progress report mechanism in cirrhotic males · it is claimedthat koechling (1835) (cited by...

Gut, 1977, 18, 843-853

Progress report

Mechanism of hypogonadism incirrhotic males

For many decades, the pathogenesis of the testicular atrophy and overtfeminisation that occur in some men with chronic liver disease has fascinatedboth clinicians and biochemists. A widely accepted explanation for thesechanges was first proposed by Edmondson and colleagues in 19391, whosuggested that in these patients the diseased liver was unable to inactivateendogenously produced oestrogens. Inadequate methodology has for manyyears prevented the confirmation or refutation of this hypothesis but recentmajor advances in biochemical and endocrinological techniques havestimulated a renewed interest in the problem. The purpose of this report is toreview some of the more recent studies and to re-examine some of the theoriesof the pathogenesis of these changes. The specific problem of haemochroma-tosis will not be discussed.

Clinical features of hypogonadism and feminisation

It is claimed that Koechling (1835) (cited by Bergonzi (1934)2) was the firstto recognise the association of gynaecomastia and liver cirrhosis in men, butthe clinical triad of gynaecomastia, testicular atrophy, and liver cirrhosisbecame widely acknowledged only after Italian hepatologists had rede-scribed these features in the mid-1920s3'4.

HYPOGONADISMClinical hypogonadism in cirrhotic men is manifested by reduced testicularsize and the clinical features of inadequate testicular function. Between50-75% of cirrhotic men have both macroscopic5-7 and histological8-'0testicular atrophy. Associated with this, 80-90% of cirrhotic men areimpotent7""',12 and seminal fluid characteristics are grossly abnormal in thesmall minority of patients who are able to produce an ejaculatell 2. Othersigns of hypogonadism include reduced body hair7"3, decreased beardgrowth", and reduced prostatic size". Histologically, cirrhotic men have adecreased incidence of benign prostatic hypertrophy'0.

FEMINISATIONGynaecomastia, the hallmark offeminisation, may be found uni- or bilaterallyin about 40% of cirrhotic men5 6.7,2,415 It is caused by hyperplasia ofglandular tissue elements'0. Less dramatic signs of feminisation include afemale escutcheon", female body habitus'6, and cutaneous arterial spidernaevi6b7 which are said to be related to a hyperoestrogenic state'7.A differential incidence of some of these endocrine signs has been found

depending on the aetiology of the liver disease. Thus, three groups find843

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gynaecomastia to be more common in alcoholic cirrhotics7"4"15 but others6 12could not confirm this. Similarly, testicular atrophy has been reported asbeing more common in alcoholic cirrhotics6,7, although this finding is notuniversal either'8. It has been suggested that the more frequent occurrence ofendocrine signs in alcoholic liver disease is attributable to greater liverdysfunction in these patients7, but there is, in fact, no clear relationshipbetween the degree of liver dysfunction and the incidence of endocrinechanges'8.

Biochemical basis of hypogonadism

Biochemical hypogonadism is well established in cirrhotic men. Total plasmatestosterone concentrations are lower than normal".'9-22. This modestdecrease masks a far greater fall in the non-protein bound (biologically active)fraction of plasma testosterone'2"15'20 caused by the increased concentrationsof sex-hormone binding globulin (SHBG) in cirrhotic men23-25. SHBG isthe most important plasma protein in determining the protein-binding ofplasma testosterone26.The low plasma testosterone in cirrhotic men is caused by a reduced

production of testosterone by the testes. Kinetic studies have shown that theatrophic testes of cirrhotics produce only one-quarter of the normal amountof testosterone27,28. Furthermore, 15 % of testosterone produced in these menis derived not from the testes but from peripheral conversion of circulatingandrostenedione28 (Fig. 1). Testosterone production by the testes of cirrhoticmen is therefore grossly inadequate.

Biochemical basis of feminisation

The three principal unconjugated oestrogens (oestrone, oestradiol, andoestriol) are found in the plasma of normal men. They are derived both from

PRECURSOR POTENTIAL PATHWAYS FOR ANDROGEN -OESTROGEN INTER CONVERSIONIN_NORMAL MEN

ANDROSTENEDIONE AOESTRONE - (El) OESTRIOL- (E3)

170HYDROGENASE 17jHYDROGENASE

11 A 11TESTOSTERONE M OESTRADI_OL 17- (E2)

5aREDUCTASE

5a- DIHYDROTESTOSTERONE

Fig. 1 Potential pathways for androgen-oestrogen interconversion. In normal mensignificant androgen-oestrogen interconversion occurs at sites other than in the liver orendocrine glands.

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Mechanism ofhypogonadism in cirrhotic males

direct glandular secretion (for example, by the testes-25 % of oestradiol29;by the adrenals-5-10 0% of oestrone30) and from peripheral conversion of themajor circulating androgens (for example, 50 % of oestradiol originates fromcirculating plasma testosterone31; 25 % of oestrone originates from circulatingandrostenedione31-Fig. 1).

Oestradiol is the most biologically potent oestrogen. Like testosterone, it isbound in the plasma by SHBG23 and albumin. However, the affinity ofSHBG for oestradiol is less than that for testosterone, while the affinity ofalbumin for oestradiol is higher than that for testosterone77. As a result,changes in plasma SHBG exert a far more profound effect on the free testos-terone fraction than on the free oestradiol fraction32. The effect of isolatedchanges in albumin concentration on the relative binding of testosterone andoestradiol has not been specifically studied.Unlike the biochemical evidence ofhypogonadism, biochemical feminisation

in cirrhotic men has not been adequately established. Early studies ofurinary oestrogens, using biological" 33-36 and biochemical37-39 methods,were contradictory with findings of normal35-37 or high"033,34,38,39 urinaryoestrogens in cirrhotics. Since the advent of more sensitive methods hasenabled the measurement of unconjugated plasma oestrogens, most reportshave concerned plasma oestradiol. In cirrhotic men, total unconjugatedplasma oestradiol has been reported as normal"15'6 , minimallyraised7'22'42'43, or greatly raised20'44'45. There is equal disagreement aboutunbound (biologically active) plasma oestradiol in cirrhotic men with reportsof normal'5'41, marginally raised7, or markedly raised20 free plasma oestradiol.The technique of steady-state gel filtration46 is probably the most physio-logical method of measuring the free fraction and both groups using thistechnique'5'4' found no change in protein-binding of oestradiol in cirrhoticmen.

It is difficult to reach firm conclusions in view of all these contradictoryreports. It would seem that total plasma oestradiol concentrations may beminimally raised in significant proportion of cirrhotic men, while free plasmaoestradiol concentrations appear marginally raised in only a minority ofcirrhotic men. Although in the largest single study7 a slight correlation wasfound between gynaecomastia and total plasma oestradiol concentrations,many patients with gynaecomastia had consistently normal total and freeplasma oestradiol concentrations. The significance, therefore, of marginallyraised plasma oestradiol concentrations, when they occur in cirrhotic men, isnot readily apparent. It may be that there is, in cirrhotic men, increasedsensitivity of breast tissue to circulating oestrogens.There is more agreement about plasma oestrone concentrations in cirrhotic

men. Oestrone is the metabolic precursor of oestradiol but it is a weakoestrogen with only about one-twelfth of the feminising potency ofoestradiol47. Many groups41'43-45,48 have found raised plasma oestrone incirrhotic men but only two41'48 have found that this rise correlates with thepresence of gynaecomastia. The poor feminising ability of oestrone (ascompared with oestradiol) makes the significance of this finding uncertainand a similar conclusion applies even more forcibly to the marginally raisedunconjugated plasma oestriol concentrations also found in cirrhotic men4143

Kinetic studies have only partially clarified these confusing findings. Onegroup45 have found an increased production rate of oestradiol in cirrhotic

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men but this has not been confirmed7. The different conclusions from thesetwo studies hinge entirely on their different findings for plasma oestradiolconcentration, as both had found a normal metabolic clearance rate foroestradiol in cirrhotic men. The production rate of oestrone has been foundto be raised in cirrhotic men in two studies49'50. In one study49, the less directurinary production method was used, while, in the other50, the method usedwas not specified. The findings from these studies would be consistent withraised plasma oestrone concentrations.

Kinetic studies have also shown that, in cirrhotic men, there is increasedperipheral conversion of androgens to oestrogens-both of testosterone tooestradiol7'51,52 and androstenedione to oestrone50,52'53. However, theassessment of the quantitative importance of these interconversions dependson the plasma concentrations of the precursor compound. Since plasmatestosterone is low in cirrhotic men, the mass of testosterone converted tooestradiol per unit time is no higher than normal. Similarly, the quantitativeimportance of the androstenedione-oestrone interconversion is difficult toassess as plasma androstenedione in cirrhotic men has been found to be eitherincreased28'49'53 or normal22'54. Therefore, although there is increasedperipheral conversion of androgens to oestrogens in cirrhotic men, thequantitative importance of these interconversions in explaining changes inplasma oestrogens is not clear.The inability to show unequivocal hyperoestrogenism in cirrhotic men

has led to a search for less direct indices of biochemical feminisation. It hasbeen suggested that increased plasma SHBG is indirect evidence of biochemicalhyperoestrogenism16. This finding in cirrhotic men, however, has other poten-tial explanations. Increased plasma sex-hormone binding globulin has beenreported in male hypogonadism of any cause24 and also in non-cirrhoticchronic alcoholics64. Raised plasma SHBG in cirrhotic men does not thereforeconstitute strong evidence of hyperoestrogenism in these men, although inother situations hyperoestrogenism is one of the most potent causes ofincreased plasma SHBG concentrations26. Plasma prolactin is to someextent oestrogen-responsive55 and has been found by one group48 to be raisedin cirrhotics but this finding has not been confirmed56'57 (see the section onhypothalamic-pituitary function).To summarise, there is no clear evidence of increased circulating concen-

trations of biologically potent oestrogens in cirrhotic men. There is goodevidence that plasma oestrone is raised in these patients; this may be partlycaused by an increased production of oestrone which might, in turn, becaused by increased peripheral conversion of androstenedione to oestrone inthese men. The metabolic importance of the raised plasma oestrone, abiologically weak oestrogen, is not apparent.

Hypothalamic-pituitary function

The contribution of hypothalamic-pituitary dysfunction to the endocrinechanges of cirrhotic men has recently been clarified. Figure 2 shows a sim-plified diagram of the hypothalamic-pituitary regulation of testicular functionin normal adult men.

Early studies of urinary gonadotrophins in cirrhotics, using bioassay, hadbeen contradictory with reports that these were low36.58, normal5, or high35.

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THE CONTROL OF TESTICULAR FUNCTIONIN ADULT NORMAL MEN

HYPOTHALAMUS

ANTERIOR PITUITARY- - - _

NEGATIVE FEEDBACK LH. F.SH. NEGATIVE FEEDBACK

lLEYDIG UBULAR 7CELLS CELLS INHIBIN"- ___

TESTOSTERONE < t?TESTIS SPERMATOZOA

Fig. 2 Hypothalmic-pituitary control of testicular function in normal men. The products oftesticular function, spermatozoa and testosterone, in some way exert a negativefeedbackregulation of the hypothalamic-pituitary control ofgonadotrophin (LH, FSH) secretion.(Gn RH = Gonadotrophin releasing hormone;LH = luteinising hormone; FSH = folliclestimulating hormone).

Although there is a similar wide range of reported values for plasma gonado-trophins as determined by radioimmunoassay in cirrhotics7,11,12,15,20,21,40the broad consensus of findings is that plasma gonadotrophins are normalin the majority of cirrhotic men and only a minority have high values. Lowvalues are seen pre-terminally7.

There are two implications from this finding of normal plasma gonado-trophins in the majority of cirrhotics with frank testicular failure. The firstis that there may be in these patients a primary testicular defect, as the testesare hypofunctional despite a normal trophic drive. The second is that theremust also be a hypothalamic-pituitary abnormality because in other causes ofprimary hypogonadism, where there is a comparable degree of testicularfailure, plasma gonadotrophin concentrations are markedly raised59. Anabnormal plasma gonadotrophin response to clomiphene administration incirrhotics1' confirms the presence of a hypothalamic-pituitary defect in thesemen and this defect has been further localised to the hypothalamus, as thepituitary response to gonadotrophin releasing hormone (Gn RH) in cirrhoticsis either normal or supranormal12.The absence of galactorrhea in cirrhotic men with or without gynaeco-

mastia would suggest that plasma prolactin concentrations in these men arenormal. Although one group has reported raised plasma prolactin in cirrhoticmen48, two other groups have found normal plasma prolactin in cirrhotics,using both bioassay58 and radioimmunoassay57. The latter group has furtherfound a normal plasma prolactin response to stimulation with thyrotrophinreleasing hormone (TRH) in cirrhotic men57.To summarise, recent studies have shown that cirrhotic men have defective

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hypothalamic-pituitary secretion of gonadotrophins, caused by a hypothalamicdefect.

Aetiology and pathogenesis of endocrine changes

Many different hypotheses have been proposed to explain the pathogenesis ofendocrine changes in cirrhotic men. A number of these will be considered inthe light of recent findings.

ROLE OF DERANGED HEPATIC METABOLISM OF OESTROGENIn the diseased liver of both men and animals, both in vivo and in vitro studieshave shown abnormalities of hepatic metabolism of many oestrogeniccompounds (for reviews-Adlercreutz, 197060 and 197461). Despite these,recent in vivo studies in cirrhotic men have shown that neither the plasmahalf-life62 nor the metabolic clearance rate7,45 of plasma oestradiol is signifi-cantly different from normal. These findings are strong evidence against theoriginal Edmondson hypothesis' but do not entirely refute it, as there maystill be delayed metabolic clearance of other, less biologically activeoestrogens-for instance, oestrone.

Increased peripheral conversion of androgens to oestrogens, shown incirrhotic men, would not seem to be directly caused by altered hepaticmetabolism of these compounds. Preliminary evidence from two studies50'52indicates that in cirrhosis the transhepatic aromatisation of both testosteroneto oestradiol and androstenedione to oestrone is much lower compared withthat occurring in extraplanchnic sites. Thus, any role that liver disease mayhave in causing these metabolic changes must be indirect.To summarise, it would seem that the original hypothesis of Edmondson

and colleagues is now less likely to be correct. Recent studies have failed toshow significant changes in the hepatic metabolism of biologically potentoestrogens in cirrhotic men and it is apparent that the role of liver disease inthe pathogenesis of such changes as have been shown may only be indirect.

ROLE OF ALCOHOL (ETHANOL) CONSUMPTIONAlthough there is no doubt that alcohol consumption can lead to manycomplex changes in the metabolism of sex hormones, it is not necessary toinvoke these biochemical effects to explain the endocrine disturbances ofestablished hepatic cirrhosis. This is because the endocrine changes in cirrhosisare comparable whether caused by alcohol or not6,7,12.The endocrine consequences of alcohol consumption in non-cirrhotic

subjects are, however, of some interest. In general terms, two possible waysin which alcohol consumption might exert a specific effect on endocrinefunction have been considered. The first is that alcohol consumption mightinduce specific alterations in the hepatic metabolism of sex hormones andrelated compounds (other than by non-specific hepatic damage) and thesecond is that alcohol might be directly toxic to one or more elements of thehypothalamic-pituitary-gonadal axis.As recent studies have shown that endocrine changes caused by alcohol

consumption differ markedly depending on whether consumption is short-term or chronic, these two situations are considered separately.

Short-term alcohol consumption in non-cirrhotic menIn a recent study of short-term (four weeks) alcohol consumption63, evidence

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of increased hepatic metabolism of testosterone was found together with anincreased metabolic clearance rate of testosterone from plasma. Plasmatestosterone fell over the period of study but so, interestingly, did the protein-binding of plasma testosterone. As there was no consistent change in serumluteinising hormone (LH), the authors interpreted these findings as evidenceof direct suppression by alcohol of both testicular function and hypothalamic-pituitary function. An alternative explanation is that, although total plasmatestosterone was lowered, free testosterone might have remained normal(because of decreased protein binding) and this, together with the normalplasma oestradiol (that was found), would have obviated the need forhypothalamic-pituitary compensation.

Chronic alcohol consumption in non-cirrhotic menThe endocrine changes found in non-cirrhotic chronic alcoholics are quitedifferent from those of short-term consumers. In chronic alcoholics, plasmaSHBG is markedly raised18 22.64, which reduces the free fraction of plasmatestosterone below normal. There is increasing evidence that many of thesepatients with fatty livers have raised plasma gonadotrophins65 with onlymarginally lowered concentrations of free testosterone18. This pattern ofchanges seems similar to that found in men with thyrotoxicosis66,67 wherethe primary abnormality would seem to be an increased plasma SHBG. Therecent study by Israel and colleagues68, showing that both thyrotoxicosis andchronic alcohol administration have markedly similar effects on hepaticmetabolism, is therefore of interest.

It has been suggested that chronic consumption of alcohol directly reducesspermatogenesis by inhibiting the testicular conversion ofretinol to retinal69-the latter being essential for spermatogenesis in animals70. This conversion isunfavourably influenced by high NADH concentrations which might resultfrom intratesticular reduction of ethanol by alcohol dehydrogenase69.Experimental support for this theory is confined to animal studies and furtherobservations are awaited. In another animal study71, chronic feeding ofalcohol to developing rats was shown to result in smaller testes at maturity.This does not parallel the human situation, however, in which a secondaryatrophy is presumed to occur in a previously normally developed testes.To summarise, alcohol consumption would appear to play no specific role

in the endocrine changes of established cirrhosis, as these changes are seenequally in non-alcoholic cirrhotics. In non-cirrhotic men, both short-term andchronic consumption of alcohol induce a variety of biochemical effects onsex hormone metabolism, but there is as yet no unequivocal evidence of adirect toxic effect of alcohol on either the testes or the hypothalamic-pituitarysystem in man; many of the endocrine consequences of alcohol consumptionin non-cirrhotics may result from changes in hepatic synthesis of SHBG.

Role ofprimary hypogonadismThe possibility that many, if not all the endocrine changes in cirrhotic menresult entirely from a primary testicular defect has recently been reconsidered.In this respect, evidence for a direct toxic effect of alcohol on the testes isunproven (see relevant section) but it has recently been suggested thattesticular damage might be mediat.d by autoimmune mechanisms72, pre-sumably triggered by non-specific hepatic damage.

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Although a primary testicular defect would explain the low plasmatestosterone,1"9-22, high plasma SHBG24, and possibly the increased peri-pheral conversion ofandrogens to oestrogens73, there are two major objectionsto this as a unifying hypothesis. The first is that it cannot alone explain thehypothalamic-pituitary suppression found in most cirrhotics or the occurrenceof gynaecomastia in only a few (who do not necessarily have the lowest totaland free plasma testosterones'2). The second, more fundamental objection isthat it is far from clear that the undoubted hypogonadism of cirrhotics is ofprimary origin. Much of the evidence for a primary testicular defect rests onan inadequate plasma testosterone response to human chorionic gonado-trophin (HCG)7"l112, but the ability of this test to differentiate primaryhypogonadism from hypogonadotrophic (secondary) hypogonadism isextremely questionable74 7

Therefore, a primary testicular defect in cirrhotic men, if it exists at all,would alone be an inadequate explanation for the endocrine changes seen inthese men.

MiscellaneousfactorsGynaecomastia is a side effect of many non-oestrogen drugs59. In particular,spironolactone76 is often used in cirrhotic men and may contribute toendocrine changes in a proportion7. The role of this and other agents,however, must be subsidiary in view of the high incidence of endocrinechanges observed long before the availability of these drugs5.Although knowledge of the pathogenesis of gynaecomastia in other clinical

situations might, by analogy, further the understanding of gynaecomastia incirrhotic men, the pathogenesis of gynaecomastia in other situations remainsas obscure as it is in cirrhotic men. The only situation in which the patho-genesis of gynaecomastia appears to be readily understandable is in men withprostatic carcinoma receiving pharmacological quantities of exogenousoestrogens.

Summary and conclusion

Men with chronic liver disease frequently develop clinical signs of hypo-gonadism and overt feminisation. Associated with these features, they havebeen found to have a reduced production of testosterone with low plasmaconcentrations, but only a minority of cirrhotic men would seem to have amarginal increase in circulating biologically potent oestrogens. Furthermore,this latter finding does not correlate with the presence of clinical feminisation.The original hypothesis to explain these changes now seems less likely to

be true and no other single hypothesis has, on its own, been found to providean adequate explanation for all the clinical and biochemical features foundin cirrhotic men. It may be that the pathogenesis of endocrine changes incirrhotic men is multifactorial-for instance, a combination of decreasedhepatic clearance of some oestrogenic compounds, an autoimmune mediatedprimary testicular defect, and a specific potentiation effect by alcohol.Alternatively, it may be that none of these suggested mechanisms is of im-portance and that the endocrine changes are mediated instead by othermechanisms which remain, as yet, undiscovered or unconsidered.

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Mechanism ofhypogonadism in cirrhotic males 851

The fascination which this problem has held for clinicians and biochemistsfor many years seems likely to persist for some time to come.

J. R. B. GREENDepartment of Gastroenterology

St Bartholomew's HospitalLondon

Received for publication 11 May 1977

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47Hisaw, F. L. (1959). Comparative effectiveness of estrogens on fluid imbibition and growth ofthe rat's uterus. Endocrinology, 64, 276-289.

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"1Vermeulen, A., Mussche, M., and Verdonck, L. (1972). Testosterone and estradiol productionrates and interconversion in normal males and male cirrhotics. Proceedings of the 4th Inter-national Congress on Endocrinology. Abstract 305, p. 123. Excerpta Medica: Amsterdam.

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63Gordon, G. G., Altman, K., Southren, A. L., Rubin, E., and Lieber, C. S. (1976). Effect ofalcohol (ethanol) administration on sex-hormone metabolism in normal men. New EnglandJournal of Medicine, 295,793-797.

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67Clyde, H. R., Walsh, P. C., and English, R. W. (1976). Elevated plasma testosterone andgonadotropin levels in infertile males with hyperthyroidism. Fertility and Sterility, 27, 662-666.

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71Van Thiel, D. H., Gavaler, J. S., Lester, R., and Goodman, M. D. (1975). Alcohol-inducedtesticular atrophy-an experimental model for hypogonadism occurring in chronic alcoholicmen. Gastroenterology, 69, 326-332.

72Van Thiel, D. H., Gavaler, J. S., Smith, W. I., and Rabin, B. S. (1976). Does autoimmunitycontribute to the hypogonadism of alcoholic men? Gastroenterology, 71, A-40/933.

73Wang, C., Baker, H. W. G., Burger, H. G., DeKretser, D. M., and Hudson, B. (1975). Hormonalstudies in Klinefelter's syndrome. Clinical Endocrinology, 4, 399-411.

74Anderson, D. C., Marshall, J. C., Young, J. L., and Russell Fraser, T. (1972). Stimulation testsof pituitary-Leydig cell function in normal male subjects and hypogonadal men. ClinicalEndocrinology, 1, 127-140.

75Mahoudeau, J. A., Valcke, J-C., and Bricaire, H. (1975). Dissociated responses of plasmatestosterone and estradiol to human chorionic gonadotropin in adult men. Journal of ClinicalEndocrinology and Metabolism, 41, 13-20.

76Clark, E. (1965). Spironolactone therapy and gynecomastia. Journal of the Amnerican MedicalAssociation, 193, 163-164.

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