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FIG. I.-The undifferentiated stage of urogenital development. The problem of hermaphroditism is one which the complicated method by which the male and has always attracted attention so that much has female genital tracts and external genitalia are been written on the subject. One of the finest derived, and particularly to the fact that this works appeared in 1937, with the publication of development is common to both in early embryonic Young's monograph1 and this has become a classic. life (Fig. I). In recent years, Lawson Wilkins and his co- workers at Johns Hopkins have, more than anyone The Gonads else, furthered our knowledge of the subject and Up to the sixth week, therefore, the gonads are much of the information in the present article is identical in both sexes and the embryo potentially derived from their writings2-15 and from personal bisexual. Changes in the gonad take place communication with Dr. Wilkins. Liberal use earliest if the embryo is to become male when, at also is made of the present author's publica- the seventh week, the elements of the testes appear, tions16-18 on the subject as well as more recent being derived from the medulla of the gland. personal experience. If the foetus is to become female no distinctive features appear until the tenth week when the Embryology germinal epithelium, consisting of epithelial The occurrence of hermaprhoditism is due to nests and primordial follicles containing ova, is 590 POSTGRADUATE MEDICAL JOURNAL December 1956

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PLATE I.-P.M. specimen showing congenital adrenal hyperplasia. The hyperplastic adrenal glands are seen to be larger than the kidneys. The infantile uterus tubes and ovaries are well shown. derived from the cortex of the gland. It is part ovary and part testis or that one gonad apparent therefore, that the testis develops from becomes an ovary and the other a testis. the medulla and the ovary from the cortex of the gonad, but even this adult differentiation is not The Genital Ducts complete since the normal testis contains' female ' In the undifferentiated stage (Fig. I) two pairs (cortical) components and the ovary contains of genital ducts lead from the gonad to the ' male' (medullary) components. In this light it urogenital sinus-the male or Wolffian ducts and is understandable that on very rare occasions the the female or Mullerian ducts. These ducts foetal gonad may develop into an ovo-testis, being are not ambisexual and remnants of the pair December 1956 JOLLY: Hermaphroditism 591 belonging to the opposite sex are to be found in age. The problems of homosexuality and trans- adult life. The Wolffian ducts become the vestism will not be discussed in this paper since epididymis, vas deferens and seminal vesicles in they are psychological problems only. the male, whereas, in the female, their remnants exist as the epo6pheron, paro6pheron and Gartner's (I) Female Pseudohermaphroditism with Adrenal ducts. The Mullerian ducts become the Fallopian Hyperplasia tubes, uterus and vagina, the latter two structures This is the commonest of all types of her- being formed by fusion of the two ducts. Their maphrodites and Money quoted by Wilkins et al. remnants in the male are the appendix testis, (I955)11 in a recent survey of published cases utricle and verumontanum. betweren I895 and I95o has shown that the condition occurs as frequently as all the types of The Urogenital Sinus intersex. In the undifferentiated stage the bladder and The hyperplasia of the adrenal cortex (Plate I) both sets of genital ducts open into the urogenital commences in early foetal life and produces a sinus. In the male the urogenital sinus becomes massive masculinizing stimulus from the out- the lower part of the prostatic urethra and penile pouring of androgens. This action begins in the urethra. In the female this sinus becomes the fourth month by which time the gonads have shallow vestibule which contains the orifices of already differentiated to form ovaries but the the urethra and vagina. This is separated from Mullerian ducts have only developed as far as the the vagina by the hymen whose inner surface is formation of Fallopian tubes and uterus. The lined by vaginal epithelium derived from the further development of the genital ducts now takes Mullerian duct and outer surface from urogenital place along male lines as a result of the androgenic sinus epithelium. stimulus, so that the urogenital sinus persists as External Genitalia in Fig. 2, type A, instead of giving way to a separate The genital tubercle enlarges in both sexes to urethra and vagina. This figure shows the form the phallus and as it does so a median groove commonest anatomical arrangement in these appears on its caudal surface. The raised margins patients, there being one external orifice only so of this groove are the urethral folds. In the male that the vagina appears to open into the floor of the the phallus lengthens to become the penis and as it urethra. The phallus steadily enlarges instead of does so the urethral folds fuse round the urogenital remaining small as a normal clitoris and the labio- sinus from behind forwards in such a way as to scrotal folds fuse to some extent and thereby give carry the penile urethra, which has formed from the impression of a scrotum rather than labia the urogenital sinus, to the tip of the penis. The majora. The ovaries however do not descend so two labioscrotal folds which have appeared on that the ' scrotum' is always empty. each side of the base of the phallus become fused Other varieties of this condition may occur, in the male to form the scrotum. the next most common being shown as type B in In the female the becomes the Fig. 2. Here the urogenital sinus opens externally phallus clitoris, through a funnel-like orifice which is larger than while the genital and labioscrotal folds do not fuse the previous type so that the urethra appears to but become the labia minora and majora open into the roof of the vagina. Three other respectively. much rarer types have occurred. In type C, there Classification is no communication between vagina and urethra; Two distinct groups of hermaphrodites should in type D the urethra has been carried forward first be separated on the basis of aetiology, the one by fusion of the urethral folds so that its orifice being due to an adrenal disorder and the other not. is at the tip of the clitoris. In type E the vagina Thus we have: and urethra have differentiated to become separate (I) Female pseudohermaphroditism due to as in the normal female, and one can only presume congenital adrenal hyperplasia. that in this case the androgenic stimulus did not (II) Intersex. commence until after the fifth month of foetal life. In this latter group there is no endocrine dys- At birth then, the child, who is of average function and the aetiology is unknown, although rather than large size, will be normal apart from a genetic factors play a part. It includes the remain- large clitoris, and in most cases will have a single ing varieties of pseudohermaphroditism and all external orifice serving both urethra and vagina. true hermaphrodites. A varying degree of fusion of the labioscrotal In female pseudohermaphroditism with adrenal folds will be present and the uterus can usually hyperplasia there is progressive virilization from be felt on rectal examination. After birth the birth, whereas in intersexes no further changes androgenic stimulus continues so that the child take place until puberty which occurs at the usual grows more rapidly than normal and the epiphysial 592 POSTGRADUATE MEDICAL JOURNAL December 1956

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C' £ FIG. 2.-Varieties of female pseudohermaphroditism with adrenal hyperplasia.

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PLATE 2.--Female pseudohermaphrodite with adrenal hyperplasia. These photographs were taken when the child was first seen at the age of five years and before cortisone therapy was commenced. The thickened and enlarged phallus can be appreciated, together with the growth of pubic hair and the single external orifice. December I956 JOLLY: Hermaphroditism 593 bone age is advanced. The phallus continues to of the diagnosis is required. The urethrQscope is increase in size, being much thicker than a normal passed into the capacious urogenital sinus until clitoris, but not so long as a penis. It is bound the vaginal opening is visible in the floor of the downwards in a curve-a condition known as sinus as a slit-like aperture surrounded by folds. chordee. Grossl9 states that the enlarged clitoris This opening is usually large enough toallow the can be differentiated from the penis by the two passage of the urethroscope into the vagina until small folds which run down on either side of its the cervix can be seen as a smaller slit and into midline to join the labia minora. In the penis which an ureteric catheter can usually be inserted. there is a single frenulum on the ventral surface. If necessary, a radio-opaque dye can be injected Erections of the enlarged phallus become increas- and watched under the X-ray screen as it passes ingly frequent and may be painful. The voice along the Fallopian tube and out into the peritoneal deepens as a result of the same changes in the vocal cavity through the fimbriated opening (Plate 3). cords that occur in the normal male at puberty. If the child is not seen until a few years after Pubic hair appears between the age of two to five birth the diagnosis is very much easier on account years and is followed by axillary and facial hair of the progressive virilization which will have taken with acne of the face a common accompaniment. place. This is shown by an acceleration of growth Muscular development becomes marked although and epiphysial development as well as by the the bodily contours remain predominantly femi- presence of sexual hair, the muscular development nine (see Plate 2 and Jollyl8 photos of cases 56 to and the deepened voice. 6o). A few patients have hypertension. The condition of' premature pubarche ' (Silver- No breast development or menstruation occurs man et al.5) may cause some confusion with these at the time of an expected puberty but by this age patients and should be mentioned. It is a con- epiphysial fusion has occurred to such an extent stitutional variation of adolescence whereby chil- that further growth is impossible. Therefore, after an initial spurt of growth in early childhood, putting the child head and shoulders above those of her own age, she ends up much shorter than the average. Diagnosis. This must be made as soon as possible after birth since early treatment is essential. However, at this early age the condition can easily be confused with some varieties of YI(:·" intersex which may have the same anatomical MiitL' "::.'I: configuration. Further evidence is therefore ··::· required in order to prove the presence of adrenal hyperplasia and thereby confirm the diagnosis. This proof is given by the rise in urinary excretion of I7 ketosteroids from the normal of less than 0.5 mg. in 24 hours at birth to a level of 2 to 5 mg. within the first few weeks of life. The level continues to rise as the child grows and by adolescence may reach levels of 25 to 8o mg. In the early weeks of life the I7 ketosteroids may give ambiguous results but in these cases the finding of an increased excretion of pregnanetriol in the urine is diagnostic of congenital adrenal hyperplamia (Bongiovanni and Clayton20). Laparotomy has frequently been used in the ······::;: past for confirmation of the diagnosis but is un- necessary and dangerous, since adrenal failure may be the Perirenal in- precipitated by operation. PLATE 3.-Female pseudohermaphrodite. Anterior sal- sufflation to outline the enlarged adrenals has been pingogram. The urethroscope lies in the vagina recommended by some writers, but this also is a with its tip at the cervix, while the ureteric catheter dangerous practice, and in any case the rise in 17 can be seen in the left Fallopian tube. Dye has ketosteroids is a much better to the state of filled the uterus and passed up both Fallopian tubes, guide finally spilling over into the peritoneal cavity, where the glands. it forms shadows which are less well defined. Urethroscopy is the only further investigation (Reproduced with permission from the Proceedings which should be performed if further confirmation of the Royal Society of Medicine.) 594 POSTGRADUATE MEDICAL JOURNAL December 1956 dren of both sexes, though more particularly girls, that the explanation is not as simple as this and develop a premature growth of pubic hair. No Wilkins3 (p. 54) has suggested that the condition other signs of precocity are present, except that may be due to the secretion of types of glyco- skeletal maturation, and I7 ketosteroid excretion genetic hormones (such as I7 hydroxycorticoster- may be slightly increased, and a normal puberty one) which increase the excretion of salt. will occur at the usual age. Silverman et al. Treatment. All patients should be given cortisone suggest that the condition is due either to an undue provided the. condition is diagnosed during the sensitivity of the hair follicles to androgen secretion first year or two. The exception to this rule is the or to an early elaboration of adrenal androgens child who in error has already been brought up as a before the gonadotropic mechanism of the pituitary boy and may be better left unchanged in sex and has been activated. therefore untreated with cortisone. This problem An adrenal tumour may also lead to diagnostic is discussed more fully in the later section on the difficulties from its virilizing effect, but the con- psychological aspect of hermaphroditism. Under dition occurs after birth and the anatomical de- no circumstances should partial adrenalectomy, a velopment of the genitalia will be normal. There popular operation in the past, be performed. The is a similar rise in the 17 ketosteroids, but the operation carries a considerable risk and its effects administration of cortisone produces no fall in are only temporary. their excretion as compared with the dramatic fall The aim of cortisone therapy is to reduce the in cases with adrenal hyperplasia. level of I7 ketosteroids as rapidly as possible and Heredity. Carter2' states that some, and perhaps then, by trial and error, to find the smallest main- all instances of congenital adrenal hyperplasia are tenance dose to keep them at this low level. In inherited as an autosomal recessive condition and older children it may not be possible to reduce the Grumbachl4 has found that if one patient of the level below 4 to 6 mg., but in small infants it saltl4osing type has occurred, all other affected should be possible to reach 0.5 mg. Cortisone may children born into that family will have the salt- be given intramuscularly or by mouth, but Wilkins losing complication as well. There are certainly prefers the intramuscular route since its action is many reports (Jolly,l8 p. 74) which illustrate the more predictable, it lasts longer and smaller doses importance of genetic factors. If congenital are required than when given by mouth. More- adrenal hyperplasia affects a male, the condition over, it may be possible to maintain suppression of of macrogenitosomia praecox results. Con- 17 ketosteroid excretion by an injection of cortisone sequently, if two members of opposite sex in a given every fourth day only. It is important that family are affected, the girl is a female pseudo- only the smallest amount of cortisone required for hermaphrodite and the boy has macrogenitosomia maximum suppression of ketosteroids is given, praecox. These facts of heredity should be given since an excess of cortisone suppresses growth. to the parent of any child with congenital adrenal During periods of infection there may be a tem- hyperplasia. porary release from cortisone suppression, since Prognosis. Cortisone therapy has entirely altered the adrenals are still capable of responding to the future for these patients, but it is only fair to stress, but no immediate change in cortisone say that the prognosis as to life before the days of dosage is required and this should only be made if cortisone was not as bad as was often alleged. The the rise in the 17 ketosteroids persists. present author (Jolly,l8 p. 76) refers to instances of Cortisone therapy should be started as early in elderly patients who have never received cortisone life as possible in order to prevent the secondary and there must be many others unrecorded. At structural changes in the body from taking place. the same time, the risk of adrenal insufficiency Furthermore, if cortisone is not started until the during infancy is considerable and in Gross' bone age has reached io years or more, a rapid recent survey'9 there were 27 female pseudo- and premature adolescence takes place, breast hermaphrodites and one male with adrenal hyper- development and menstruation occurring within a plasia, of whom ' 50 per cent.' showed this com- few weeks. In these cases it appears that the plication. This is an unusually high proportion pituitary-gonadal mechanism has already reached and Wilkinsl3 refers to I5 cases of the salt-losing a stage which on release with cortisone precipitates type out of a total of 67. Adrenal insufficiency in an immediate adolescence. these patients has been explained on the grounds Cortisone started shortly after birth will allow of the hyperplasia of the zona reticulata, which is normal growth and normal female development to the principal feature of the enlarged adrenal glands. take place. Wilkins et al.15 refer to two instances This hyperplasia takes place at the expense of the where pregnancy has occurred. If sexual hair has zona glomerulosa and zona fasciculata, which al'e already appeared, the further rapid skeletal growth believed to be responsible for electrolyte control. can be prevented. Similarly acne, and hyper- Recent experimental work with ACTH has shown tension if present, disappear, as do the frequent December 1956 JOLLY: Hermaphroditism 595

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PLATE 4.-True hermaphrodite. This boy had well-developed breasts, as seen in the left-hand photo taken at the age of 5 years. The genitalia, photographed at 12 years, showed a penis with a hypospadic urethral meatus at its base. An ovotestis was found in the right side of the scrotum and a left ovary in the correct position. Uterus, vagina and Fallopian tubes were present. (This patient was under the care of Mr. Denis Browne and his case has been recorded by Williams (1952), Brit. med. J., i, 1264.) and sometimes painful erections of the clitoris ment for the cases of congenital adrenal hyper- which occur in many of the children. If the voice plasia of the salt-losing type: has already become deep the cortisone cannot alter i. When first seen the child should be given it, as permanent structural changes have taken large doses of sodium chloride (3 to 6 g. daily) in place in the vocal cords. order to correct the dehydration and salt lack. It is still too early for the assessment of the 2. When the immediate emergency is over corti- long-term results of cortisone therapy, but present sone should be given and its dose adjusted while findings (Wilkins9) indicate that the suppression continuing with the large doses of sodium chloride. of adrenal activity persists to some extent after the 3. When the dose of cortisone has been adjusted withdrawal of the drug. This possibly indicates desoxycorticosterone (DOCA) should be given and that the adrenal disorder may be permanently the dose of DOCA and salt worked out in order to altered so that no relapse will occur when cortisone obtain normal electrolyte levels. is withdrawn, comparable to the treatment of 4. The calculated dose of DOCA should be hyperthyroidism with thiouracil. given by implantation. Some of the patients, particularly infants, may The advantage of giving DOCA is that it reduces show electrolyte disturbances from adrenal in- the amount of salt required, so that the large doses sufficiency and the patient may first present with of salt can be kept for emergencies. these symptoms. This adrenal lack manifests With early treatment the removal of the enlarged itself as a failure to thrive, persistent severe vomit- clitoris is seldom necessary and even in those ing, diarrhoea and attacks of acute circulatory diagnosed later the organ should not be removed failure. The child becomes dehydrated and there unless the large size is causing distress, in which is a fall in serum sodium and carbon dioxide levels case early amputation is desirable. Hampson22 has with a rise in potassium. shown that amputation of the clitoris in childhood Wilkins recommends the following line of treat- does not prove detrimental to subsequent sexual 596 POSTGRADUATE MEDICAL JOURNAL December I956 responsiveness, as stated by some authors, and if male may develop along either line. Feminine the parents have been in doubt about the child's development, when it occurs, is' due to the secre- correct sex the removal of the enlarged clitoris will tion ef oestro-ens by the testes. assist their adjustment. A vaginoplasty should be B. Female External Genitalia. The external carried out in order to provide an adequate orifice genitalia of these patients are entirely feminine ex- for the vagina and Gross19 recommends that this cept that in some the clitoris may be slightly en- should be undertaken when the child is in her larged. The urethra and vagina are usually separ- 'teens. ate and the latter often ends blindly owing to absence of the uterus. At puberty development (II) Intersex is always along female lines with normal breast The varieties of this condition have been sum- formation but no menstruation. Sexual hair in marized by Wilkins in the following table (repro- some is entirely absent. duced with permission from Pediatrics, i6, 288, 3. Female Pseudohermaphrodites (without adrenal 1955), where findings are compared with those in hyperplasia). This is the rarest type of intersex cases of female pseudohermaphroditism associated and Wilkins et al.1l state that only iz authenticated with adrenal hyperplasia. cases have been recorded. The genital tract is I. True Hermaphrodites. In these rare patients identical with that found in female pseudoherma- the gonads differentiate so that both testicular and phrodites with adrenal hyperplasia but the ovarian tissue is present in the same individual. patients differ in showing no virilization. Normal The commonest finding is that one or both gonads secondary sexual development occurs at puberty are ovotestes, the other being an ovary or testis if with menstruation taking place through the only one ovotestis is present. Less commonly, urethral meatus. The ovaries mature and show one gonad is a testis and the other an ovary. The evidence of ovulation with formation of corpora ovotestis may descend as a normal testis, but an lutea. ovary seldom reaches the inguinal canal. Many Diagnosis of Intersex. The first step in the different arrangements of the external genitalia diagnosis is to exclude female pseudoherma- have been reported (Plate 4). phroditism due to adrenal hyperplasia. This To make the diagnosis both gonads must be is done on the basis of the progressive virilization biopsied and one cannot predict the type of already discussed. secondary sexual development which will take The next step is urethroscopy and dye studies alace at puberty. No case of true hermaphroditism as already described, in order to determine the has been type and extent of the internal genitalia. This pchieving parenthood in either sex should be followed by laparotomy to examine the reported. internal genitalia and make biopsies of both 2. Male Pseudohermaphroditism. In these patients gonads. As an additional diagnostic aid the the gonads are morphologically testes and are sited chromosomal sex should be determined by means in the abdomen or in the labioscrotal folds. If of Barr's technique of skin biopsy (Moore et al.23; they are in the abdomen they lie either in the site Barr24) which is based on the smaller size of the of the ovaries or in the inguinal canal. The tubules Y chromosome. Females have an XX chro- are immature, being composed of undifferentiated mosome combination and the mass of sex germinal cells, but after puberty Sertoli cells may chromatin formed by the fusion is sufficiently predominate and numerous Leydig cells are often large to be visible. It forms a planoconvex mass found in large clumps. just under one micron in diameter and usually There are two principal types of male pseudo- lies against the inner surface of the nuclear mem- hermaphroditism, one in which the external brane but is occasionally free in the nucleoplasm genitalia are male or ambiguous, and the other in or adjacent to the nucleolus. Males have an XY which they are female. Familial factors play a combination which is too small to be distinguished part so that more than one case may occur in the from the general particulate chromatin. same family (Plate 5). Barr's results have so far shown that all male A. Male or Ambiguous External Genitalia. A pseudohermaphrodites and female pseudoher- varying degree of phallic development and labio- maphrodites with adrenal hyperplasia tested, scrotal fusion exists, while uterus and tubes may have given correct results. True hermaphrodites be present and fully developed. In other cases the and female pseudohermaphrodites without adrenal uterus is incompletely developed and one or both hyperplasia may have either male or female type tubes absent. Paradoxically, if the genital ducts nuclei. It will be apparent that those giving are predominantly female, the child is likely to correct results involve by far the largest group of develop male secondary characteristics at puberty, those with ambisexual development. whereas those in which the ducts are predominantly It had been hoped that this work would demon- December i956 JOLLY: Hermaphroditism 597

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PLATE 5.-Two male pseudohermaphrodite brothers, aged ten months and three years respectively. The gonads, which proved to be testes, were found in the site of the ovaries and surrounded by structures resembling Fallopian tubes, including fimbriated ends. No uterus or vagina was seen. strate the ' dominant' sex-in equivocal cases but data and particularly the psychological factors. this has not proved to be so. For example, male It is for this reason that Barr pleads for the use of pseudohermaphrodites with strongly feminine the terms ' chromatin positive' or 'chromatin characteristics both anatomically and psycho- negative' rather than female or male nuclei, logically still show a male chromatin pattern. pointing out that much unnecessary distress might It is for this reason that Barr, both in his earlier be caused to a patient were he or she to learn that and later writings25,26 has emphasized that the the cell nuclei were of a different sex from that in chromatin pattern should not unduly influence which he or she had been brought up. clinicians in their decisions as to which sex a child Research is continuing to discover other sites should be brought up. The test is a valuable in the body from which material can be obtained diagnostic aid but the decision as to the sex of for the sexing of nuclei and in particular to obviate upbringing must be decided on all the available the need for a biopsy. Davidson and Smith27 have 598 POSTGRADUATE MEDICAL JOURNAL December I956 used the polymorph nuclei in blood films while role.' This term is used to signify all those Moore and Barr28 have recently described a things that a person does or says to disclose him- method based on scrapings of oral mucosa which self or herself as having the status of boy or man, they state are easier to interpret than skin biopsies. girl or woman respectively. It includes, but is not Differential Diagnosis. Two conditions-Gonadal restricted to, sexuality in the erotic sense. Their Dysgenesis and Klinefelter's Syndrome--which research has shown that the gender role and may enter into the diagnostic problems of intersex orientation as a male or female closely conforms to remain to be mentioned. the sex to which the patient has been assigned Gonadal Dysgenesis. This condition was pre- and reared and that it is largely independent of viously called ' ovarian agenesis' but recent work gonadal, hormonal or chromosomal sex or the state (Polani et al.29; Wilkins et al.30) has shown that the of the genitalia. nuclei are most often male. Grumbach et al.10 As part of their work 22 patients, who had lived have therefore suggested the title of ' Gonadal with a contradictory genital appearance for periods Dysgenesis.' (Dysgenesis rather than agenesis of five to 47 years, were studied. In all but one since varying amounts of rudimentary mesonephric case these patients had come to terms with their elements are present in the genital ridge.) These anomaly and had a sexual orientation consistent patients with gonadal dysgenesis and male type with their assigned sex and opposite to their nuclei must be regarded as the most extreme form external appearance. The conclusion was reached of male pseudohermaphrodite-in other words, that the psychological aspect of sex is undiffer- genetic males who are completely feminized. entiated at birth and becomes differentiated as the The patients have a normal female appearance result of the experience of growing up. The but are stunted in growth. Secondary sex gender role is well established by the age of two and characters fail to develop at puberty except that a half years and remains so indelibly printed that sexual hair develops. Laparotomy shows the not even gross discrepancies between it and the presence of an infantile uterus and tubes with a thin external appearance of the patient will displace it. strip of tissue in the site of the ovary. This tissue Ellis35 in a different type of study reached similar contains no germ cells but is composed of cells conclusions. Eighty-four cases from the medical resembling ovarian stroma although this is not in literature were studied and it was shown that the fact sex-specific. The diagnosis is confirmed by great majority assumed a sexual role which the finding of a high level of follicle stimulating accorded with the sex of upbringing rather than hormone (FSH). Associated anomalies, parti- with the internal or external genital characteristics. cularly webbed neck, cubitus valgus and coarcta- From the practical point of view, this work tion of the aorta may be present. indicates that any change in the child's sex must Klinefelter's Syndro.me. This condition, which be made before the age of three years, since the affects males, was described by Klinefelter et al.31 gender role is by then established. After this age in I942. The patients have small testes, azospermia changes of sex should only be made at the request and an increased urinary excretion of FSH. of the patient and after the most careful considera- Secondary sexual characteristics may be fairly well tion. In these cases the decision would only be developed but the testes are of preadolescent size made after puberty. and the configuration of the body may be feminine. In the management of all hermaphrodites it is Gynaecomastia is a common accompaniment and imperative that the common feeling of the child it is particularly for this reason that diagnostic that he or she is half boy and half girl should be difficulties may arise as in the true hermaphrodite removed. This can be dealt with by an explanation recorded by Williams32. that he or she is a boy or girl and that it is only the genital development which is incomplete. The Psychological Aspect of Hermaphrodites In deciding the correct sex of upbringing the Selection of Sex of Rearing in Cases Seen in psychological aspect is probably of more im- Infancy portance than all the other methods used for the I. Congenital Female Pseudohermaphroditism with determination of sex, namely, the gonadal, hor- Adrenal Hyperplasia monal and chromosomal sex as well as the type These patients should always be brought up as of internal and external genitalia. This statement girls and given cortisone unless seen later in child- is based on my own experience (Jolly,18 page 8o), hood and already brought up as boys, when no and is supported by the recent careful and very change should be made and no cortisone given. important studies of Money, Hampson and Hamp- 2. Intersex son.22, 33, 34 These workers have carried out ex- Male Pseudohermaphrodites and True Hermaphro- tensive studies on many hermaphrodites of different dites. In these cases the best guide is the state of types and emphasize the importance of the' gender the external genitalia, and particularly the size of December 1956 JOLLY: Hermaphroditism 599 TYPES OF AMBISEXUAL DEVELOPMENT Secondary Labial Sex Gonads Phallus Fusion Genital Ducts Develop- ment I. Congenital adrenal hyperplasia: Female pseudohermaphrodites .. Ovaries Large + + +-- O Female Male precocious II. Intersexes: I. True hermaphrodites .. .. Mixed Variable Variable Mixed Male or female Predominantly 2. Male pseudohermaphrodites: female Usually (male vestiges) male Large to A. External genitalia simulating medium + +-+ + Predominantly male or ambiguous .. male Male or Testes (female female (Abdominal vestiges) or inguinal) Predominantly B. External genitalia simulating female uterus Usually female ...... Small O usually absent female (male vestiges) Large (may .3. Female pseudohermaphrodites .. Ovaries have penile + + + Female Female urethra) the phallus or the presence of a serviceable vagina. scribed in the light of embryological knowledge. If the phallus is of a reasonable size the child Particular attention is paid to the psychological should be brought up as a boy, but if it is small, aspect, since the sex in which a hermaphrodite is and female external genitalia are present, the child reared is more important than any other feature in should be brought up as a girl, particularly since determining the ' gender role,' that is, the sex male pseudohermaphrodites of this type most which he or she feels they are. This gender role often become more feminine at puberty. is firmly established by the age of two and a half The question of orchidectomy in these patients years and only very rarely should any change in is debatable. With true hermaphrodites the ideal sex be made after this age. is to remove the gonad and the internal organs With the development of newer methods for the which do not conform to the assigned sex. If male detection of sex, such as the examination of cell pseudohermaphrodites are to be brought up as nuclei, one must beware lest patients are thereby girls, removal of the testes has been recommended forced to take up a sex contrary to their own desires on the grounds of an increased risk of future and inclinations. In general (apart from cases of malignant change. On the other hand, this will female pseudohermaphroditism), it is the external remove the source of the oestrogens which can be genitalia which determine the sex in which the expected in those with female external genitalia patient can lead the happiest life. and necessitate later oestrogen therapy. However, this is not too serious and in all cases the correct Acknowledgments hormone should be given at puberty as required, in I would like to thank Mr. Denis Browne and order to enhance the secondary sexual charac Mr. D. Innes Williams for permission to reproduce teristics. photographs of their patient (Plate 4). I am also Female Pseudohermaphroditism without Adrenal grateful to Mr. Derek Martin and the Photographic Hyperplasia. These patients should be brought up Department of the Hospital for Sick Children, as girls, since they will later menstruate. A vagino- Great Ormond Street, London, and to the same plasty and possibly amputation of the clitoris will department of the South Devon and East Cornwall be required. Hospital, Plymouth, for the illustrations. REFERENCES Summary I. YOUNG, H. H. (I937), ' Genital Abnormalities, Hermaphro- ditism and Related Adrenal Diseases,' Williams and Wilkins, A survey of present-day views on hermaphro- Baltimore. ditism is presented and the different types de- Continued on page 607. December I956 FAWCETT AND DHILLON: Leukaemoid Re-action in Bronchogenic Carcinoma 607 TABLE I 1956 Feb. 27 March 5 March 8 March 12 March 15 March 17 R.B.C.s (n./c.mm.) ...... 4.2 - 3.0 3.3 Hb. (g. IOO ml.) ...... 3.5 12.3 93 10.1 10.7 W.B.C.s (n./c.mm.) ...... 370,000700,000 100,000 I10,000 I110,000 N. polvmorphs () ...... 87 8i 90 87 90 91 Eosinophils (%) ...... Band cells (%) ...... 9 5 3 I 4 5 N. myelocytes (%) ...... I I Iymphocytes(%) ...... 4 7 3 7 3 3 Monocytes (%) ...... 5 4 4 2 Platelet (thousands per c.mm.) (Lemport) 220 200 200 same histological picture as the primary bronchial Summary carcinoma. A case of carcinoma lung with severe leukaemoid reaction is reported. The absence of leukaemic Discussion infiltration in kidney, liver and spleen differentiated Hinshaw et al.2 have reported a case of severe the condition from true leukaemia. leukaemoid reaction associated with bronchogenic carcinoma; the leucocyte count reached I44,000 Acknowledgments and majority of the cells were mature granulocytes. We are indebted to Dr. Blackburn, the con- Several observers have reported leukaemoid blood sultant haematologist, for his help and criticism in picture in association with malignancy.3 4 5 In preparing this paper. REFERENCES our patient the diagnosis of leukaemia could not be I. KRUMBHAAR, E. B. (1926), ' Leukaemoid Blood Picture in excluded until the examination of the Various Clinical Conditions,' Amer. J. Med. Sc., 172, 519. histological 2. HINSHAW, D. B., and HOXIE, H. J. (I949), ' Leukaemoid organs at autopsy. Hill et al.6 have discussed the Reactions in Cardinoma,' Calif. Med., 71, 300-301. 3. DOWNEY, H., MAJOR, S. G., and NOBLE, J. F. (1934), problem of leukaemoid reactions and have made 'Leukaemoid Blood Pictures of the Myeloid Type,' Folia several useful in at the correct Haematol., 8, 383. suggestions arriving 4. MEYER, L. M., and ROTTER, S. D. (x942), 'Leukaemoid diagnosis during life. Reaction in Malignancy,' Amer. Clin. Path., X2, 218. 5. KLEEMAN, C. R. (I95I),' Lymphocytic Leukaemoid Reaction This case also illustrates the value of angio- Associated with Primary Carcinoma of the Breast,' Amer. J. in of the car- Med., 10, 522. cardiography assessing operability 6. HILL, J: M., and DUNCAN, C. N. (I94I), 'Leukaemoid cinoma lung. Reactions,' Amer. J. Med. Sc., 20o, 847-857. Continued from page 599 .-Hugh Jolly, M.D., M.R.C.P., D.C.H. 2. WILKINS, L. (I949), Pediatrics, 3, 533. Foundation Colloquia on Endocrinology, Vol. VIII, Churchill, 3. WILKINS, L. (1950), 'The Diagnosis and Treatment of London. Endocrine Disorders in Childhood and Adolescence,' Thomas, I6. JOLLY, H. R. (1950), Arch. Dis. Childh., 25, 207. Springfield. I7. JOLLY, H. R. (I95I), Proc. Roy. Soc. Med., 44, 459. 4. WILKINS, L., LEWIS, R. A., KLEIN, R., GARDNER, I8. JOLLY, H. R. (I955), ' Sexual Precocity,' Thomas, Springfield. L. I., CRIGLER, J. F., ROSEMBERG, E., and MIGEON, I9. GROSS, R. E. (I955), Pediatrics, I6, 303. C. J. (195 ), J. clin. Endocr., x, i. 20. BONGIOVANNI, A. M., and CLAYTON, G. W. (1954), 5. SILVERMAN, S. H., MIGEON, C., ROSEMBERG, E., and Bull. Johns Hopkins Hosp., 94, I8o. WILKINS, L. (I952), Pediatrics, 10, 426. 21. CARTER, C. O. (1955), in ' Paediatrics for the Practitioner', 6. WILKINS, L., GARDNER, L. I., CRIGLER, J. F., SILVER- edited bv Gaisford and Lightwood, Butterworth, London. MAN, S. H., and MIGEON, C. J. (1952), J. clin. Endocr. 22. HAMPSON, J. G. (I955), Bull. Johns Hopkins Hosp., 96, 265. & Metab., 12, 257. 23. MOORE, K. L., GRAHAM, M. A., and BARR, M. L. (1953), 7. WILKINS, L., CRIGLER, J. F., SILVERMAN, S. H., Surg. Gynec. Obstet., 96, 64I. GARDNER, L. I., and MIGEON, C. J. (1952), Ibid., 24. EARR, M. L. (1954), Ibid., 99, i84. 12, 1015. 25. BARR, M. L. (I954), Lancet, i, 779. 8. CRIGLER, J. F., SILVERMAN, S. H., and WILKINS, L. 26. BARR, M. L. (1956), Ibid., i, 47. (1952), Pediatrics, o1, 397. 27. DAVIDSON, W. M., and SMITH, D. R. (I954), Brit. med. J., 9. WILKINS, L. (1952), J. Pediatrics, 41, 86c. i, 1379. Io. GRUMBACH, M. M., VAN WYK, J. J., and WILKINS, L. 28. MOORE, K. L., and BARR, M. L. (1955), Lancet, ii, 57. (I955), J. clin. Endocr. & Metab., 15, i i6i. 29. POLANI, P. E., HUNTER, W. F., and LENNOX, B. (I954), 11. WILKINS, L., GRUMBACH, M. M., VAN WYK, J. J., Ibid., 2, I20. SHEPHARD, T. H., and PAPADATOS, C. (1955), 30. WILKINS, L., GRUMBACH, M. M., and VAN WYK, J. J. Pediatrics, I6, 287. (I 954), J. clin. Endocr. & Metab., I4, 1270. I2. SILVERMAN, S. H., MIGEON, C., ROSEMBERG, E., and 3I. KLINEFELTER, H. F., REIFENSTEIN, E. C., and WILKINS, L. (I952), Ibid., 1o, 426. ALBRIGHT, F. (I942), J. clin. Endocr., 2, 615. 13. WILKINS, L. (1955), Report of 13th M. and R. Pediatric 32. WILLIAMS, D. I. (I952), Brit. med. J., i, 1264. Research Conference. 33. MONEY, J. (1955), Bull. Johns Hopkins Hosp., 96, 253. 14. GRUMBACH, M. M., Ibid. 34. MONEY, J., HAMPSON, J. G., and HAMPSON, J. L. 15. WILKINS, L., BONGIOVANNI, A. M., CLAYTON, G. W., Ibid.,97, GRUMBACH, M. M., and VAN WYK, J. (1955), Ciba 35. ELLIS,(I955),A. (I945), Psyc.'t.sownaticr81. Medicine, 7, IO8.