Inl J Gynaecol Obstet 16: 8-19, 1978

Postnatal Formation of Ovarian Stroma and Its Relation to Ovarian Pathology P. £ . Hughesdon Department of Morbid Anatomy, University College Hospital Medical School, London, England

ABSTRACT Hughesdon PE (Dept of Morbid Anatomy, University College Hospital Medical School, London, England). Postnatal formation of ovarian stroma and its relation to ovarian pathology. IntJ Gynaecol Obstet 16: 8-19, 1978 Ovarian development was studied in 113 patients ranging from birth to 15 years of age. After a short pause the ovary becomes highly active during the first year, subsides slowly to a trough between ages 3 and 5 and then resumes activity. During the early activity, central ripening follicles and their associated edema expand the ovary and then hold the ground gained by the progressive conversion during atresia of theca and some granulosa into medullary stroma. This later becomes amorphous and reduced in quantity. Cortical stroma forms separately and concurrently by proliferation of the interfollicular mesenchyme to form a lattice. Externally this matures to the tunica and internally anchors some ripening follicles to contribute retrogressed theca to its deeper layers. Cellular ovarian stroma probably develops as a proliferative response of loose ovarian mesenchyme to stretch, and so forms round individual ripening follicles and round the ovary as a whole stretched by the follicular complement and its associated edema. At both sites, therefore, its formation is dependent on the follicular mechanism. This explains the stromal poverty of dysgenetic and related ovaries and the stromal excess of Stein-Leventhal ovaries, while the direct follicular ancestry of medullary and some deep cortical stroma may explain the proneness of these sites to develop lutein foci and tumors of specifically gonadal morphology. A note is added on "Pfluger's tubes, " which furnish a little cortical stroma and show disturbed development along with that of the ovary in prematurity, Turner's syndrome and mongolism.

(5, 6, 21, 22, 32, 34, 43, 44, 49, 51, 59, 62). These deal mainly with the follicular apparatus. Prenatal ovarian development differs from testicular development in being dominated by the stockpiling and enclosure of germ cells. Much of the definitive structure therefore is formed postnatally, including the bulky and characteristic cellular stroma. Two main sources for this have been proposed, namely, steady proliferation of the scanty neonatal mesenchyme and retrogressive conversion into stroma of the theca and probably some granulosa of atretic follicles. Both the first process (43) and the second (45) have been favored as the major contributor, but as the second links stroma formation to follicular behavior and so can be used to explain variations of stromal quantity and form (25), the question deserves further study. Stieve (62) first noted that the theca of atretic follicles reverted to a stromal form, after the proliferation entailed had increased its bulk, while previous workers (11, 55, 70) were more concerned with its possible provision of an "interstitial gland." A similar conversion of the granulosa into stroma has been claimed in girls (45) and briefly documented in mice and guinea pigs (8). There is better evidence for a comparable conversion into macrophage like cells, both in prenatal (20) and postnatal (61) human ovaries and in those of lower vertebrates (18, 23). General accounts of the architecture and form changes of the ovarian stroma have been given by several authors (4, 7, 12, 16, 41, 46, 47).

MATERIALS A N D M E T H O D S

INTRODUCTION Ovarian development from birth to puberty has been the subject of eight specific studies (1, 14, 38, 40, 45, 57, 67, 68) and of many incidental contributions by authors concerned with it only in part

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Ovarian material from 113 patients was studied. This total included 46 stillbirths and early neonatal deaths, ranging in crown-rump length (CRL) from 180 to 360 mm (16 of 180-250 mm, 16 of 250-300 mm and 14 of 300-360 mm) and furnishing bilateral pairs in all but one. There were also 67 routine necropsies of infants and children, at ages ranging

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from 2 weeks to 15 years, comprising 17 aged 2 weeks to 3 months, 15 from the rest of the first year, 7 from the second year, 8 aged 2-5, 15 aged 5-10 and 6 aged 10-15, furnishing bilateral pairs in seven only. Five of the second group followed acute deaths, three in the First year and two between ages 5 and 10, and the rest followed longer illnesses which may have marginally reduced follicle ripening (40). Most blocks were made from the ovarian long axis, together with a few transverse ones which were not used for follicle counts. Sections were cut at 5, 10, 15 and 20 /xM and stained with hematoxylin and eosin (HE), periodic acid-Schiff and hematoxylin (PAS) and a reticulum method. T h e thicker sections accentuated variations of stromal density and vascular pattern, and eosin was cleared from them in 1% aqueous phosphomolybdic acid. Gross measurements were not feasible: several authors have given them (1, 21, 2 8 , 5 1 , 5 7 , 6 4 , 6 8 ) . Ovarian terminology has no consensus. The terms primordial, primary, secondary and tertiary follicle are here used to refer, respectively, to follicles with a single layer of flattened granulosa, a single layer of cubical granulosa, more than one layer of granulosa without an antrum, and the same with an antrum regardless of its size. T h e terms tunica albugínea, cortex and medulla are invincibly vague. Gray's Anatomy up to the 31st edition (27) defines the cortical stroma as the subtunical cellular layer surrounding primordial and early ripening follicles, extending the definition in later editions to include the deeper stroma surrounding larger follicles (the zona parenchymatosa). Most authors, but not all (46, 47), favor the second usage. Here the term is used to mean merely the continuous layer of cellular stroma forming a middle circumferential zone between narrow outer (tunical) and broad inner (medullary) zones which are usually less cellular. As such it is not a stable anatomical entity, being frequently reduced for a time by encroaching central edema, but no confusion results in the present context.

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order. Variation is common, notably retarded development (1). Inner zone Tertiary follicles were rare in all neonates of under 300 mm C R L , with an average antrum count of 0.05 per ovarian cross section at 180-250 mm and 0.33 at 250-300 mm. They were common in mature fetuses of 300-360 mm (count of 4.7) and the next two days (4.0), rare for the next 18 days (0.14), very common overall for the first year (7.2), slightly less so at 1-3 years (4.6), falling to a trough at ages 3-5 (1.6) and recovering at ages 5-15 (5.6). In detail follicles resembled those of the adult, save for the absence of corpora lutea and albicantia. T h e degree of individual theca luteinization ran parallel with the number ripening to the tertiary stage, as did the extent of interstitial edema; so that active ovaries developed general interstitial edema

RESULTS The ovary at birth consists of a narrow, poorly cellular outer zone containing remains of Pflüger's tubes; a broad middle zone of crowded primordial follicles and loose stroma; and an inner zone of ripening and atretic follicles, poorly cellular stroma, and vessels entering from the hilus (Fig. 1). These will, respectively, evolve into the tunica, cortex and medulla. Their average development will be described, as far as possible, separately, in reverse

Fig. 1. Ovary of stillborn with a crown-rump length of 290 mm, showing from above down narrow, poorly cellular outer zone, broad middle zone of primordial follicles and loose stroma, and inner zone of ripening follicles and fibrovascular tissue extending from mesovarium on left, with prominent Pflüger's tubes in juxtahilar zone on right (HE, X 45).

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Subsequent atresia of these ripening follicles reconverted their multiplied theca cells into cellular stroma which steadily filled up the inner zone with variegated mottled clouds (Fig. 3). T h e theca cells shrank, lost most of their cytoplasm and formed a dark wavy halo round a pale target like center of shrinking fluid, loose stroma and hyaline membrane. This sequence affected the theca externa and such cells of the theca interna as remained small and minimally luteinized, retaining a finely divided reticular framework. Larger and better luteinized theca cells with a dense pericellular reticulum underwent foamy change followed by atrophy, with expansion of the intervening fibers, to form a continuous or interrupted pale zone internal to a darker stromal mantle (Fig. 4). T h e apparent conversion of granulosal into stromal cells during atresia was seen only in some secondary and small tertiary follicles. After a slight thickening of the basement membrane,

Fig. 2. Aged one month. Very active ovary, showing congested edematous inner zone containing many tertiary follicles, surrounded by ill-defined narrow grey cortex, and mesovarium on right (HE, x 11).

with fibrillary dissociation and dilated venules (Fig. 2), while occasional inactive ovaries showed dense central stroma and inconspicuous vessels. During the third year the vessels became better developed and acquired a perivascular reticular sheath, remaining always conspicuous, while perifollicular edema became more local. T h e central swelling produced by ripening follicles and their associated edema rounded up the ovary, abolished residual fetal angulation and expanded the inner zone, which changed from a few branching seams clothed by broad folded cortex (Fig. 1) to a broad ovoid center forming most of the organ and surrounded by variably stretched cortex (Fig. 2). This remained as a distinct layer, but some of its deeper primordial and primary follicles became dislocated into the inner zone by expanding and migrating follicles. Counts of such dislocated follicles per ovarian cross section ran parallel with the a n t r u m count, being 7.7 at 0-1 years, 6.6 at 1-3, 0.8 at 3-5 and 5.5 at 5-15.

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Fig. 3. Aged three months. Less active ovary, showing peripheral dark cortex speckled with primordial follicles; central inner zone containing atretic follicles, early below, late and distorted above, with dark surrounding stroma of regressed thecal origin; and mesovarium on right (HE, x 13).

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deeper surface was more prone to atrophy. This contrast increased after the third year, along with better development of the medullary vessels (Fig. 9) and the medulla tended to clear (Fig. 10). There was much variation, however, and some cellular stroma always persisted at the hilar border (Fig. 10) and around some of the principal vessels. Middle zone Concurrently, the middle or cortical zone first loosened a little and became variably stretched round the expanded inner zone (Fig. 2). Cellular stroma formed within it gradually by proliferation in situ of the interfollicular spindle cells to form a submarginal darker b a n d (Fig. 11). This was seen focally in one ovary at one month, commonly at two months and always at three months: thereafter it progressed and became complete circumferentially at one year. T h e resulting latticework was somewhat curvilinear, owing to its enclosure of separate and clustered follicles. Its development varied, being least near the hilus and always maximal at the

Fig. 4. Aged 11. Tent-shaped follicle in late atresia, showing from within outward poorly cellular stroma, clusters of foamy regressing theca-lutein cells, and dark stromal rim of regressed thecal origin with thicker cap above connecting it to cortex (HE, x 88).

narrow connective tissue septa grew from the theca into the granulosa to divide it into islands and cords (Fig. 5). As the septa expanded, the granulosal islands dissociated and blended with it, apparently acquiring stromal form (Fig. 6). In larger tertiary follicles, and generally at the antral border, the granulosa either degenerated or flattened and evolved into macrophages. The medullary stromal islands so formed changed gradually in ways masking their follicular ancestry. In inactive ovaries they tended to disperse, spreading out from the crenated follicular remnants to blend with one another and with the cortical stroma (Fig. 7). In more active ovaries, later follicular activity deformed them, often into a bowlike shape (Figs. 3 and 8). Both processes might occur, reducing the follicular center to an ill-defined pale patch of any shape, scarcely recognizable if the hyaline membrane was poorly formed, as was often the case. At all ages thecal conversion to stroma was greatest on the cortical side of the follicle (Fig. 4), while the

Fig. 5. Neonate with a crown-rump length of 230 mm, showing secondary follicle in early atresia with thecal connective tissue invading and subdividing the granulosa (HE, X 450).

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of the tunica between about ages 3 and 5, proliferation appeared to slacken a little, while the superficial cortical lattice elongated slightly parallel to the surface, and the primordial follicles became more strung out there (Fig. 9). Measurements of average cortical thickness (mm) in the sections showed 0.58 for the first year, 0.71 from 1-3, 0.73 from 3-5, 0.63 from 5-10 and 0.63 from 10-15. T h e measurements are admittedly rough owing to the often unsharp and meandrine inner border. Areas of developmental arrest which had temporarily escaped these changes were common, especially near the hilus. These still showed poorly cellular stroma and crowded primordial follicles, some of them sharing a granulosal envelope to give binovular and multiovular forms which were common in the first year. Primary follicle atresia with granulosal

Fig. 6. Neonate with a crown-rump length of 340 mm, showing small tertiary follicle in later atresia with hyaline membrane on left, loose connective tissue blending with dissociated small dark granulosal islands, and residual antrum lined by flattened cells budding off macrophages (HE, x 160).

medullary junction where the stromal pattern changed from radiate to interlacing (Fig. 11). This maximum persisted (Figs. 7, 9, and 10) with occasional slight augmentation round tertiary follicles (Fig. 12). In addition, the deeper surface came to receive accretions from the retrogressed theca of atretic tertiary follicles in the adjacent inner zone. These often remained tethered to the cortical lattice by a triangular proliferated cap (Figs. 4 and 9), derived from it and giving rise centrally to the so-called "theca cone" (41, 63). Such tethering only occurred after adequate formation of the lattice in the second half of the first year, and it caused some mediumsized follicles and their products to remain somewhat peripheral (Figs. 9 and 10), as later, instead of accumulating centrally, as earlier (Figs. 3 and 7). After the first year further stretching and stromal proliferation increasingly separated the primordial follicles (Fig. 12). However, with the consolidation

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Fig. 7. Aged nine months. Inactive ovary, showing broad cortical rim attenuating near hilus with included corpus fibrosum below and inner zone containing several corpora fibrosa with dark stromal haloes of regressed theca blending with one another (HE, x 12).

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still more after nine years. However, there was much variation of detail locally and in timing. A feature of the first few months, mainly of the outer zone but extending into the cortex, were residual "Pflüger's tubes," eg, clusters of small primary oocytes contained in a granulosal envelope or net often still continuous with the surface epithelium or an infolding (Fig. 1). These evolved by degeneration of some germ cells and conversion of others into clusters of primordial follicles with granulosal bridges. As the follicles detached, isolated granulosal islands and cords remained, often acquiring a lumen near the surface and assuming a spindly form in the middle zone, with seeming conversion into stroma (Fig. 14). Tiny clusters of such cells were seen adjacent to the hilus as late as the fifth year. Isolated deeper portions of Pflüger's tubes sometimes scattered through the middle into the inner zone where granulosal proliferation and theca formation converted them into so-called "eggball-follicles" (50).

Fig. 8. Aged seven months. Inner zone with dark stromal patches of regressed thecal origin enclosing atretic follicles with pale centers, well-defined centrally and below but reduced to an attenuated thread in the bowed dark patch above (HE, x 40).

clustering was everywhere common, as was an occasional oocyte with diastase-fast PAS-positive cytoplasm. This had progressed to calcification in 12 ovaries, ten of them from between ages 2 and 7. Outer zone Infant ovaries showed a surface layer of dark cubical epithelium, often lost from autolysis, becoming flat near the hilus. Later it often flattened elsewhere, especially after the age of 5 years. This layer rested on a thin PAS-positive basement membrane, often faint in flatter areas. The subjacent zone showed at first a thin interrupted semihyaline layer of condensed reticulin. This thickened a little and was gradually supplemented by a tunica of more adult type, developed in the first year from the cortical stroma as its outer maturation layer. As this approached the surface its lattice stretched, abruptly or progressively, to a nearly circumferential orientation with concurrent reticulin condensation (Fig. 13), especially after the age of three years and

Fig. 9. Aged three, showing from above down tunica, cortex, and medulla with folded hyaline membrane of follicle in late atresia with atrophied theca below, nearby prominent vessels, and dark cap of stromal conversion above continuing into cortex (HE, X 65). IntJ Gynaecol Obstet 16

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line" (Fig. 7). Clusters of perineural mesovarian hilus cells were seen at birth in two fifths of cases of 180-250 mm C R L , three fifths of cases of 250-300 mm and four fifths of cases of 300-360 mm. A few were seen in the first three months but not later. DISCUSSION There is ample reported precedent for tertiary follicle formation in the mature fetus, with a postpartum pause of 2-3 weeks (34, 44, 59) and resumption at an increased rate during the first year (5, 44), although Merrill (38) found the second year more active. A later trough of reduced antrum formation was found here at ages 3-5. T h e larger antra may show a slight trough at lVfe-4 years (44) or no constant change (40). T h e postnatal burst of activity is perhaps ultimately due to release from previous inhibition by steroids or prolactin, or both (71); but

Fig. 10. Aged five, showing pale medulla containing some corpora fibrosa, ripening follicles at inner border of cortical rim, and residual medullary stroma at hilus, continuous with cortex (HE, x 13).

These were not seen after seven months, but their fate was uncertain. Increased prominence of Pfliiger's tubes was seen locally in areas of poor stromal cellularity, always near the hilus (Fig. 1) and sometimes elsewhere; and more generally in two grossly premature births (both at 24 weeks) with long survival (29 and 89 days). A comparable picture was seen in a case of Turner's syndrome in a neonate where the prominent granulosal cords received a supplement of follicular granulosa after oocytic death. A comparable picture was also seen in a case of mongolism in a neonate of 330 m m C R L in whom the ovary was so immature as to fit about half this C R L , save that the scanty follicles were more scattered and the mesenchymal septa wider. Hilar zone Near the hilus the outer zone thickened at the expense of the middle at the site of the future "white

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Fig. 11. Aged three months, showing from left to right pale outer zone, middle zone with commencing stromal proliferation seen as an ill-defined dark band, and looser inner zone with radiate vessels and stroma (HE, X 66).

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probably reflect only the great variability of most regressive changes. This sequence would progressively enlarge the ovary throughout reproductive life by continuous new formation of stroma, for which one study claimed constancy of nuclear density (37), unless limited by contrary factors. O n e such factor may be the better vascular development after the third year, which correlates with apparent reduction of the medullary stroma and may operate through a proposed growth-controlling effect of CO2 tension (35). Another factor, operating later when ovulation is established, may be the supposed stroma-inhibiting effect of progesterone (12). If so, then the high stromal content of the h u m a n ovary compared with that of other mammals (31, 57) may reflect both reduction of litter size and increased duration of immaturity, including anovulation. Most of the cortical stroma arises by proliferation in situ during the first year of the loose interfollicular mesenchyme. This region has been noted as becom-

Fig. 12. Aged 13 months, showing from left to right surface epithelium, tunica, dark cortex with mainly peripheral primordial follicles and slight augmentation round two secondary follicles below (HE, x 42).

only the immediate cause relates to the visible effects. T h e first expansion of the infant ovary is functional and due to its enlarging tertiary follicles and their associated interstitial edema. Since these correlate in degree and since fluid from the larger follicles is a modified filtrate from plasma (56, 72), a common cause is suggested in increased seepage from dilated perithecal vessels (9), possibly evoked by histamine (30) and prostaglandins (54) liberated locally by pituitary luteinizing hormone (LH). The expansion is then made permanent by the progressive formation of cellular medullary stroma, derived mainly from the retrogressed theca of atretic follicles, with a small apparent supplement from granulosa divided and dissociated by ingrowing connective tissue, as reported in some rodents (8). Only the earlier stages of the last have been described in the h u m a n ovary and there considered abnormal (36, 39). However, they are common in infancy and

Fig. 13. Aged 11. Subsurface region showing irregular curvilinear reticular latticework, tending to flatten and condense its fibers toward the surface (Gordon and Sweet, x 150).

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Fig. 14. Aged 11 weeks, showing from above down surface epithelium and infoldings, tunica and middle zone with primordial follicles continuous in places with granulosal cords representing remains of Pfliiger's tubes, undergoing apparent metamorphosis into stroma below (HE, x 280).

ing progressively stretched (57), which may well be the essential stimulus to stromal proliferation; for the proportion of cortical stroma to primordial follicles varies inversely with cortical thickness (1). In time this stroma matures to the collagenized outer tunica, better adapted for resisting stretch, reducing later growth of the stroma and yielding the rough overall pattern of central radiate, middle interlacing and peripheral circumferential stroma (41, 67). Production of both cortical and medullary stroma could be assigned a common ultimate cause by the postulate that ovarian mesenchyme, when loose, responds to stretch by proliferation, especially at boundary areas subject to tension. Proliferation occurs, therefore, round ripening follicles, forming peri- and prothecal tissue, and round the ovary as a whole in response to the collective stretch effect of all such follicles and their associated edema. This yields the familiar pattern, as shown in Fig. 15, and implies that most stroma formation is dependent on

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the follicular mechanism. Proliferation of fibroblastlike cells is poorly understood, but, since tension augments and orientates fiber formation (17), it probably entails also some proliferation. Craig (12) ascribed stromal proliferation around ripening follicles to local estrogenic stimulation. However, since some proliferation may also occur around germinal inclusion cysts, estrogens more probably potentiate the effect of stretch, as in the rat uterus (13). This conclusion has four possible implications for ovarian pathology. Two of these relate to the dependence of stroma formation on the follicular mechanism and two to the double immediate origin of the stroma. 1. If follicles are congenitally absent or scanty, as in ovarian dysgenesis and hypoplasia (29), or if they remain virtually unstimulated because almost no gonadotropin is secreted (19, 58) or because they are congenitally insensitive to it (15, 29), then very little stroma is formed and the ovaries remain small or tiny. T h e second pair of conditions have been reported as showing rather variable follicular and stromal development, roughly in parallel. However, even dysgenetic ovaries may contain a few follicles at birth (10), and variations in the number, location and behavior of these may explain the minor variations of form reported in the first pair (29, 65). Extrafollicular stretch stimuli may be possible in dysgenesis, notably from the dilated medullary canals found in some cases (25). 2. If, on the contrary, follicle ripening is numerically and persistently excessive at an age when follicles are numerous, as in a typical case of SteinLeventhal syndrome, then the cortical stroma is further stretched and augmented, both in its illdefined deeper layers and in its increasingly collagenized tunica, while the ovarian center is gradually expanded by new cellular stroma of retrogressed thecal origin. T h e stromal mass often shows this origin by an association with corpora fibrosa or other follicular landmarks, as well as dislocated primary follicles, which implies that the factors limiting new stroma formation have been overcome. Areas of medullary stromal hyperplasia often develop secondarily, so that whatever causes these probably fosters the earlier stromal survival; but its increased production by the augmented follicle ripening, coupled with the increased liability to atresia with degree of maturation (22), may also be factors. In my material, central stromal increase is greatest in cases with the longest history, and the liability of this stroma to focal luteinization has earned them the alternative name of "hyperthecosis" (66), implying nosologic separateness. Nearly all cases have some deep stromal increase, however,

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Fig. 15. Diagram showing proposed mode of formation of ovarian cellular stroma at areas bounding zones of expansile pressure, indicated by arrows. Such stroma forms, therefore, round the ovary as a whole, owing to pressure from expanding follicles and edema, to yield the interlacing cortical stroma which matures to the more collagenized circumferential tunica; and round the ripening follicles (1 ), (2) and (3), thickening at first with growth and then thinning with more rapid expansion from fluid seepage, and remaining when the follicle shrinks during atresia, (4) and (5), as the source of the medullary stroma.

perhaps not apparent in a superficial wedge, and an operation for its selective removal has been devised (2). 3. T h e thecal origin of most medullary and some deep cortical stroma may confer on these sites a special readiness to reluteinize in response to pituitary LH and explain their greater proneness to lutein foci in later life (7). Stromal proliferation is often associated with such foci and hence ascribed to a similar cause: certainly in the cortex it starts in the deeper part. An accessory factor may be the cortical deposits of endometrial stroma (benign stromatosis) commonly found after age 40 (26), acting as a local stimulus. 4. There is some evidence that those stromatogenous ovarian tumors with distinctively gonadal patterns or cells (granulosa-theca cell tumors, arrhenoblastomas, hilus cell tumors and their relatives) start in the medulla (24) or the deeper cortex (53), that is, from stroma of follicular ancestry. However, this evidence is scanty, as relevant data, such as the exact sites of very small tumors, are seldom clearly reported. Prenatal and postnatal ovarian differentiation are both centrifugal. T h e immature peripheral struc-

tures originally called "Pflüger's tubes" were first described in postnatal material, chiefly cats and dogs (42). Extension of the term to the fetal ovigerous cords has left the postnatal structures without an appropriate name. They could usefully resume the original one. T h e "tubes" usually die out in the first 3-4 months (5, 14, 68), but apparent residues have been found at 11 months (1), 18 months (52), and here at five years at the hilus. Their mainly granulosal later stages have been figured only occasionally (43) and probably contribute to the cortical stroma a minute addition which, having recent surface epithelial rather than follicular antecedents, may lack normal potencies. Over a century ago the prominence of Pfliiger tubes was noted locally in poorly cellular areas (69) and diffusely in cases of prematurity with long survival (33). T h e granulosal cords of some neonatal T u r n e r ovaries have been recorded and variously interpreted by several authors, listed elsewhere (25). Similar structures develop in expiants of h u m a n fetal ovaries (3). I know of no reports of the neonatal mongol ovary, but later cases may show diminished follicle ripening (40) or hypogonadism (60). More severe dysgenesis is reported in trisomy 18 (48).

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ACKNOWLEDGMENTS T h e author is much indebted to Professor A. E. Claireaux of the Department of Morbid Anatomy, T h e Hospital for Sick Children, Great Ormond Street, London, W C l , for the loan of many blocks of infant a n d child ovaries; to his colleague Dr. A. Taghizadeh for most of the neonatal ovaries; and to Miss S. M. Calcutt for technical assistance.

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Address for reprints: P. E. Hughesdon Department of Morbid Anatomy University College Hospital Medical School University Street London, WC1E6 JJ England

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