POSTGRAD. MED. J. (I963), 39, 205

SOME ENDOCRINE CHANGES INLIVER DISEASE

G. A. MARTINI, M.D.Assoc. Professor of Medicine, University of Hamburg (Germany)

AMONGST the numerous metabolic functions ofthe liver are those concerned with the catabolismor inactivation of hormones. One would thereforeexpect to find liver disease frequently accompaniedby endocrine disturbances; and attempts to corre-late certain liver disease with disturbances inendocrine function are not new. In addition,there are certain features of liver disease such asthe 'characteristic' skin changes which areattributed to altered hormone metabolism.The close relationship between liver disease and

the gonads appears to be obvious. In the malethere is gynaecomastia and an alteration in thesecondary hair distribution with loss of axillaryand chest hair and a female distribution of pubichair. Loss of libido, impotence and testicularatrophy complete the characteristic picture ofhormonal disturbances in the human male withchronic liver disease. Oligospermia is common(Voegt and Weller, 1959). Prostatic hyper-trophy in men with chronic liver disease is rare(Stumpf and Wilens, I953). The incidence ofthese endocrine disturbances varies remarkablyas between different countries. Gynaecomastia andtesticular atrophy, a combination also known asthe Silvestrini-Corda syndrome after the authorswho first described it (Corda, I925; Silvestrini,1926), was found by Lloyd and Williams (1948) tooccur in 42% of 55 men with cirrhosis of theliver. The same workers reported 75% incidenceof testicular atrophy in their patients. However,the incidence of gynacomastia in our own casesand in others, as for instance in England, isdistinctly low. The same applies to other signs ofchronic liver disease such as parotid swellingand Dupuytren's contracture (Davidson, Sherlock,Summerskill, Turner and Wolfe, I960). It isquite possible that alcoholism alone, or rather theaccompanying malnutrition, like that in prisonersof war during the period of nutritional re-feeding(Klatskin, Salter and Humm, 1947; Kark, Moreyand Paynter, 1951), plays a decisive part in thedevelopment of these signs. 'Alcoholic' cirrhosispredominates in the American cases, but is notnearly so common in England or in Germany.Moreover it is difficult to determine whether

the altered distribution of secondary hair isconstitutionally conditioned or whether it is theresult of liver disease. Since Chvostek describedthe 'habitus' known by his name it has not beenpossible to determine whether or not men withthis type of constitution are more susceptible tothe development of cirrhosis. It is therefore veryimportant to question patients about their hairdistribution in the 'pre-cirrhotic' phase. Manypatients can provide evidence and often photo-graphs to prove that they never had a heavygrowth of pectoral, axillary or pubic hair beforedeveloping cirrhosis.Women with chronic liver disease usually have

amenorrhaea or dysmenorrhcea and may havecystic mastitis or acne. Sterility is the rule andconception is very rare. In certain age groups,about puberty (Bearn, Kunkel and Slater, 1956;Waldenstr6m, 1952) and after the menopause(Alsted, 1947; Cattan, Vesin and Bodin, I957;Martini and D6lle, I960), women are prone todevelop a peculiar form of hepatitis of unknownaetiology with a chronic course and with 'post-necrotic' cirrhosis. Altogether the sex ratio ofpostnecrotic cirrhosis in women to men is 3: I,in contrast with Laennecs's cirrhosis, which ispreponderant in men. Women who developvirus hepatitis during the menopause are especiallysusceptible to the development of postnecroticcirrhosis.Both men and women with chronic liver

disease develop certain vascular changes in theskin, such as arterial spiders, 'white spots' (Martiniand Staubesand, I953; Martini, I955) and palmarerythema. These skin changes occur with almostequal frequency in pregnant women and disappearagain soon after parturition. These observationsled Bean, (1945) to regard the vascular changes asa manifestation of 'hypercestrogenism'. Anincrease in cestrogens is a normal feature ofpregnancy. In chronic liver disease the liver issaid to be incapable of inactivating cestrogens;hence the (estrogen level in the blood rises. Thisinterpretation is disarmingly simple. It was indeedpossible to induce the development of arterialspiders and palmar erythema in one third of 30

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patients with cirrhosis by the administration ofoestrogenic substances, but two thirds of thepatients showed no such response (Bean, 1958).Nor have such phenomena been observed inpatients with carcinoma of the prostate who havereceived very large doses of oestrogens. In anycase a purely hormonal factor would not explainthe localisation of the spider naevi and theirdistribution. They are practically confined to theso-called exposed parts of the skin (face, neck andarms). This localization suggests that beside thehormonal or 'internal' factor in the production ofarterial spiders, an 'external' factor may beoperating: the structure and function of theaffected portion of the skin and of its smallestvessels and their altered reaction to the action ofsunshine, wind and light (Martini, I955).The most important question, however, is

whether there is actually an cestrogenic excess inpatients with chronic liver disease and if so,whether there is any correlation between thecestrogen levels and the clinical signs such asgynaecomastia, altered hair distribution and skinchanges.The Metabolism of (EstrogensOur knowledge about the nature and quantity of

circulating oestrogens in the plasma of patientswith liver disease is scanty, and therefore theevidence in favour of the before mentioned'hypercestrogenism' in liver disease remainscircumstantial (Diczfalusy, I962). In pregnancythe ratio unconjugated (free) to conjugatedI7-p3-oestradiol was higher than similar ratiosfor oestrone and oestriol. If this could be confirmedin patients with liver disease it could well be thatthis shift towards free oestradiol accounts for the'hyperoestrogenism' (Diczfalusy, I962).

Since Zondek's work (i934) it has been knownthat the healthy liver plays an important part inthe inactivation of oestrogenic hormones. In thisprocess conjugation of the hormones withglucuronic acid or sulphuric acid is particularlyimportant. However, it is still not decidedwhether conjugation and inactivation are one andthe same thing or not (Cameron, 1957 a& b). It hasbeen found that under certain conditions theglucuronic acid ester of the hormones is apparentlyas active as the free hormones. Some conjugates,when administered, are easily hydrolyzed in thebody. In contrast to other steroid hormoneswhich are inactivated by enzymatic reductionbefore conjugation, oestrogens are conjugated inthe active form.

It seems doubtful whether the estimation of freeand conjugated oestrogens can in any way yieldmore information about disturbed liver function.Even if this particular liver function of conjugating

aestrogens were disturbed there would still be theintestine to compensate for it. According toSandberg and Slaunwhite (I957), there exists anentero-hepatic circulation of oestrogens not onlyin animals but also in man. When radioactiveoestrogens were given, 50% of the radioactivity.was recovered in the bile, but only 7% excreted inthe fieces. Up to 80% was excreted in the urine.It is not yet decided whether oestrogens areabsorbed as free oestrogens after hydrolyzation inthe intestine or in conjugated form. It was shownrecently that in man the intestine is able toconjugate free aestrogens which were brought intothe intestinal lumen at operation (Diczfalusy,Frankson and Martinsen, I96I). A retafdationin this bilio-entero-hepatic cycle was postulatedby Rupp, Cantarow, Rakoff and Paschkis (I951)and Dohan, Richardson, Bluemle and Gyorgy(1952), to account for the disturbed oestrogenmetabolism in patients with cirrhosis.A further difficulty arises from the indecision

about which of the various known aestrogenichormones is to be regarded as the primary hormone.Oestradiol, oestrone and oestriol have all beennominated. But these three represent only 20%of all aestrogens. Brown and Marrian (1957)suggested the following metabolic pathways forthese oestrogens:

CEstradiol-I7 PCEstrone

I 6o-Hydroxycestrone I6B-HydroxyoestroneCEstriol i6 epi-(Estriol

In addition, until the last few years the onlymethod available for estimating cestrogens wasthe biological method of the Allen-Doisy test;this was the method used in most of the reportedstudies of oestrogen excretion in liver disease.Since then new biochemical methods have beendeveloped, and it is expected that they willprovide more accurate quantitative information.Comparison of the two methods is rendered evenmore difficult by the fact that they estimatedifferent oestrogenic fractions. The Allen-Doisytest estimates oestradiol rather than oestrone oroestriol, whereas Brown's biochemical methodestimates all three hormones, (I955). Althoughmuch work has been done in the past thereis no clear answer yet to the question whether theexcretion pattern of oestrogens differs quantita-tively and qualitatively in patients with liverdisease from that in normals.The results obtained with the biochemical

method are in direct contrast with those obtainedby means of the biological assay (Bennett,Baggenstoss and Butt I950; Dohan and others,

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1952; Glass, Edmonson and Soil, I944; Rupp andothers, I951), which had shown an increase intotal cestrogen excretion in nearly half of thepatients with cirrhosis, the hormones appearingin the urine mainly as free oestrogens. This wasalso shown by Miiller (1958) using a fluorimetricmethod. Cameron (1957) was not able to confirmthese results using Brown's method. He found,as others had done before him, (Pincus, Rakoff,Cohn and Tumen, 195i) that there was noincrease in free cestrogen excretion in his groupof 12 patients with cirrhosis, except in 2. His mostremarkable finding in half of his patients was anincrease in the proportion of cestriol excreted witha corresponding reduction in the amounts ofcestrone and cestradiol. This was the result inmeasuring the excretion of endogenous cestrogens.When larger amounts of oestradiol were adminis-stered in patients with severe liver disease a'shift' towards increased oestradiol excretion tookplace (Lyngbye and Mogensen, I96I).The discrepancy between the results of the

biological and the biochemical assays can beexplained by postulating that certain of the newlyidentified cestrogenic hormones, such as epioestrolor i6a-hydroxyoestrone, are responsible for theendocrine stigmata in patients with cirrhosis: thecestrogenic activity of these substances would beapparent in the biological assay, but not in thebiochemical method employed.

In fact, i6a-hydroxyoestrone seems to be just asactive as oestriol (Loraine, 1958), and has beendemonstrated in considerable amounts in theurine of pregnant women (Brown and Marrian,I957). An inhibition of the conversion of cestradiolinto cestriol was demonstrated by Lyngbye andMogensen (I96I). If such an inhibition occurredin the conversion of i6o-hydroxyoestrone intooestriol the former substance could accumulatewithout being estimated in the urine by thebiochemical method.

It is important, however, not to seek facileexplanations until reliable quantitative resultsabout aestrogen excretion have been obtained. Itmay then perhaps be possible to establish that adefinite correlation exists between the particularendocrine features in liver disease and both thequantity and the quality of cestrogens excreted.The morphological changes in the endocrineorgans of patients with cirrhosis neverthelesssuggest a strong cestrogenic effect (Bennett andothers, 1950; Barr and Sommers, 1957): approxi-mately half of 30 female patients had adenofibrosisof the breast or cystic mastitis and endometrialhyperplasia. Two thirds of 70 male patientsexamined showed the 'characteristic' changes inthe prostate and testis. Other remarkablefindings in these male patients were a marked

increase in the basophil cells of the pituitary andadrenal atrophy.Again it will be necessary to consider the

variety in 'normal' levels, depending on race,nutrition, age etc. For instance normal Bantumales are reported to have a much higher oestrogenexcretion than normal white males in SouthAfrica. The aestradiol fraction was particularlyincreased in these Bantus. In Bantus with chronicliver disease the cestradiol fraction further increased.

In white men with liver disease it was thecestriol fraction which increased. One can specu-late whether malnutrition causes an increase of'normal' cestrogen levels and/or changes itspattern and moreover, if this increase in turncauses liver disease and cancer with breastchanges which are so frequent in Bantus (Bloom-berg and others, 1958; quoted in Diczfalusy andLauritzen, I96I.The Metabolism of AndrogenThe original findings of Fraser, Forbes, Albright,

Sulkowitch and Reifenstein (1941), that theexcretion of I7-ketosteroids is diminished in theurine of patients with chronic liver disease haverepeatedly been confirmed and are consideredfirmly established (Peterson, I960). Birke andothers found the urinary output of I7-ketosteroidsin cirrhotics both male and female as low as inadrenal cortical insufficiency (Birke 1962). Evenafter testosterone administration the urinary outputof I7-ketosteroids is much decreased in patientswith liver disease. Whereas some authors(Williams, Cantarow, Paschkis and Havens, 1951;Birke, I962) found no decreased ability to converttestosterone to I7-ketosteroids, some othersthought it to be disturbed (West, Tyler, Brownand Samuels, I95I). Both the conjugation withglucuronic acid and sulphuric acid are disturbed(Birke, Diczfalusy and Plantin, 1959), but nofree 17-ketosteroids were excreted (Bongiovanniand Eisenmenger, 195I). Apparently both theI7-ketosteroids originating in the adrenal cortexand in the testis are diminished (Cameron, 1957).However, this diminution is probably not alonedue to faulty conversion of testosterone to 17-ketosteroid, but to reduced androgen productionas well. The resultant imbalance between andro-gens and cestrogens could also account for the'hyperoestrogenism' even in those males who havea normal oestrogen output in the urine. For thereis an undoubted antagonism between oestrogensand the other steroid hormones (Szego andRoberts, 1953). The diminution in androgenproduction still requires explanation. An excessof oestrogens might depress androgen productionby inhibiting the production and release ofgonadotropin from the pituitary gland. The

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urinary gonadotropin excretion has been found tobe greatly reduced in some cases (Voegt andWeller, I958). Or, there could be a primaryreduction in androgen production owing tomalnutrition with protein deficiency whichfrequently accompanies alcoholic cirrhosis.Reduced pituitary function in malnutrition wasreported by Fletcher and Brown (I959). Anotherpossibility is the direct damaging effect of alcoholon the endocrine system; for the 'endocrinestigmata' are undoubtedly more common inalcoholic cirrhosis than in posthepatitic cirrhosis.But this is speculation.Adrenal HormonesThe great deal of interest aroused in recent

years by the adrenal hormones has also directedattention to the relationship between adrenalcortical hormones and the liver. There arecertain clinical observations which suggest distur-bances in adrenal hormone metabolism but theexact nature of these disturbances has not yetbeen defined. Bearn and coworkers (I956) havedescribed signs of 'hypercorticism' especially inthe peculiar form of chronic hepatitis whichoccurs in girls and young women. The signsinclude acne, moonface, striae, and more rarelyhirsutism. These girls often have amenorrhoeaand react to oestrogen administration by rise inthe bilirubin level. Waldenstr6m (1952) hasreported similar findings. The incidence of eachof the signs ascribed to adrenal cortical hyper-function is so variable that there is a good dealof justified doubt about the existence of such asyndrome. (Willcox and Isselbacher, I96I).This group of patients does more commonlyshare other signs such as polyarthritis andhypergammaglobulinaemia, rarely the LE-cell; andit has therefore been suggested that an auto-immune pathological process may be involved(Mackay, I96I). Incidentally, these patientsrespond particularly well to cortisone treatment.Further details about the treatment of liverdisease with corticosteroids will not be discussedhere and the reader is referred to the paper byGoldgraber and Kirsner (1959).

Recent observations have shown the importanceof the liver in the elimination of exogenouslyadministered hydrocortisone. Only about %of the free form of this hormone appears in theurine. About 3% is excreted as unconjugatedmetabolites, 80 to 90% appears as conjugated,water-soluble metabolites (Schedl, I962). In miceabout 70% of labelled hydrocortisone was foundin the liver within five minutes of administration.Plager, Tyler, Hecht and Samuels (I954) havereported similar findings in man. They detectedmuch less radioactivity in the hepatic venous

blood than in the arterial blood after intravenousadministration of radioactive hydrocortisone.

In patients with chronic liver disease the plasmalevels of free corticosteroids and its rise afterACTH administration were the same as in normalsubjects (Englert, Brown, Wallach and Simon,I957; Birke and others, 1959). However, hydro-cortisone administered to patients with liver diseasedisappeared much more slowly from the bloodstream and appeared in the urine in much lowerconcentration than in normal subjects. Sur-prisingly, cortisone, corticosterone and tetrahydro-cortisone were found to disappear from the bloodstream with equal rapidity in patients with liverdisease and in normal subjects (Englert andothers, 1957; Peterson, I960). These findings arebest explained by the existence of a specific TPNH-dependent enzyme, theA-4-hydrogenase, whichreduces cortisol to dihydrocortisol. Dihydro-cortisol is then further reduced to tetrahydro-cortisol. These reduced forms are conjugated inthe liver with glucuronic acid or sulphuric acidand then excreted in the urine. Apparently it isonly the enzymatic reduction which is disturbedin liver disease and not the conjugation withglucuronic acid. When the 'right' combinationsare presented as for instance tetrahydrocortisol,conjugation proceeds normally (Brown, I957).The amount of urinary unconjugated steroids inpatients with liver disease seems to be slightlyraised above normal and consists mainly of 6-3-hydrocortisol (Katz, Lipman, Frantz and Jailer,I962).Thus it appears that the rate of cortisol meta-

bolism is decreased in liver disease. The bodypool of cortisol is normal or slightly increased,whereas the turnover rate of the pool is abouthalf normal (Peterson, I960). This means that inpatients with liver disease the physiologic actionof cortisol is prolonged. This in turn will inhibitcorticotropin secretion and thus consequently leadto the depression of cortisol synthesis and secretion.These patients-although seemingly being'eucorticoid'-actually have an adrenal corticalinsufficiency as regards the quantity of cortisolsynthesized (Schedl, 1962). Since the diseasedliver has partly lost its capacity to inactivatecortisol the plasma level remains within the normalrange. It has frequently been noted that theadrenal glands of patients with cirrhosis aresmall in size with narrow cortices and a decreasedlipoid content (Barr and Sommers, 1957). Werealise then that the liver together with theadrenal and the pituitary plays an important partin the corticosteroid homceostasis of the organism(Birke, I962).These observations are particularly interestingin comparison with rather different recent findings

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in relation to the other equally important adrenalhormone, aldosterone (Koczorek and Wolff, I959).Aldosterone plays a very special role in thepathogenesis of ascites. The patients with cirrhosislose the ability to excrete sodium and water atsome particular point of time. Sodium and waterthen undergo excessive reabsorption by the renaltubules. Sodium reabsorption is largely influencedby aldosterone which is excreted in the urine ingreater than normal amounts in cirrhotic patientswith ascites (Luetscher and Johnson, 1954;Wolff, Koczorek and Buchborn, 1958). However,as other patients with oedema but with normalliver function also excrete excessive quantities ofaldosterone in the urine, it seems that aldosteroneis probably not solely and primarily responsiblefor the development of ascites.

Normally 60% of the endogenous productionof aldosterone is excreted as a glucuronic acidconjugate oftetrahydroaldosterone which is biologi-cally inactive; about 20% is excreted as the so-called 3-oxo-conjugate which can be convertedto aldosterone by acidification of the urine atpH i (the so-called pH i extractable conjugate).Only 0.2% of the total is excreted as free aldo-sterone. About 20% of the excreted metabolitesare not yet identified (Koczorek, I962). Both of themajor metabolites of aldosterone are formed inthe liver. In patients with chronic liver disease thealtered metabolism of aldosterone is characterizedby an increased aldosterone secretion rate and adecreased rate of plasma clearance, the plasmahalf-life time of labelled steroid being 68 minutesagainst 35 minutes in normals it is furthercharacterized by an increase in the proportion ofaldosterone which is metabolized to the 3-oxo-conjugate and a decrease in the proportion whichis converted to tetrahydroaldosterone (Coppage,Island, Cooner and Liddle, I962). The data onaldosterone secretion, however, are somewhatconflicting. Not in all investigations was thesecretion rate found to be increased, but sometimesto be decreased. This perhaps could be explainedby the different degree of impaired liver function.Thus in patients with cirrhosis and ascites the aldo-sterone levels in urine are usually markedlyincreased whereas in patients without ascitesnormal or only slightly raised levels are found.

In the belief that the adrenals play a dominantrole in the development and maintenance ofascites surgeons have undertaken bilateral adrenal-ectomy on individual patients who had failed torespond to medical efforts at inducing diuresis(Marson, 1954; Giuseffi, Werk, Larson, Schiff andEllioth, 1957). After operation there was a sodiumdiuresis but no definite water diuresis and thereac:umulation of ascites was prevented only byuse of diuretics and a low sodium diet-measures

which had proved ineffective before adrenal-ectomy.

This operation has been rendered obsolete bythe use of aldosterone antagonists. This will notbe discussed here but the reader is referred toa recent monograph (Bartter, I960).As mentioned before, adrenal factors are not

primarily responsible for the disturbances inwater and electrolyte balance in patients withchronic liver disease. Preedy and Aitken(1956 a & b) have shown that the administrationof oestriol is followed by well marked sodium andwater retention in cirrhotic patients with ascites.Cirrhotic patients without ascites behaved likenormal subjects and showed no sodium or waterretention when given aestriol. They concludedthat the salt-retaining action of aestriol dependedmainly on the blood-flow through the liver andonly secondarily on disturbances in liver cellfunction. Recently Layne, Meyer, Vaishwanarand Pincus (I962) showed that aldosteronesecretion could be increased by oestrogen admini-stration. If the same occurred in patients withliver disease, this could explain the salt-retainingeffect of cestrogen.On the whole, the interdependence of hormones

and their metabolites will certainly influence theregulation of steroid metabolism and makes iteven more difficult to judge the specific action ofone hormone.

In normals, for instance, the oestrogens increasethe binding of cortisol to the protein 'transcortin'(an a-globulin) and, if this is saturated, to plasmaalbumin. This means that less free or active, andmore protein-bound or inactive cortisol is circu-lating (Mills, Schedl, Chen and Bartter, 1960).(Estrogens equally prolong the plasma half-lifeof cortisol but not of the dihydro or tetrahydrocompounds of this steroid; besides they decreasethe synthesis rate of cortisol (Peterson, Nokes,Chen and Black, I960). Thus it appears that this'oestrogen-effect' in persons with normal livers isvery similar to the disturbed cortisol metabolismin patients with liver disease. Could it be that thesupposed 'hypercestrogenism' in patients withcirrhosis accounts for this? Eymer, Schwarz andWeinges, (1961) reported that the 'oestrogen-effect' is missing in patients with chronic liverdisease. Cortisol did not increase after admini-stration of cestriol. Biicher suggested that thismight be due to the lack of proteins in cirrhosis(discussion of Eymer's paper).

Birke (1962) recently has stressed the fact thatdifferent hormones can act differently on thecatabolism of steroids by enhancing (oestrogens,hyperthyroidism) or diminishing (androgens,hypothyroidism) the ability of the normal liver toact on the A4-3-ketosteroids, or, vice versa, on

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the side chain. The implication of these observa-tions on the steroid catabolism in disturbed liverfunction must be awaited, but here certainly is afascinating field for future research.

The AntidiureticHormone

Finally, brief mention must be made of theantidiuretic hormone (ADH) of the pituitary; itssignificance in the development and maintenanceof ascites has not been clarified. Wolff and others,

(1958) found no difference between the anti-diuretic hormone plasma level in healthy subjectsand in patients with liver disease. Lee andBisset (1958) on the other hand were able todetect higher levels of antidiuretic hormoneactivity in blood from the internal jugular veinthan in blood from the median cubital vein andthey found a distinct elevation of antidiureticactivity in blood from the internal jugular vein in5 patients with cirrhosis and ascites. The signi-ficance of these findings awaits interpretation.

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J. clin. Endocr., 17, 1017.BARTTER, F. C., Editor (1960): 'The Clinical Use of Aldosterone Antagonists'. Springfield, Illinois: Charles C Thomas.BEAN, W. B. (1945): The Cutaneous Arterial Spider: a Survey, Medicine, 24, 243.

(1958): 'Vascular Spiders'. Springfield, Illinois: Charles C. Thomas.BEARN, A. G., KUNKEL, H. G., and SLATER, R. J. (1956): The Problem of Chronic Liver Disease in Young Women,

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DOHAN, F. C., RICHARDSON, E. M., BLUEMLE, L. W., and GYORGY, P. (I952): Hormone Excretion in Liver Disease,J. cin. Invest., 31, 481.ENGLERT, E., Jr., BROWN, H., WALLACH, S., and SIMON, E. L. (1957): Metabolism of Free and Conjugated 17-Hydroxy-corticosteroids in Subjects with Liver Disease, Y. clin. Endocr., 17, 1395.EYMER, K. P., SCHWARZ, K., and WEINGES, K. (1961): Klinische Untersuchungen fiber den Ostrogeneffekt auf das

Plasma-Cortisol bei Leberzirrhosen, Gastroenterologia (Basel), 96, i66.FLETCHER, R. F., and BROWN, P. S. (1959): Pituitary Function in Malnourished Women, Clin. Sci., i8, 367.FRASER, R. W., FORBES, A. P., ALBRIHT, F.,, SULKOWITCH, H., and REIFENSTEIN, E. C. (94): Colorimetric Assay of

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April 1963 MARTINI: Some Endocrine Changes in Liver Disease 2Ir

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MULLER, J. (I958): tJber die Oestrogenausscheidung bei der Lebercirrhose des Mannes, Acta endocr. (Kbh.), 28, 205.OFSTAD, J., STOA, K. F., and EMBERLAND, R. (1962): Adrenal and Urinary Corticosteroids in Terminal Hepatic Failure.

Report of a Case, Acta endocr. (Kbh.), 39, 123.PETERSON, R. E. (1960): Adrenocortical Steroid Metabolism and Adrenal Cortical Function in Liver Disease, J. clin.

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PLAGER, J. E., TYLER, F. H., HECHT, H. H., and SAMUELS, L. T. (1954): Metabolism and Excretion of IntravenouslyAdministered 4-C'4-I7-Hydroxycorticosterone, J. clin. Endocr., 14, 780.PREEDY, J. R. K., and AITKEN, E. H. (I956a): The Effect of Oestrogen on Water and Electrolyte Metabolism. II.

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SANDBERG, A. A., and SLAUNWHITE, W. R., Jr. (1957): Studies on Phenolic Steroids in Human Subjects. II. TheMetabolic Fats and Hepato-Biliary-Enteric Circulation of 14C-Oestrone and 14C-Oestradiol in Women, J. clin.Invest., 36, 1266.

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STOA, K. F., BASSOE, H. H., and EMBERLAND, R. (1958): Oestrogen Metabolism in Normal and Pathological LiverFunction as Studied by Chromatographic Urine Analysis, Acta endocr. (Kbh.), 28, 357.STUMPF, H. H., and WILENS, S. L. (1953): Inhibitory Effects of Portal Cirrhosis of Liver on Prostatic Enlargement,Arch. intern. Med., 91, 304.

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WEST, C. O., TYLER, F. H., BROWN, H., and SAMUELS, L. T. (1951): Role of Liver and Kidneys in Metabolism ofIntravenous Testosterone by Human Subjects, J. clin. Endocr., II, 897.WILLCOX, R. G., and ISSELBACHER, N. J. (1961): Chronic Liver Disease in Young People, Amer. 5J. med., 30, i85.WILLIAMS, T. L., CANTAROW, A., PASCHKIS, K. E., and HAVENS, W. P., Jr. (1951): Urinary 17-Ketosteroids in ChronicLiver Disease, Endocrinology, 48, 651.

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