopathic hirsutism. In children virilizing tumours of the adrenal are (2) Stein-Leventhal syndrome. frequently malignant, though they may remain en- (3) Cushing's syndrome. capsulated for a long time. Presenting symptoms (4) Ovarian tumours. include more rapid growth in height and muscular (5) Congenital adrenal hyperplasia. development. In boys the penis increases in size (6) Adrenal tumours. and becomes pigmented and in girls the clitoris The studyofthe clinical picture and the cnemical hypertrophies. Pubic hair may also be present. investigations are directed towards deciding which These patients are readily distinguished from those gland is responsible for the excessive androgen with idiopathic precocity because they excrete secretion and whether surgical intervention is large amounts of 17-ketosteroids. These are not indicated. It is rapidly becoming apparent that suppressed by cortisone and the pregnanetriol is there may not be any good correlation between Protected by copyright. normal: this differentiates them from patients with histology of a tumour and the hormones produced congenital adrenal hyperplasia. Usually fractiona- by it (e.g. testicular tumour secreting only corti- tion of the urinary I7-ketosteroids will reveal sol ;24 ovarian tumour with cells resembling appreciable amounts of dehydroepiandrosterone. granulosa cells but secreting testosterone21). This excludes the testis (or ovary) as the gland In general, it may be said that severe virilization, responsible for the virilization. With pure if due to adrenal androgen, is associated with high androgen-secreting tumours the rest of the adrenal 17-ketosteroid excretion; if it is associated with is normal and shows a normal hydrocortisone normal 17-ketosteroid excretion the androgen response to ACTH, but the I7-ketosteroids are most probably comes from the ovary and probably unaffected (Table 4). includes testosterone.m, 21 The data required to differentiate the various INTERSTITAL CELL TUMOUR OF TESTIS conditions causing adult virilization are shown in

These tumours are comparatively rare. The Table 5. The ratios of i i-hydroxyandrosterone to http://pmj.bmj.com/ children resemble those with the adrenogenital i i-oxygenated aetiocholanolones and I i-deoxy syndome or with androgen-secreting tumours of x7-ketosteroids to I i-oxygenated aetiocholano- the adrenal. The tumour is usually unilateral and lones have been reported by Brooks and Prunty77 not malignant. If it is large enough, one testis and Figs. 4 and 5 are based on their results. will appear Iarger than the other. The size of the tumour has varied from less than I cm. to I2 cm. (I) IDIOPATHIC HIRSUTISM The smaller ones may be difficult to detect. The This diagnosis is best reserved for those women urinary i7-ketosteroids are raised, but the de- who have hirsutism beginning after puberty, on September 29, 2021 by guest. hydroepiandrosterone is not. The corticoid usually around the age of 20. They usually have response to ACTH is that of a normal child and normal menstrual cycles and do not have enlarge- the I7-ketosteroids are not suppressed by corti- ment of the clitoris. Their resting 17-ketosteroids sone. Pregnanetriol excretion is normal. These are usually around the upper normal levels, but chemical tests serve to differentiate patients with when given ACTH some of them have exaggerated these tumours from those with adrenal tumours or 17-ketosteroid responses (Fig. 7). Their 17-keto- with congenital adrenal hyperplasia. It is im- steroids can be suppressed with cortisone and portant to remember that some of the latter may their pregnanetriol excretion is often around or have testicular enlargement associated with what just above the upper limits of the normal range some authorities call ' adrenal rests' and others (up to 2 mg./day). Fractionation of the I7-keto- call 'clumps of Leydig cells'. The cortisone steroids suggests increased production of I- POSTGRADUATE MEDICAL JOURNAL March I960

X84 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from TABLE 5 THE DIFFERENTIAL DIAGNOSIS OF ADULT VIRILISM

17-ketosteroids Resting ACTH Suppression Ratio I* Ratio 11* Preg- Menstrua- Pneumo- Response Test nanetriol tion peritoneum Idiopathic Normal Normal Suppress Increased Increased Normal Normal Hirsutism or high or high Stein-Leventhal Normal Normal Suppress Increased Normal Normal Irregular Ehlarged or high or high or or absent ovaries increased Cushing's Normal Normal May Increased Normal Normal Irregular or high or high suppress or absent Ovarian tumour Normal Normal Poor Normal Increased Normal Irregular Enlarged or high or low suppression or absent ovary or palpabletumoour Adrenogenital Normal Normal Suppress Increased Increased High Normal or high or high or absent Adrenal tumour High No change No change Normnal or Increased Normal Normal or increased irregular

I Ratio I I -hydroxyandrosterone # Ratio =I Ii-deoxy I7-ketosteroids Protected by copyright. i I -oxyaetiocholanolones i -oxyaetiocholanolones hydroxyandrostenedione and the precursors of diagnosis will sometimes depend upon the urinary androsterone and aetiocholanolone. corticoid excretion and its response to a normal Long-term suppression of 17-ketosteroids with ACTH-suppressing dose of dexamethasone. In all cortisone with or without oestrogen in addition cases except Cushing's syndrome the urinary causes diminution of hair growth in some in- corticoids would be. suppressed by 2 to 3 mg. of dividuals. The results are certainly not dramatic. dexamethasone in divided doses every six hours for two days. The 17-ketosteroids often take (2) STEIN-LEVENTHAL SYNDROME longer to fall even if they are of adrenal origin. This will be dealt with in greater detail else- where in this issue. The point that should be (4) OvARiAN TUMOURS emphasized here is that it may be very difficult to It is much more important to establish that an differentiate these patients from those with idio- ovarian tumour is the cause of virilization than tohttp://pmj.bmj.com/ pathic hirsutism. The data of Brooks and Prunty7 predict before operation what type of tumour show that the same adrenal disturbance may occur might be found. in both groups of patients. Menstrual disturbance The I7-ketosteroids are rarely much raised in is common in the Stein-Leventhal syndrome, but patients with ovarian androgen excess. This sug- the diagnosis can only be established if the typical gests that when virilization is severe a very potent polycystic ovaries are demonstrated. Either androgen is being secreted. It has been shown

vaginal examination or pneumoperitoneum may that testosterone was being synthesized by two on September 29, 2021 by guest. reveal ovarian enlargement. ovarian tumours.25,21 An ovarian tumour is frequently large enough to (3) CUSHING S SYNDROME be palpable, but sometimes it is not and then In severe cases there is very little problem in various tests may suggest that the androgen excess distinguishing between Cushing's syndrome and originates in the ovary. With ACTH the rise in other causes of hirsutism. However, the milder 17-ketosteroids is poor (see Table 2). This may cases may well present difficulties. Presence of be because the androgen-stimulating hormone is purple striae would be very much in favour of suppressed by the ovarian androgen. On-the other Cushing's syndrome. Hypertension and plethoric hand, the i7-ketosteroids are not well depressed facies may also occur with some ovarian tumours by suppressing endogenous ACTH with cortisone. (see below) and obesity is sometimes associated If the 17-ketosteroids are fractionated, the ratio of with the Stein-Leventhal syndrome. The final i i-hydroxyandrosterone to the i I-oxygenated March I960 MILLS: Virilizing Syndromes 185 Postgrad Med J: first published as 10.1136/pgmj.36.413.176 on 1 March 1960. Downloaded from aetiocholanolones is normal, while the ratio of may then occur. In all biochemical respects these i i-deoxy I7-ketosteroids to the i i-oxygenated patients have the characteristics of the congenital aetiocholanolones is high. This is because ii- variety of the disease, but there is no evidence oxygenation of ovarian hormones does not nor- of excessive androgen secretion before puberty. mally occur. Menstruation is frequently interfered Pregnanetriol excretion, especially in response to with: this may lead either to amenorrhoea, oligo- ACTH, is most valuable diagnostically. menorrhoea or occasionally intermenstrual bleeding. (6) ADRENAL TUMOURS Arrhenoblastoma. This is the commonest The main characteristics useful in diagnosis ovarian tumour producing androgen excess. *have been described under the section on pre- Virilization is severe, usually with marked hir- cocious puberty. In the adult the differentiation sutism, enlargement of the clitoris and deepening from an ovarian tumour is made by the high ex- ofthe voice coming on in the space of a few months. cretion of dehydroepiandrosterone. The urinary The tumour is usually palpable and may contain 17-ketosteroids are not stimulated by ACTH nor multilocular cysts. There is a gradation between depressed by cortisone. the true arrhenoblastoma and the granulosa cell tumour. Some tumours have been described REFERENCES x. AUGUST, J. T., and NELSON, D. H. (IS95), _. clin. Invest., which contain both types of histology and for 38, I964. 2. BARTTER, F. C., ALBRIGHT, F., FORBES, A. P., these the term gynandroblastoma was proposed by LEAF, A., DEMPSEY, E., and CARROLL, E. (ixsx), Meyer. The arrhenoblastoma is frequently malig- Ibid., 30, 237. nant, but is slow to metastasize. 3. BLACK, J. A., and BENTLEY, J. F. R. (IS95), Lancet, i, 21. 4. BLIZZARD, R. M., LIDDLE, G. W., and MIGEON, C. J. Masculinovoblastoma. This tumour has many (I958), Endocrine Society, San Francisco, Abstracts, p. 6o. names: virilizing lipoid cell tumour, adrenal 5. BRADLOW, H. L., and GALLAGHER, T. F. (1957), _7. biol. Chem., 229, 505. cortical cell tumour, luteoma, hypernephroma of 6. BROOKS, R. V., MATTINGLY, D., MILLS, I. H., and the ovary. The clinical features are identical with PRUNTY, F. T. G. (I960), submitted to Brit. med. 7. Protected by copyright. 7. BROOKS, R. V., and PRUNTY, F. T. G. (I960), 'Memoirs those of the arrhenoblastoma. Sometimes there is of the Society for Endocrinology,' No. 9. Proceedings of the excess excretion of oestrogen and pregnanediol. Edinburgh Meeting, I959. In press. 8. BUSH, I. E., SWALE, J., and PATTERSON, J. (I956), These latter features are of value when, as some- Biochem. 7., 62, x6P. times happens, the tumour causes the character- 9. CHILDS, B., GRUMBACH, M. M., and VAN WYK, J. J. (I956), Y. clin. Invest., 35, 213. istics of Cushing's syndrome, including poly- Io. GALLAGHER, T. F. (I957), Cancer Res., 17, 520. cythaemia, hypertension, obesity and even im- iI. GIBSON, C., and NORYMBERSKI, J. K. (I954), Ann. rheum. Dis., 13, 59. paired glucose tolerance. These characteristics I2. GREENBLATT, R. (1958), Rec. Progr. Hormone Res., I4, 335. may appear before the ovarian tumour is palpable, 13. GRUMBACH, M. M., and DUCHARME, J. R. (i959), but the virilization is frequently more severe than Y7. clin. Endocr., 19, I369. 14. HERRMANN, W. (I957), Endocrine Society, New York in Cushing's syndrome. The tumour is very rare. Abstracts, p. 26. i5. HOLLANDER, N., and HOLLANDER, V. P. (I958), 7. biol. Hilus cell tumour (sympatheticotrophic cell Chem., 233, 1097. tumour). There is no way clinically of dif- I6. JAILER, J. W. (I953), Bull. N.Y. Acad. Med., 29, 377. ferentiating this tumour from other virilizing 17. KELLER, M., HAUSER, A., and WALSER, A. (I958), _7. clin. Endocr., ig, 1384. http://pmj.bmj.com/ ovarian tumours. Histologically it is of interest I8. LINDER, H. (I960), 7. Endocr. Proceedings of the Society because the cells resemble the Leydig cells of the for Endocrinology. In press. I9. MEYER, A. (I955), Biochim. biophys. Acta, 17, 441. testis, even to being in close association with non- 20. MILLS, I. H. (I958), Rec. Progr. Hormone Res., 14, 326. myelinated nerves and having crystalloids of 21. MILLS, I. H., BROOKS, R. V., and PRUNTY, F. T. G. Reinke. (I959), Proc. roy. Soc. Med., s2z, 151. 22. PRUNTY, F. T. G. (I956), Brit. med. _7., ii, 6I5 and 673. Dysgerminoma. This has never been shown to be 23. SAMUELS, L. T. (i955), 'Progress in the Chemistry of Fats producing hormones, but it is sometimes associ- and other Lipids,' vol. 3, p. 395. 24. SAVARD, K., DORFMAN, R. I., BAGGETT, B., and ated with pseudohermaphroditism. ENGEL, L. L. (I956), Fed. Proc., 15, II34. on September 29, 2021 by guest. 25. SAVARD, K., DORFMAN, R. I., GABRILOVE, J. L., and SOFFER, L. J. (I9S7), Endocrine Society, New York, (5) CONGENITAL ADRENAL HYPERPLASIA Abstracts, p. 89. has 26. SHORT, R. V. (I960), Biochemical Society Symposium on the The diagnosis of this condition previously 'Biosynthesis and Secretion of Adrenocortical Steroids,' been discussed. However, it is important to in press. 27. WILKINS, L. (I957), 'The Diagnosis and Treatment of realize that the condition may first manifest itself Endocrine Disorders in Childhood and Adolescence.' after puberty12' 6 and that regular menstruation Oxford: Blackwell Scientific Publications.