Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from 417

THE PHYSIOLOGY OF GROWTH BY S. LEONARD SIMPSON, M.A., M.D., F.R.C.P. Consultant Endocrinologist, St. Mary's Hospital, etc.; Formerly Research Wor7Aer, Lister Institute

Although clinical and experimental evidence postulated an antagonism between growth and had previously indicated that skeletal growth sex-stimulating . Further observations depended upon the pituitary gland, it was not suggested that corpora lutea were formed before until I92I that Evans and Long, at the University ovulation occurred, and that his emulsions con- of California, demonstrated that a saline emulsion tained gonadotrophic luteinizing . Al- made from the lobe of fresh though Evans' original giant rats were apparently glands of cattle contained a growth hormone. The adipose, later work (Lee and Schaffer, 1934), hypophyses were thrown into 40 per cent. ethyl showed that there was a retention of nitrogen and alcohol, agitated with a glass rod, transferred to a relative excess of body protein. This was also two changes of sterile normal saline, and triturated true of the excess of tissue deposited in and with force and speed with ocean sand, diluted with around the abdomen. Evans stated in a recent saline, and decanted. The layers of sand, cell discussion in London that rats treated with pure fragments and opaque pink fluid permitted the growth hormone, unlike those in the initial latter to be decanted. This emulsion, when experiments with crude extracts, were not injected daily in doses of I to i ml. intraperiton- adipose. eally into young rats, accelerated their skeletal Another fundamental step was the development growth rate, compared with controls, and con- by P. E. Smith (I926) of a technique of completecopyright. tinued this growth for 20o days, or more, after hypophysectomy on the rat, without interfering growth normally ceases. Later, improved chemical with the . There resulted ' an methods permitted the preparations of alkaline almost complete growth stasis and a rapid regres- extracts which contained the growth hormone sion in the size of the adrenals (involving chiefly in purer form. It is interesting and important to the cortex), the and the sex apparatus ' note that Evans (1923-4) recorded that success, (Fig. i). At the Institute of Biology at Berkeley in mammals, with parenteral injections of beef University, California, rats are completely hypo- hypophysis extracts was only obtained ' after physectomized without complications in about failure in a long series of massive oral administra- two minutes for each operation, and there is http://pmj.bmj.com/ tions '. There is no doubt that in mammals the always a plentiful supply of hypophysectomized groWth hormone is ineffective when given by rats for experimental work. Such rats may be mouth, although this well-established experi- used for the assay of growth hormone, either by mental fact is still ignored by some clinicians. The weight increase, or by tail growth (Freud et al., rat is a particularly suitable animal for testing 1935, I939). Smith and MacDowell (I930) growth hormone because its epiphyses remain studied a strain of black silver dwarf mice, brought open until late in life. from England by Professor L. C. Dunn in I928, The effect of extracts containing pituitary in whom the characteristic of dwarfism was shown on October 1, 2021 by guest. Protected growth hormone has also been dramatically by Snell to be recessive. These mice cease to demonstrated in hypophysectomized rats and in grow after the end of the second week, but, congenitally dwarfed mice. Evans (1923) termed although there is some delay in sexual develop- his normal rats injected with pituitary emulsions ment, reproduction takes place. The essential ' hypophysis giants', and stated that they were physiological defect is absence of the growth 'twice as heavy as the largest individuals known hormone, and the essential histological defect in to us from our own and published records for this the pituitary gland of these animals is a complete animal species'. They were fat animals ; 'the absence of the eosinophil cells. Implantation of skeleton, most of the viscera especially the heart the pituitary glands of these dwarf mice into and lungs, liver, kidneys, and alimentary tract immature female mice of a normal strain produces showed a true overgrowth, but not so the repro- no acceleration of growth but accelerates sexual ductive tract, the uterus and oviduct remaining development. The injection of growth hormone infantile'. He also observed that the growth and will produce growth in these dwarf mice. Furtier maturation of ova were-impaired' or prevented, a'nd experimenta' evidence to the effect that ''the Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from 4I8. POSTGRADUATE MEDICAL JOURNAL August I 950 eosinophil cells are the source of the growth Is there a Specific Growth Hormone ? hormone was provided by Smith who showed that Pituitary extracts containing growth hormones the peripheral part of the bovine gland contains were found by earlier observers to contain also eosinophil cells, and, when stripped from the adrenotrophic and thyrotrophic hormones as well central basophil portion, will yield growth hor- as prolactin. Apart from any direct effect on mone. Clinically, gigantism is often associated skeletal growth attributable to hormones of the with an eosinophil adenoma. adrenal cortex and thyroid and possibly to pro- It is also of interest to note that the thyroid and lactin, it is probable that these hormones have adrenal cortex of Dunn's dwarf mice were hypo- effects on metabolism which indirectly favour plastic, suggesting that the eosinophil cells are the growth, especially in hypophysectomized animals source of the thyrotrophic and adreno-cortico- in which these glands are hypoplastic or atrophic. trophic hormones. Riddle and Bates (I938) suggested therefore that certain pituitary extracts owe their action upon Measurement and Site of Action of Growth growth to a balanced combination of prolactin, Hormone thyrotrophic and adrenotrophic hormones rather Since the epiphyses of normal rats remain open than to a special growth hormone. Earlier experi- in adult life, earlier methods of assay of growth ments, however, indicated that the growth hor- hormone depended upon observations on the mone was a specific entity. Thus Evans (I924) re- body weight of normal rats after ' a plateau' in cords that Smith and Allen showed that beef their weight curve was established, indicating hypophysis is effective by mouth in producing cessation of growth. After the technique of growth in hypophysectomized tadpoles, but that it hypophysectomy was mastered, the effect on the does not produce metamorphosis or repair the weight of the hypophysectomized rat appeared to atrophied adrenal cortex (interrenal body) or the have a greater exactitude and specificity. Freud, thyroid. Smith, in 1930, demonstrated that whereas Levie and Kroon (I939) used the tail of the intramuscular transplantation of living pituitary hypophysectomized rat as a more exact measure- glands from adult rats into dwarfed hypophysec- ment of the effect of the growth hormone (Fig. 2). tomized rats restored the size and function of the copyright. They also made radiographic and histological thyroid, adrenals and gonads as well as producing studies of fundamental importance. Using an growth, injections of a saline suspension of fresh almost purified growth hormone, they demon- gland affected growth only. It would therefore strated its specific chondrotrophic effect. In the appear that although extracts of growth hormone normal growing rat, the epiphyseal zone shows as usually prepared contain adrenotrophic and cells arranged in columns, little cartilaginous thyrotrophic hormones which have some effect on matrix, vascular connective tissue and a fine growth, there is a specific growth hormone which network of cancellous bone. In the hypophysec- can be chemically separated. This is in keeping

tomized rat (Fig. i), the regular columns of with the existence of clinical conditions in which http://pmj.bmj.com/ cartilage cells characteristic of growing cartilage the only defect appears to be that of growth are undeveloped and irregularly placed, the hormone, although other clinical conditions con- longitudinal arrangement is lost, mitosis is firm that the thyroid, the adrenals and the gonads minimal, the matrix has increased and the fine themselves have an important influence on growth. primary cancellous bone has disappeared. Growth We shall see later that further purification of the hormone immediately repairs this histological growth hormone led to more conclusive proof of picture, which reverts to normal, and shows active its specificity. growth of cartilage. There is no alteration in the on October 1, 2021 by guest. Protected development of bone tissue itself, and the growth The Thyroid and Growth hormone is seen to have a biologically typical point In the strain of congenitally dwarfed mice of attack at the proliferating cartilage. Freud, referred to above, thyroid extract alone produced Levie and Kroon (I934) found that the epiphyses an increase of growth, although not as much as of the tail of the rate soon become closed after pituitary growth hormone (Bates et al., 1935). hypophysectomy. Thus after four weeks a trans- The rate of growth of young normal mice is verse bony plate closes the epiphysis, from which a consistently accelerated by thyroxine injected number of massive bony processes project towards daily, but the period of this acceleration lasts for the diaphyseal marrow cavity. This can be en- only five weeks after which time the control mice tirely prevented by the early use of growth hor- overtake the'treated animals and the ultimate size mone after hypophysectomy, but it cannot be is the same. The skeleton of rats thyroidectomized reversed after it has *occurred. Smith (I930), at birth does not develop beyond the skeletal age of however, found replacement therapy renewed iS days, even with pituitary growth extract, unless growth three months after hypophysectomy. thyroid is also given (Salmon, 194I). Neverthe- Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from August 1950 SIMPSON: Physiology of Growth 419

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FIG. i -Left: Hypophysectomized rats (with litter-mate control) showing failure of growth after hypophysectomy at 26 days old. (Photograph at I22 days.) Right: Nos. 13, I4 and i5 illustrate sections of adrenal cortex, normal rat, hypophysectomized rat and hypophysectomized rat given pituitary transplant. Nos. I6, I7 and i8 illustrate respectively sections of thyroid vesicles of normal rat, hypophysectomized rat and hypophysectomized rat given http://pmj.bmj.com/ anterior pituitary transplant. (By courtesy of Dr. P. E. Smith) less, if the rats are thyroidectomized at 35 days oestradiol produce dwarfing by inducing prema- of age, pituitary growth hormone will produce ture union of the epiphyses. Larger doses inhibit growth above that of normal rats, even without the secretion of growth hormone and cause additional thyroid, although thyroid augments the degranulization of the chromophil cells of the effect. In thyroidectomized-hypophysectomized pituitary. In mice, both testosterone and oestradiol on October 1, 2021 by guest. Protected rats greatest growth is produced by pituitary cause an acceleration of certain age changes in the growth hormone plus thyroid ; considerable epiphyseal cartilage by inhibiting proliferation of growth by pituitary growth hormone alone; the cartilage cells and by promoting degeneration but thyroid alone has no effect in the absence of the and hyalinization of the cartilage and sclerosis and pituitary gland according to Evans, Simpson, and calcification of the cartilaginous growth substance Pencharz (I939). Since thyroidectomy results in (Silberberg and Silberberg, I94I). In I939 loss of the eosinophil cells from the pituitary gland, Gaarenstroom and Levie showed that oestrone the resulting stunting of growth would appear to and diethyl stilboestrol inhibited tail-growth in be due to the diminished or absent secretion of rats. The epiphyseal apertures narrowed, the growth hormone, as well as to the diminished rate cartilage cells became smaller and decreased in of metabolism. number, the normal arrangements of cartilage cells in vertical columns became disordered and Sex Hormones and Growth cartilage cells were resorbed. However, there was In some mammals such as dogs, testosterone or no closure of the epiphyseal junction by formation Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from 4i20 POSTGRADUATE MEDICAL JOURNAL August 1950

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Tail vertebra, normal, Mallory. x 56. Schematic drawing of the tibia, normal, Mallory. x 56. copyright.

Tail vertebra, Hypophysectomized, Schematic drawing of the tibia, Hypo- http://pmj.bmj.com/ Mallory. )< 56. phy,sectomizeci, Mallory. X 56. on October 1, 2021 by guest. Protected

Tail vertebra, Hypophysectomized and Schematic drawing of the tibia, Hypo- treated, Mlallory. x 56. phvsectomized and treated, Mallory. >x 56. (BY courtesy f Y.. Freud, L H Levie, and D. B: Kroo) FIG. 2 Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from August I1950 SIMPSON: Physiology of Growth 421 of a transverse bony plate, as occurs after hypo- injected rats, compared with I6 per cent. protein, physectomy. It was postulated that oestrone does 15 per cent. fat and 6o per cent. water in the control not act merely by inhibiting pituitary growth rats. Since the specific gravity of fat is less than hormone secretion, but by a direct action on the unity while that of protein-containing tissue, with epiphyseal junction antagonistic to that of growth a substantial percentage of water, is above one, the hormone. Reiss, Fernandez and Golla (1946) injection of pituitary extract in Young's experi- found, using the hypophysectomized rat, that ments led to a rise in specific gravity of the body testosterone (or oestrone) given at the same time mass and of its tissues. Young quotes the work of as growth hormone, considerably diminished the Lee and Schaffer (1934), referred to above, as normal action of the latter in producing growth of showing a similar nitrogen retention effect of the tail, and that testosterone by itself could pituitary growth hormone. produce no growth of the tail at all in such hypo- Puppies were found by Young to behave as rats, physectomized animals. Although their experi- but in older dogs increase in weight and growth ments indicate peripheral growth inhibiting action usually stopped when diabetes developed. Even of sex hormones, the histological sections of the so a positive nitrogen balance was often sustained combined action of growth hormone and testo- in the presence of glycosuria and ketonuria and sterone do not shiow serious disturbance of the with a maximum D/N ratio. When the animal structure of the epiphyseal cartilage or failure of became resistant to the pituitary diabetogenic repair after hypophysectomy. It is difficult to extracts, the positive nitrogen balance reverted to correlate the absernce of growth augmenting effects normal at the same time as the glycosuria stopped. of testosterone, cr even more so its peripheral Young therefore concluded that the growth inhibitory effect, with the positive results in activity as indicated by this nitrogen retention, is clinical medicine, e.g. in eunuchoidism and closely related to the diabetogenic activity of a infantilism. Gar Iner and Pfeiffer (I943) found pituitary extract, and that the mechanism of that oestrogens ,.ause a deposition of calcium 'growth hormone activity' consists of the induc- in the bones of mice, and refer to earlier observa- tion of hyperfunction of the pancreatic islets and

tions that the blood calcium may rise considerably hypersecretion of insulin. If a closer correlation copyright. in birds during the maturation of the eggs with with epiphyseal cartilage growth is demonstrable, injected oestrogens. Simpson, Kibreck, Becks and especially if the histological chondrotrophic effect Evans (1942), using young adult female rats, of growth hormone can be induced by insulin found that oestrogens caused an involution of the action directly, the theory put forward will prove proximal growth cartilage, and although after even more attractive. Further evidence for the three weeks' treatment the epiphyseal cartilage insulotrophic and diabetogenic effects of purified partially recovered its growth capacity, a striking growth hormone can be found in the work of mass of thick bony trabeculae filled the upper part Marx, Herring and Evans (I944), Gaarenstroom, of the diaphyseal marrow cavity. Huble and de Jongh (1948), Cotes, Reid and Young (I949), and Campbell, Davidson, Snair and http://pmj.bmj.com/ Insulin and Growth Lei (1950). An associated piece of evidence is Growth is normally accompanied by nitrogen the demonstration of a galactopoietic activity of retention, and Mirsky (1939) suggested that the purified anterior pituitary growth hormone by nitrogen-retaining action of anterior pituitary Cotes, Crichton, Folley and Young (1949), since extracts is mediated, in part, by the islets of such activity is found with the diabetogenic Langerhans of the pancreas. Young (I944, 1945), hormone. It seems justified, in the present state stated that the growth hormone has not been of knowledge, to conclude that the pancreatic on October 1, 2021 by guest. Protected separated from the pituitary diabetogenic hormone. islets can be considered as capable of playing a He further observed that in rats, where the very important part in both experimentally pituitary ' diabetogenic' extract produces hyper- induced or natural growth. This is not going so trophy of the islets of Langerhans but not diabetes, far as to conclude unequivocally that the growth growth is accompanied by nitrogen and water hormone is identical with the pituitary pancrea- retention, and by a catabolism of fat. This is true totrophic (insulotrophic) hormone or the ' dia- in paired feeding experiments, and also where the betogenic hormone.' injected rats are permitted to indulge an increased appetite, but in the latter experiments the loss of The Adrenals and Growth fat is not so great. In both types of experiments The fact that early crude preparations of the rats appeared much fatter and better nourished growth hormone contained adrenotrophic hor- than the uninjected controls. Analysis of the mones gave rise to the suggestion that the adrenals tissues, however, showed i8 per cent. protein, played a part in growth. A preparation of pure 7 per cent. fat and 6o per cent. water in the growth hormone free from adrenotrophic hor- Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from

422 422 POSTGRADUATE MEDICAL JOURNAL A4ugust I1950 mone, and the preparation of pure adrenotrophic treated extract of pituitary growth hormone, which hormone free from growth hormone, have nega- led to a purification and' a marked decrease in the tived any direct augmenting effect on epiphyseal thyrotrophic, lactogenic and gonadotrophic hor- cartilage growth by the adrenals. Further, in mone contamination.' In I944 Li and Evans Herbert Evans' laboratory (personal communica- announced ' the isoJation of pituitary growth tion) pure growth hormone has& produced giant hormone,' and in 1945 there was further infor- rats after the animals have been adrenalectomized mation in a paper by Li, Evans and Simpson, but maintained alive on salt. The normal phy- entitled ' Isolation and properties of the anterior siological functions of the adrenals or some of hypophyseal growth hormone.' The main features these functions may, however, by their effect on of the method of preparation were acetone dried metabolism ensure that normal endogenous powder, calcium hydroxide extract, globulin growth hormone can exercise its optimum effects. fractionation, sodium chloride fractionation, am- Adrenalectomy may-possibly influence the struc- monium sulphate and isoelectric precipitation. ture and function of the anterior pituitary gland From a solution of the hormone, ball-shaped in relation to the secretion of growth hormone, 'particles' of uniform size and shape were pre- although the loss of chromophil cells after adrena- cipitated and were found to have the same growth lectomy appears to affect the basophil rather than potency as the original solution. The hormone the eosinophil cells. was protein in character, behaved as a single In I943, Evans, Simpson and Li drew attention substance on electrophoresis, was free from to the inhibriting effect of adrenocorticotrophic lactogenic, thyrotrophic, adrenocorticotrophic or hormone on the growth of male rats, an effect gonadotrophic activity, had a molecular weight of originally noted by Moon (I937). The inhibition 44,250 and had an isoelectric point of pH 6.85. did not occur in adrenalectomized rats. In a On 27-day hypophysectomized rats O.O0i mg. of supplementary histological study with Becks and the hormone caused an increase of io gi. in Marx (i944), they showed that A.C.T.H. alone body weight when injected daily for ten days. hardly affected the tibial epiphyseal cartilage of hypophysectomized rats, but A.C.T.H. given The Anatomy and Physiology of Bonecopyright. with growth hormone reduced the reparative Development effect of growth hormone on this cartilage. In Bone is a highly specialized variety of connective 1949, Li, Simpson and Evans found, in hypo- tissue which is rendered rigid by the impregnation physectomized rats fed on a limited quantity of of its ground substance with calcium salts. The food, that pure growth hormone caused an increase skeleton contains about 97 per cent. of the total in protein and water content of the tissues of the calcium of the body. From the point of view of carcase with a lowering of the fat content, whereas development there are two kinds of bones: (a) adrenocorticotrophic hormone resulted in a de- membranous (bones of the cranial vault) and

crease in the water and a gain in the fat content. (b) cartilaginous (long and most other bones). In http://pmj.bmj.com/ The protein content was unchanged, but in normal both tvpes embryonic connective tissue is trans- animals A.C.T.H. causes a reduction in the total formed into bone by the activity of the specially weight of the animal, a loss of nitrogen from the modified fibroblasts known as osteoblasts; but tissues into the urine, and an increase of tissue whereas with membranous bone this is a direct fat (Li, I950). Green (I950) demonstrated the process, with cartilaginous bone there is an inhibition of skin mitosis in the mouse by intermediate deposition of cartilage which acts as A.C.T.H., and regards this as only one indication a temporary framework and is ultimately replaced of the effects of A.C.T.H. on body growth, by true bone. In both instances the growth and on October 1, 2021 by guest. Protected eosinopenia, failure of granulation tissue forma- changing shape of bones is a destructive as well as a tion, inhibition of chondro-osteogenesis and even constructive process. The former, which consists diminution of lymphoid tissue. This effect on of the removal of the first-formed bone,. is due to mitosis may prove important clinically and the activity of large multinucleated osteoclasts antagonistic to the newly discovered neoplasmo- which originate from the same source as the genic action of growth hormone on viscera, osteoblasts and have the power of dissolving bone. including the lungs, to which Professor Herbert A long bone is at one stage a homogeneous Evans briefly referred recently in a talk to the cartilaginous structure. As such it can grow in Endocrinologicdl Society. any direction, except that it is invested with a thickening of embryonic connective tissue which Physico-Chemical Isolation of Growth tends to maintain its shape. This is the investing Hormone perichondrium and, at a later stage, the In I940 Fraenkel-Courat, Meamber, Simpson periosteum. At certain chronological stages, and Evans, reported the preparation of a cysteine centres of ossification appear in the middle of Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from August I1gso SIMPSON: Physiology of Growth 423 the shaft (diaphysis) and at either end (epiphyses) however, have a powerful augmenting influence on of the long bones. The process of ossification growth in infantilism and eunuchoidism, which spreads from these centres outward, whilst from is apparently contrary to the physiological experi- the periphery, or circumference, bone is laid down ments. From the point of view of the clinician, along the whoJe length of the shaft from the testosterone would have prior claim to the title of periosteal layer. Ultimately the whole of the growth hormone, although experimentally it lacks bone and of the two ends become completely any stimulating effects on epiphyseal cartilage ossified, except for a line of cartilaginous cells growth. Kinsell, Michaels, Li and Larsen (1948) which separates the shaft of the bone from either put forward the theory that there are two phases of end. This important layer of cartilage (epiphy- growth (i) pre-pubertal, associated with high seal plate) is the site at which growth takes place. serum phosphorus and due to pituitary growth The cartilage cells proliferate, but the layer hormone, and (2) post-pubertal, associated with remains narrow as the proximal older cells are normal serum phosphorus and due to gonadal replaced by oeteoid tissue which bec6mes calci- and adrenal androgens. They produce further fied. Growth therefore takes place at both ends of evidence that androgens as well as oestrogens will a long bone. At a certain age, usually i6 to i8, the depress serum phosphorus in acromegaly. Some epiphyseal plate itself becomes replaced by bony eunuchs and eunuchoids may be tall and continue tissue and the epiphysis is then said to be closed or growing until the third decade of life ; the to have joined the diaphysis. At this stage growth epiphyses in these cases are open, and.one must is no longer possible. In endocrine disorders, assume that growth is either due to continued closure of the epiphyses may be premature or it secretion of pituitary growth hormone or to may be delayed ; even in apparently normal adrenal androgens. Growth is also accelerated with people there is a considerable variation in the adrenal or gonadal sexual precocity and, since this age of closure. includes female oestrogenic precocity, it would appear clinically that oestrogens as well as andro- Gleanings from Clinical Studies gens can augment skeletal growth, although both The clinical facts of acromegaly and gigantism union of the also accelerate bone age and epiphyses. copyright. have been already dealt with in the first part of In the syndromes of adipose gynandrism and this article (April 1950), and are in harmony with adipose gynism described in the Clinical Section our physiological knowledge. In I946, Reifen- of this article (April I950) there is also augmented stein, Kinsell and Albright observed a high serum growth in childhood, but union of the epiphyses phosphorus in the active phase of acromegaly and tends to be early in girls, e.g. 14, but not in boys, in growing children, and that oestrogens by so that the ultimate height of the males tends to inhibiting the pituitary secretion of growth be on the tall side. There is no evidence, clinically hormone in acromegaly, lowered the serum or by assay, of an excess of adrenal androgens, so phosphorus. Li, Geschwind and Evans (I949) that the augmented growth must be ascribed to correlated this clinical finding with earlier know- pituitary growth hormone and/or oestrogens. The http://pmj.bmj.com/ ledge of the lowering of serum phosphorus by occurrence of gynaecomastia in some of the males hypophysectomy, and showed that pure growth suggests oestrogens, as does the early closure of the hormone prevented this fall and even elevated the epiphyses in the females. There is some evidence serum phosphorus level above that of-the controls. that diabetic children are taller than the average at In clinical medicine, pituitary growth hormone the onset of their diabetes, and it is well known that as generally available has proved disappointing and inadequately controlled diabetic children do not usually futile, the only unequivocal exception in grow as rapidly as normal- children or well- on October 1, 2021 by guest. Protected my experience being with very massive and painful controlled diabetics. These facts may be held doses in a girl of i8 with infantilism and open to support the insulotrophic and diabetogenic epiphyses, shown by me at the Endocrine Section action of growth hormone. The predisposition of of the Royal Society of Medicine on October 22, fat people to diabetes in adult life may be corre- 1947 (not published). Dr. Hans Lisser in Cali- lated with a pituitary origin of the diabetes. A fornia informed me that in one case of infantilism pituitary insulotrophic effect might be held to where the pure crystalline growth hormone was cause an initial adiposity, as there is experimental made available, no growth and no nitrogen re- and clinical evidence for the conversion of carbo- tention followed its use. The failure of growth hydrate to fat by insulin under certain conditions. may be related to the work of Freud, Levie and This may also be the explanation of the adiposity Kroon (1939), previously referred to, but the in adipose gynandrism and gynism, either as a failure of nitrogen retention is more difficult to direct pituitary stimulus or as a counteraction to understand. adrenal i i -oxysteroids. However, the possibility Testosterone (and occasionally oestrogens), of a more direct influence of adrenal steroids on Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from 424 POSTGRADUATE MEDICAL JOURNAL August 1950 fat synthesis and deposition cannot be excluded. of acute rheumatic fever. Reddish purple striae These ' gleanings' from clinical studies are, it were noted on the 24th day of treatment, when is appreciated, not entirely based on established his weight had increased by 3 lb. They were over foundations, but their hypothetical nature does not the hips and flanks. A second course of treatment exclude their potential usefulness in the further with cortisone after an interval of I3 days, and exploration of growth and metabolism by the lasting 28 days, led to the striae becoming broader experimentalist and biochemist. and deeper in colour and a further increase in weight. Several weeks after stopping cortisone Conclusions therapy, the striae lost their colour. Similar red There is ample experimental evidence to or purple striae resulting from cortisone therapy indicate that the growth hormone is secreted by were observed in six additional patients, five of the eosinophil cells of the pituitary gland, and whom were young. that the adrenals, thyroid, pancreatic islets and Since the diabetogenic action of cortisone has gonads produce hormones as a result of a pituitary been clearly demonstrated experimentally and in stimulus. These bring about an important humans, particularly in Addison's disease, with augmentation of growth hormone effect, and may or without co-existing diabetes mellitus, and since even be effective in the absence of the pituitary diabetogenic effects have been observed occa- gland. Nevertheless the pituitary growth hormone sionally in Sprague's studies referred to above, it is a specific protein entity, now isolated from might be asked why diabetes was not present in adrenotrophic, gonadotrophic, thyrotrophic, lac- the cases described by me as adipose gynandrism togenic and other hormones, which has a specific and gynism. The answer would appear to be that effect on epiphyseal cartilage, an activity asso- there is normally a balance between pancreatic in- ciated with elevation of serum phosphorus. Such sulin secretion on the one hand and pituitary and pure growth hormone has an insulotrophic and adrenal diabetogenic hormone on the other; and diabetogenic action under appropriate conditions, that when there is an excess of the latter hormones, and the identity of these hormones has been or of cortisone itself, the islets of Langerhans postulated. From a therapeutic angle, testosterone respond by an excessive production of insulin to copyright. has a powerful effect on somatic growth, not balance the diabetogenic tendency, which is thus easily correlated with experimental evidence and hidden and undetected by blood sugar deter- different in character from that of growth hormone. minations. At a certain point the increased insulin In the author's clinical experience oestrogens may secretion may become inadequate and hyper- have a similar somatotrophic action in some types glycaemia then follows. It also seems probable of infantilism and may succeed when androgens that the secondary hyperinsulinism is an important and growth hormone have failed. factor in determining gain of weight and adiposity, although a more direct adrenal anabolic fat Addendum factor cannot be excluded. The insulinotrophic http://pmj.bmj.com/ In the April number of this Journ'al the writer action of pituitary growth hormone may also play referred to a personal communication from a part. Dr. R. G. Sprague of the Mayo Clinic, relating The following acknowledgments were omitted to the production of red and purple lineae dis- from the first clinical article: To Dr. F. S. W. tensae by cortisone injections. Attention was Brimblecombe, of Princess Louise Children's drawn to the importance of this as a basis for the Unit of St. Mary's Hospital, and to Dr. Ivor diagnosis of hyperfunction of the adrenal cortex, Williams of the Willesden General Hospital, for not only in Cushing's classical syndrome, but in help in the preparation of case notes; to the Oxford on October 1, 2021 by guest. Protected other conditions in which such coloured striae were University Press for permission to reproduce present, and particularly in the syndrome described Figs. 5, 9, 15, I7, 22 (a) and (b) and 39 from the as adipose gynandrism and adipose gynism. author's book ' Major Endocrine Disorders' ; The actual article by Sprague and eight col- to Dr. W. W. Payne, who very kindly undertook leagues (1950) has since been received. Their the majority of the I7-ketosteroid assays at the first patient was a youth 17 years of age, who Pathological Laboratories of Great Ormond Street received 200 mg. of cortisone daily for I9 days, Hospital for Sick Children. To all these and other and ioo mg. daily for five additional days because junior colleagues, the writer expresses appreciation. BIBLIOGRAPHY BATES, R. W., LOANES, T., and RIDDLE, 0. (I935), Proc. COTES, P. M., REID, E., and YOUNG, F. G. (I949), Nature, ro. Soc. Exp. Biol. Med., 33, 446. I64, 209. BECKIS, H., SIMPSON, M. E., MARX, W., LI, C. H., and EVANS, H. M., and LONG, J. A. (I92I), Anat. Rec., 2I, 62. EVANS, H. M. (I944), Endocrinology, 34, 311. CAMPBELL, J., DAVIDSON, I. W. F., SNAIR, W. D., and LEI, EVANS, H. M., and LONG, J. A. (1923-4), The Harvey Lectures, H. P. (I950), Endocrinology, 46, 273. Lippincott & Co., Philadelphia. COTES, P. M., CRICHTON, J. A., FOLLEY, S. J., and YOUNG, EVANS, H. M., SIMPSON, M. E., and PENCHARZ, R. J. (x939), F. G. (I949), Nature, I64, 992. Endocrinology, 25, I75. continued on page 435) Postgrad Med J: first published as 10.1136/pgmj.26.298.417 on 1 August 1950. Downloaded from August 1950 BROSTER: Surgery of the Adrenal Glands 435 incision. Special instruments and retractors tied when closing the wound. The perinephric fat made by Meyer and Phelps are helpful. is opened, the kidney held down with a special retractor, and a deep retractor pulls up the ribs. THORACIc APPROACH The adrenal gland is defined and caught in special An incision is made along the intercostal space forceps. Positive pressure is now applied by the between the ioth and iith ribs. The thoracic anaesthetist and the gland dissected from its bed. cavity is opened, the ribs are retracted, and the The main vein seen on its inner border is then diaphragm incised. The adrenal is held in special tied and the gland freed and removed. The vein forceps and dissected from its bed. The dia- is weak and if accidentally torn may give rise to phragm is repaired and the wound closed. alarming haemorrhage. This is more likely to happen if the diaphragm or vena cava are allowed THE HIGH KIDNEY INCISION lo flap. The rib is then tied and the muscle An incision 6 to 8 in. long is made parallel to layers are repaired with interrupted catgut. No the last rib, and the muscles are divided. If the drain is necessary and the skin is closed. Depend- last rib is small it is resected sub-periostally and ing on the width of the subcostal angle, the plural entrance gained into the perinephric fat by in- or peritoneal cavity or both may be accidentally cision through its bed. If it is a large rib, two opened. holes are made an inch apart at the neck, and the This operation has a shorter convalescence than rib divided between them. A strong ligature is the thoracic one, for in the latter, the lung may threaded through the holes and left in situ to be take some time to expand.

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