J Clin Pathol 1995;48:513-518

Differences in androgens of HIV positivepatients with and without Kaposi sarcoma

N Christeff, C Winter, S Gharakhanian, N Thobie, E Wirbel, D Costagliola,E A Nunez, W Rozenbaum

AbstractAim-Since most forms ofKaposi sarcomaare much more common in men thanin women, the aim of this study was toexamine serum concentrations ofsex ster-oids in HIV positive men with and withoutKaposi sarcoma.Methods-Blood samples from 34 HIVpositive men without Kaposi sarcoma(KS-) and 28 with Kaposi sarcoma (KS +)and from 35 HIV negative men (controls)were analysed for adrenal and gonadalsteroids. Further analysis was done in sub-groups classified by CD4 lymphocytecounts.Results-KS + patients had significantlyhigher serum dehydroepiandrosterone(DHEA) and testosterone concentrationsthan the KS- patients, and their DHEA,DHEA sulphate, testosterone, and andro-stenedione values were higher than inthe controls. The KS + patients with morethan 500 CD4 lymphocytes per mm' hadsignificantly higher serum DHEA, DHEAsulphate, and testosterone than the KS -patients with the same CD4 counts; thosewith 500-200 CD4 cellsimm' had higherserum DHEA and testosterone than theequivalent KS - men; and those with <200CD4 celslsmm3 had raised DHEA onlycompared with KS- men. Both KS + andKS - men had higher serum progesteroneand oestradiol than the controls. Gluco-corticoids were not significantly altered.Conclusions-The high androgen levels inKS + patients, particularly in the earlystages ofthe disease (>500 CD4 cells/mm'),may affect the immune systemby inducingan abnormal cytokine profile, or by in-creasing T8 proliferation and activation,or both. This raises the question of therelationship between androgens and Ka-posi sarcoma.(_ Clin Pathol 1995;48:513-518)

Keywords: Kaposi sarcoma, HIV infection, androgens,DHEA, steroid hormones, immune system.

Most forms of Kaposi sarcoma are much morecommon in men than in women-the ratio is10 to 15:1 for the classic and African forms.'The epidemic form of Kaposi sarcoma, whichis associated with HIV infection, is also ex-ceptionally common among male patients,"and homosexual and bisexual men are 10 timesmore at risk.' Certain factors favour the de-velopment ofKaposi lesions. Various cytokines,

particularly IL6, can act as autocrine/paracrinegrowth factor for AIDS associated Kaposisarcoma.45 Glucocorticoids also favour theformation of Kaposi lesions.6 There have beenreports7 of Kaposi sarcoma developing duringthe treatment of HIV patients with corticoids.The incidence of this condition began to in-crease with the use ofimmunosuppressive ther-apy for transplant recipients.8 Experimentalstudies also show that lesions resembling thoseof Kaposi sarcoma develop in male transgenicmice, but not in females.9There is now general agreement that the

steroid hormone profile of patients infectedwith HIV changes during the course of theviral infection.""'4 The serum concentrationsof cortisol are normal or slightly high at allstages of HIV infection." ''14 By contrast, an-drogen levels appear to be closely correlatedwith the stage of HIV infection.'4 Asympto-matic HIV positive men (stages II and III)in general have high serum concentrations ofandrogens (dehydroepiandrosterone (DHEA),androstenedione, testosterone), whereas thosewith AIDS have subnormal androgen con-centrations. There is also evidence for a re-lationship between CD4 count and serumDHEA or DHEA sulphate values in HIV in-fected men at risk of progression to AIDS.'5These changes in hormone concentrations, par-ticularly of the androgen profile, during thecourse of HIV infection might result in sig-nificant alterations in immune competence,especially cytokine profiles and T cell activityand function.'617 Androgens, such as DHEAand DHEA sulphate, enhance in vivo the cap-acity of activated helper T cell to produce IL-2,18 even in the presence of glucocorticoids,'8which inhibit IL-2 production. 18 The pro-duction of IL-2 is decreased in subjects withprogression of HIV-1 infection.'9 DHEA andDHEA sulphate supplements appear to correctthe age associated dysregulated production ofT cell lymphokines.20 The differentiation of Tlymphocytes into helper cells (T4) or sup-pressor (T8) depends on the concentrationsof androgen.'62' Testosterone stimulates theactivity and function of T suppressor cells.22Other data indicate that adult males who arevery responsive to androgens produce fewerantibodies.23These epidemiological, clinical, and ex-

perimental data suggest that the steroid hor-mone environment and the immune status ofthe host may influence the risk of Kaposi sar-coma associated with HIV infection. We there-fore studied the serum concentrations ofcorticoids, progestins, androgens, and oes-

U224, INSERM affilieeau CNRS, Faculte deMedecine X Bichat BP416, 75870 ParisCedex 18, FranceN ChristeffN ThobieE A Nunez

Service de M&decineInterne, HopitalTenon, 4 rue de laChine, 75020 Paris,FranceC Winter

Service des MaladiesInfectieuses, HopitalRothschild, 33Boulevard de Picpus,75012 Paris, FranceS GharakhanianE WirbelW Rozenbaum

B3E, U263 INSERM etSC4, Faculte deMedecine Saint-Antoine, 75571 Paris,FranceD Costagliola

Correspondence to:Dr Nevena Christeff.Accepted for publication:3 November 1994

513

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from

Chnisteff, Winter, Gharakhanian, Thobie, Wirbel, Costagliola, et al

Table 1 Clinical information on HIVpositive men classified according to the CD4 lymphocyte count

7tme sinceCD4 Number diagnosis of CD4 CD8range of Age HIV Previous Previous count count

Group (count/mm3) subjects (years) (months) infections treatment (per mm3) (per mm3)

KS- >500 n =7 37 26 0 0 944 1024(28-50) (15-32) (781-1366) (557-1733)

KS + >500 n =5 39 6 0 0 893 772(26-62) (0-23) (563-1057) (450-1246)

KS- 500-200 n=16 42 42 5 3 329 1206(29-63) (0-78) (209-444) (309-2174)

KS+ 500-200 n= 12 36 24 2 3 310 817(23-45) (0-43) (211-422) (251-2062)

KS- <200 n=11 38 60 2 8 89 565(30-44) (4-102) (3-169) (211-879)

KS+ <200 n=11 40 48 2 8 107 966(30-44) (0-78) (10-194) (239-2208)

KS = HIV positive men without Kaposi sarcoma; KS + = HIV positive men with Kaposi sarcoma

trogens in male HIV positive patients with andwithout Kaposi sarcoma and in HIV negativemen. We also determined the steroid hormoneconcentrations of HIV positive patients withand without Kaposi sarcoma classified ac-cording to their absolute CD4 lymphocytecount. These data were analysed to determine ifthere was any relationship between endogenousserum steroid hormone concentration and thepresence of Kaposi sarcoma in a cohort ofHIVpositive men.

MethodsPATIENTSSerum samples from Kaposi sarcoma negativeand positive patients in each CD4 range wereselected under double blind conditions, ac-cording to a single criterion-that the twogroups ofpatients were in the same clinical con-dition at the time the samples were taken. Wethen examined the records of the patients forrisk factors, age, previous infection, and treat-ment. All samples were taken from HIV positivepatients at the Rothschild hospital (UniversityParis VI). Twenty eight were HIV positive menwith Kaposi sarcoma (group KS +) and 34were HIV positive men without Kaposi sar-coma (group KS-). HIV infection was con-firmed by western blot. They were classifiedaccording to their CD4 lymphocyte counts.The patient data are shown in table 1. TheKS+ group included five patients with >500CD4 cells/mm3, 12 patients with 500-200 CD4cells/mm3, and 11 patients with <200 CD4cells/mm3. The KS - group included sevenpatients with >500 cells/mm3, 16 patients with500-200 cells/mm3, and 11 patients with <200cells/mm3. Two of the KS + patients were ex-amined twice (first in group 500-200, and thenin the group <200 CD4), as they suffered froma recurrence of Kaposi sarcoma after four yearsof remission. The KS + patient samples weretaken within three months of Kaposi sarcomabeing diagnosed. All except five were homo-sexual. In one KS+ patient and two KS-patients the risk factor was unknown, one KS -patient was a drug addict, and one KS - patienthad been transfused. The two groups were ofsimilar age, and had similar previous op-portunistic infections and therapy. Only themean duration of known HIV infectiondiffered; this was because the KS + patientswere seen much earlier than the KS - patients.

The CD4 cell count indicated that patientswith >500 CD4 lymphocytes had had no op-portunistic infections or treatment; in the 500-200 CD4 range, KS + patients had no op-portunistic infections but the KS - patientsincluded one who had had tuberculosis, onewith ocular toxoplasmosis, and one with gastriclymphoma. KS + patients with <200 CD4 lym-phocytes included one with toxoplasmosis, onewith cytomegalovirus (CMV) retinitis, and twowith previous Kaposi sarcomas; KS - patientswith <200 CD4 lymphocytes included one withtoxoplasmosis, one with multifocal leuco-encephalitis, and one with a lymphoma. Anti-viral therapy was given as follows: in the 500-200 CD4 cell group, one KS + patient hadtaken zidovudine, and two had taken imuthiol;two KS - patients had taken zidovudine andone had taken imuthiol; in the <200 CD4cell group, six KS+ patients had been givenantiviral treatment (four zidovudine, two zido-vudine followed by DDI), two had takeninterferon oc2b four years earlier; seven KS -patients had had zidovudine and two had hadimuthiol. Five KS + and six KS - patients hadprimary prophylactic pneumocystosis. Patientswere not treated with ketoconazol, gluco-corticoids, or interferon at the time the westernblots were taken.The control group consisted of 35 HIV neg-

ative male blood donors aged 18-50 years.

BLOOD SAMPLESBlood samples were collected between 0800and 1000 and allowed to coagulate before sep-aration of serum by centrifugation (3000 rpm/10 minutes at 4°C). Serum samples were storedat - 20°C until assayed.

STEROID EXTRACTION AND CHROMATOGRAPHICFRACTIONATION(1) Serum samples (1 ml) were extracted for30 min with 5 ml of organic solvent (ethylacetate/cyclohexane, 1/1) and the aqueousphase was removed by freezing (- 20°C). Theorganic phase was evaporated to dryness, takenup in 1 ml ofsolvent system I (benzene/ethanol,95/5) and placed on a Sephadex LH20 micro-column (0 5 x 6 cm). Progesterone and andro-stenedione were first eluted with 2-6 ml ofsolvent I. Oestrone was then eluted with 3 5 ml

514

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from

Androgenis anid Kaposi sarcomiia

ofsolvent I followed by 1 0 ml ofsolvent II (ben-zene/ethanol, 90/ 10). Finally, oestradiol andcortisol were eluted with 6 ml of solvent II.(2) Serum samples (0-5 ml) were extracted asabove and placed on Sephadex LH20 micro-columns: testosterone and 1 7Y hydroxypro-gesterone (177OH-progesterone) were elutedwith 5-5 ml of solvent I.(3) A third series ofserum samples (O 5 ml) wasextracted with organic solvent (ethyl acetate/cyclohexane, 1/1) for direct radioimmunoassay(RIA) of dehydroepiandrosterone (DHEA).(4) DHEA sulphate concentrations were de-termined directly without extraction. Sampleswere diluted with radioimmunoassay buffer forRIA.The yields from these extraction and puri-

fication steps were between 70°. and 95%.

RADIOIMMUNOASSAY OF STEROIDSOestrone, oestradiol, progesterone, 17ai OH-progesterone, cortisol, testosterone, andro-stenedione, DHEA, and DHEA sulphate wereassayed using rabbit antisera from Miles, Yeda,Israel (anti-El 6-thyroglobulin serum, anti-17p-oestradiol-6-BSA serum, anti-17y OH-progesterone-7-BSA serum, anti-F-2 1 thy-roglobulin serum, anti-testosterone-7-y-BSAserum, and anti-androstenedione 7-y-BSAserum) and rabbit antisera from Biosys, France(anti-progesterone- 1 1HS-BSA, anti-DHEA1 5-CH,-CO-BSA, anti-DHEA sulphate 7-n-CM-BSA). The detection limit was 18 pmol/1in all cases. All hormones were assayed asdescribed in 14. DHEA and DHEA sulphatewere determined by RIA (Biom&rieux kits,Chamberlins-les-Bains, France).The tritiated steroids 2,4,6,73H oestrone

(107 Ci/mmol), 2,4,6,73H oestradiol (99 Ci/mmol), 1,2,6,73H progesterone (82 Ci/mmol),1,2,6,73H 17aOH progesterone (89 Ci/mmol),1,2,6,73H cortisol (85 Ci/mmol), 1,2,6,73H tes-tosterone (94-1 Ci/mmol), 1,2,6,73H andro-stenedione (96 Ci/mmol), 1,2,6,73H DHEA(86 6 Ci/mmol), and 1,2,6,73H DHEA sulph-ate (7608 Ci/mmol) were purchased from theRadiochemical Centre, Amersham. All were99% pure; purity was checked by thin layerchromatography. Radioactivity was determinedon samples dissolved in 4 ml Opti-Fluor (Pack-ard) by counting in a Packard 1500 liquidscintillation analyser using the internal stand-ard for quench correction.

STATISTICAL ANALYSISThe data were analysed by the Wilcoxon non-parametric test and the Student-Newman-Keuls multiple range test. The differences wereconsidered significant at probability (p) valuesof <0 05.

ResultsSTEROID HORMONE CONCENTRATIONS OF HIVPOSITIVE (WITH AND WITHOUT KAPOSI

SARCOMA) AND HIV NEGATIVE MENThe hormone concentrations of HIV negativemen (control) and all the members of the two

groups of HIV positive men, with and withoutKaposi sarcoma, were compared.

Progestins anid cortisol Serum progesterone (fig1) in the KS- and the KS + groups washigher (125'So, p<001, and 105%, p<O.O1,respectively) than in the controls. There wasno difference between KS + and KS -patients.

0Ec

1-

O -

Controls

[3 HIV+

* HIV ± KS

Progesterone

Figure 1 Senrumi progesterone concentrations in1 HIVpositive miieni wizth (KS+) or without (KS-) Kaposisarcomiia anid in1 HITInegative mizeni (conltrols).Conzcenitrationis were detenninled by, radioinimunoassav.Conitrol, n =35 subjects; KS -, n=34 subjects; KS +,n = 28 subjects. Error bars = SEAI.KS- v control p<001; KS+ v coitrol p<OOl; KS+ vKS -: AXS.

40

30

Controls

S KS-

* KS+

DHEA DHEA sulphate A4 T(nmol/1) (PmoI/l) (nmol/l) (nmol/1)

Figure 2 Serum71 androgens [dehydroepiandrosterone(DHEA), DHEA slulphate, anidrostenedionze (14), anidtestosteronie (T)] in HIVpositive men with (KS+) orwzithout (KS-) Kaposi sarcomiza and in HIV negativemnen (controls). Concentrations were determined byradioininiunoassay. Control, n = 35 subjects; KS-, n = 34subjects; KS +, n = 28 suibjects. Error bars = SEAl.KS- v control: DHEA suilphate p<005; KS+ vcontrol: DHEA, DHEA sulphate, Tp<OO1, 14 p<O05;KS-+ v KS-: DHEA and Tp<OOI.

5 1

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from

Christeff, Winter, Gharakhanian, Thobie, Wirbel, Costagliola, et al

E0.

0 Controls

HIV+

* HIV ± KS

T

Oestrone Oestradiol

Figure 3 Serum oestrone and oestradiol concentrations inHIV positive men with (KS+) or without (KS-)Kaposi sarcoma and in HIV negative men (controls).Concentrations were determined by radioimmunoassay.Control, n =35 subjects; KS-, n =34 subjects; KS+,n = 28 subjects. Error bars = SEM.KS -v control: El NS, E2 p<005; KS+ v control: ElNS, E2 p<005; KS+ v KS-: El NS, E2 NS.

Serum cortisol and 1 7cOH-progesteroneconcentrations in KS + and KS- men were

not significantly different from control. Therewas no difference between the KS + group andthe KS- group. The serum cortisol concen-

trations were: KS-, 380 (SEM 18-8) nmol/l;KS+, 360(19-6) nmol/l; control, 337-6(19 3)nmol/l. The serum 17oxOH-progesterone con-

centrations were: KS-, 3.5(0 3) nmol/l; KS +,4 24(0.3) nmol/l; control, 3.64(0 2) nmol/l.

Androgens The serum concentrations of theandrogens DHEA, DHEA sulphate, andro-stenedione, and testosterone in KS+, KS-,and controls are shown in fig 2.The androgen concentrations were much

higher in KS + men than in controls: DHEA,DHEA sulphate, and testosterone were 60%above control values (p<001) and andro-stenedione was 25% increased (p<005).The only androgen that was significantly raisedin KS - patients was DHEA sulphate (35%,p<0.05). The DHEA and testosterone con-

centrations of KS + patients were higher (85%and 40% respectively, p<0.01) than those ofKS -patients.

Oestrogens (fig 3) The serum oestradiol con-

centrations in all groups of HIV positivepatients were significantly higher (50%,p<005) than in controls, but there was no

difference between the KS+ and KS- sub-jects. The serum oestrone concentrations inHIV positive men were not significantly differ-ent from control. There was no difference be-tween the KS + and KS -men.

STEROID HORMONE CONCENTRATIONS OF HIV

POSITIVE MEN ACCORDING TO THE CD4

LYMPHOCYTE COUNT

The hormone concentration of HIV positivepatients with and without Kaposi sarcoma,

classified according to their absolute CD4lymphocyte counts, were compared.

Progestins and cortisol (table 2) The pro-

gesterone concentrations were significantly low(30%, p<0.05) only in KS+ patients in the500-200 CD4 cells/mm3 stratum. The 17oOH-progesterone concentrations were high (65%,p<0.05) only in KS + patients with >500 CD4lymphocytes/mm3. There was no difference inthe cortisol concentrations of the two groups

according to the CD4 lymphocyte count.

Androgens (fig 4) Androgens were sig-nificantly higher in the KS + men than in thecorresponding KS -men in each of the CD4lymphocyte count categories. These increaseswere as follows:(1) In the >500 CD4 cell stratum, DHEAsulphate increased by 50% (p<002), DHEAincreased by 125% (p<0 02), testosterone in-creased by 85% (p<0.02), and androstenedioneincreased by 20% (NS).(2) In the 500-200 CD4 cell stratum, theDHEA and testosterone concentrations were

65% (p<0 01) and 35% (p<0.05) higher re-

spectively than in the KS - patients.(3) In the <200 CD4 stratum, only the DHEAconcentrations were increased in the KS + men

(80%, p<0 05).

Oestrogens (table 3) The serum oestrone andoestradiol concentrations in the KS + andKS- patients were not significantly different,regardless of the CD4 cell count.

Table 2 Serum progestin and cortisol levels in HIV positive men. Values are means (SEM)

CD4 range Number of Progesterone 17sOH-progesterone CortisolGroup (count/mm?) subjects (nmolil) (nmol/l) (nmolll)

KS- >500 n=7 1-02 (0 12) 2-42 (0 33) 392-0 (38 6)KS+ >500 n =5 1-00 (0 2) 4-10 (0 60)* 401-6 (61)KS- 500-200 n= 16 1-05 (0-11) 3.94 (0 45) 361-6 (22)KS+ 500-200 n= 12 0 70 (0-10)* 4.70 (0 60) 386-7 (32 6)KS- <200 n= 11 0 94 (0-13) 3-64 (0 70) 382-5 (44-2)KS+ <200 n= 11 1-10 (0-15) 3-80 (0 50) 312-0 (28 07)

Serum progesterone, 17csOH progesterone, and cortisol concentrations in HIV positive men with Kaposi sarcoma (KS +) orwithout Kaposi sarcoma (KS-), grouped according to their CD4 lymphocyte count, were determined by radioimmunoassay.* p<005 v KS-

516

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from

Androgens and Kaposi sarcoma

15 1 B

B KS-

KS+T

1o -

T TT0Ec

5-

500-200

O -4-

> 500 500-200

o0< 200 CD4

< 200 CD4

> 500

E 20C

TT

T -T

500-200

> 500 500-200

< 200 CD4

< 200 CD4

Figure 4 Serum androgens [(A) dehydroepiandrosterone (DHEA) sulphate; (B) androstenedione (A4); (C) DHEA; (D) testosterone] in HIV positivemen with (KS+) and without (KS-) Kaposi sarcoma. Concentrations were determined by radioimmunoassay. Error bars = SEM. The distribution ofpatients according to CD4 count is shown in table 1.>500 CD4, KS+ v KS-: DHEA sulphate, DHEA, testosterone p<0 01, A4 NS; 500-200 CD4, KS+ v KS-: DHEA p<0 01, testosteronep<0*05; <200 CD4, KS+ v KS-: DHEA p<005.

Table 3 Serum oestrogen concentrations in HIVpositive men. Values are means (SEM)

CD4 range Number of Oestrone OestradiolGroup (countlmm3) subjects (pmol/l) (pmol/l)

KS- >500 n=7 111 (22) 205 (77)KS+ >500 n=5 222 (78) 143 (29)KS- 500-200 n= 16 107 (18) 147 (18)KS+ 500-200 n=12 126 (33) 165 (15)KS- <200 n=Il 152 (41) 187 (40)KS+ <200 n=11 237 (55) 195 (22)

Serum oestrone and oestradiol concentrations in HIV positive men with Kaposi sarcoma (KS +)or without Kaposi sarcoma (KS-), grouped according to their CD4 lymphocyte count, weredetermined by radioimmunoassay.

DiscussionIn this retrospective study we examined theserum concentrations of adrenal and gonadalsteroids in HIV positive men with and withoutKaposi sarcoma. All hormone assays and ana-lyses were performed under double blind con-ditions, with the operator unaware of either theKaposi status or the CD4 count. There wasno difference between the KS + and KS -patients in terms of age, mean CD4 count,opportunistic infections, or treatment. The res-ults obtained suggest that only the serum con-centrations of androgens in the two groupsdiffered markedly. The differences in the otherserum steroid hormone concentrations wereeither non-significant or inconsistent.

HIV positive patients with Kaposi sarcoma

had significantly higher serum adrenal an-

drogen (DHEA and DHEA sulphate) and gon-adal androgen (testosterone) concentrationsthan the HIV positive men without Kaposisarcoma, or the HIV negative men. This differ-ence was still evident when the patients were

classified according to their CD4 lymphocytecount. The serumDHEA and testosterone con-centrations of the KS + patients were higherthan those ofKS - patients, whatever the CD4lymphocyte count. The increase in androgenlevels was much greater in those KS + subjectswith more than 500 CD4 cells per mm3. Inthese patients with Kaposi sarcoma but withoutother clinical problems, all the androgen con-

centrations were higher than in HIV positivepatients without Kaposi sarcoma. This differ-ence was very significant for DHEA, DHEAsulphate and testosterone, but not significantfor androstenedione, perhaps because of thesmall number of patients studied. High an-

drogen levels have been reported in male sub-jects in the early stages ofHIV infection (stagesII and III according to CDC Atlanta criteria) .

The present study shows that the decrease inthe absolute CD4 cell count and progressionto AIDS is accompanied by a fall in the serumandrogen concentrations. There is also a sig-nificant linear correlation between the CD4

20 -A

E 10 -

0 4-

C

> 500

T50 -

40-

30 -

20 -Ec

10 -

517

-1

T-r

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from

Christeff, Winter, Gharakhanian, Thobie, Wirbel, Costagliola, et al

cell count and the serum concentrations ofDHEA sulphate only in the KS + patients (r=0-4155, p<0 01). Both the DHEA and tes-tosterone levels ofKS + subjects with 500-200CD4 cells per mm3 were higher than those ofthe KS - patients. But in the KS+ subjectswith <200 CD4 cells/mm3, only the DHEAconcentration was higher than in KS -patients. A decrease in DHEA has been as-sociated with increased risk of progression toAIDS in men with 200-499 CD4 cells/mm3.'5A longitudinal study24 indicates that there isa correlation between the decrease in serumDHEA in HIV-1 infected men and progressionto AIDS. The association of other infectionswith Kaposi sarcoma could induce the fall inandrogens, as seen in human septic and ex-perimental endotoxin shock.2526

Studies on the relationship between the im-mune response and steroid hormones suggestthat androgens regulate the immune system,influencing lymphocyte proliferation and func-tion, and controlling the production oflymphokines.'618 An excess of androgensshould stimulate suppressor T cell function atthe expense of helper T cell function.162' Theadrenal androgens, DHEA and DHEA sul-phate, enhance the capacity of activated T cellsto produce interleukin-2 and y-inferferon, andreverse glucocorticoid induced inhibition ofthese important lymphokines. The high andro-gen levels observed in KS + patients, par-ticularly in early stages of the disease (with>500 CD4 cells/mm3), may affect the immunesystem by inducing an abnormal cytokine pro-file and increased CD8 proliferatiion.

Various clinical and epidemiological datahave been associated with Kaposi sarcoma,for example, gender,'2 age,2 homosexuality orbisexuality,3 and immunosuppressive therapy.8Whatever the exact mechanism by which Ka-posi sarcoma develops, this report suggests thatthe clinical progression of Kaposi lesions isclosely associated with the hormonal status,notably the androgen levels, of the patients.Further studies on the relationship betweenandrogen concentrations, the cytokine profile,andT cell proliferation, activity, and function inHIV associated Kaposi sarcoma should indicatethe exact position of androgens in the causeand effect interactions leading to this disease.Hence a clear understanding of the hormonalenvironment may provide a sound basis for thedevelopment of new therapeutic strategies.

This work was supported by grants from UER Xavier Bichat(University Paris VII). The authors are grateful to Dr Beckerand Dr Elias (Centre de Transfusion Sanguine, H6pital Bichat,Paris) for the blood samples. We thank Dr Owen Parkes forcorrecting the manuscript and Mrs P Ho Kuo Chu for secretarialassistance.

1 Safrai B. Pathophysiology and epidemiology of epidemicKaposi's sarcoma. Semin Oncol 1987;14:7-12.

2 Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi'ssarcoma amongpatients with AIDS: a sexually transmittedinfection? Lan2cer 1990;335:123-8.

3 De Jarlais DC, Marmor M, Thomas P, Chamberland M,Zolla-Pazner S, Sencer DJ. Kaposi's sarcoma among fourdifferent AIDS risk groups. N EnglJ Med 1984;310: 1119.

4 Miles SA, Rezai AR, Salazar-Gonzales JF, Van der MeydenM, Stevens RH, Logan DM, et al. AIDS Kaposi's sarcoma-derived cells produce and respond to interleukin-6. ProcNail Acad Sci USA 1990;87:4068-72.

5 Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, LarssonL, Beaver B, et al. AIDS-Kaposi's sarcoma-derived cellsexpress cytokines with autocrine and paracrine growtheffects. Science 1989;243:223-6.

6 Gill PS, Loureiro C, Bernstein-Singer M, Rarick MU, Sat-tler F, Levin AM. Clinical effect of glucocorticoids onKaposi sacoma related to AIDS. Ann Intern Med 1989;11:937-40.

7 Bruet A, Mahe A, Sei JF, Mathe C, Felsenheld C, Le-chevalier L, et al. Sarcome de Kaposi compliquant unecorticotherapie au long cours pour asthme severe. RevMed Interne 1990;11:322-4.

8 Harwood A, Osoba D, Hofstader S, Golgstein MB, CardellaCJ, Holecek MJ, et al. Kaposi's sarcoma in recipients ofrenal transplants. Am J Med 1979;67:759-65.

9 Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G. TheHIV tat gene induces dermal lesions resembling Kaposi'ssarcoma in transgenic mice. Nature 1988;335:606-1 1.

10 Membreno L, Irony I, Dere W, Klein R, Biglieri EG, CobbE. Adrenocortical function in acquired immunodeficiencysyndrome. Jf Clin Endocrinol Metab 1987;65:482-7.

11 Christeff N, Michon C, Goertz G, Hassid J, Matheron S,Girard JP, et al. Abnormal free fatty acids and cortisolconcentrations in the serum ofAIDS patients. EurJCancerClin Oncol 1988;24:1179-83.

12 Croxson TS, Chapman WE, Miller LK, Levit CD, SenieR, Zummoff B. Changes in the hypothalamic-pituitary-gonadal axis in human immunodeficiency virus-infectedhomosexual men. J Clin Endocrinol Metab 1989;68:317-21.

13 VilletteJM, Bourin P, Doinel C, Mansour I, Fiet J, Boudou P,et al. Circadian variations in plasma levels ofhypophyseal,adrenocortical and testicular hormones in men infectedwith human immunodeficiency virus. J Clin EndocrinolMetab 1990;70:572-7.

14 Christeff N, Gharakhanian S, Thobie N, Rozenbaum WNunez EA. Evidence for changes in adrenal and testicularsteroids during HIV infection. JAIDS 1992;5:841-6.

15 Jacobson MA, Fusaro RE, GalmariniM, LangW. Decreasedserum dehydroepiandrosterone is associated with an in-creased progression of human immunodeficiency virusinfection in men with CD4 cell counts of 200-499. 7 InfectDis 1991;164:864-8.

16 Araneo BA, Dowell T, Diegel M, Daynes RA. Di-hydrotestosterone exerts a depressive influence on theproduction of interleukin-4 (ILA4), IL-5, and y-interferon,but not IL-2 by activated murine T cell. Am Soc Hematol1991;78:688-99.

17 Grossman CJ. Regulation of the immune system by sexsteroids. Endocrine Rev 1984;5:435-55.

18 Daynes RA, Dudley DJ, Araneo BA. Regulation ofmurine lymphokine production in vivo II. Dehydro-epiandrosterone is a natural enhancer of interleukin 2synthesis by helper T cells. EurJ Immunol 1990;20:793-802.

19 Clerici M, Hakim FT, Venzon DJ, Blatt S, Hendrix CW,Wynn TA, et al. Changes in interleukin-2 and interleukin-4 production in asymptomatic human immunodeficiencyvirus-seropositive individuals. J7 Clin Invest 1993;91:759-65.

20 Araneo BA, Woods ML, Daynes RA. Reversal of the im-munosenescent phenotype by dehydroepiandrosterone:hormone treatment provides an adjuvant effect on theimmunization of aged mice with recombinant hepatitis Bsurface antigen. J Infect Dis 1993;167:834-40.

21 Lehmann D, Siebold K, Emmons LR, Muller HJ. An-drogens inhibit proliferation of human peripheral bloodlymphocytes in vitro. Clin Immunol Immunopathol 1988;46:122-8.

22 Weinstein Y, Bercovich Z. Testosterone effect on bonemarrow, thymus and suppressor T cells in the(NZB x NZW)F1 mice: its relevance to autoimmunity. JImmunol 1991;126:998-1002.

23 Cohn DA. Sensitivity to androgen. A possible factor in sexdifferences in the immune response. Clin Exp Immunol1979;38:218-27.

24 Mulder JW, Frissen J, Krijnen P, Endert E, de Wolf F,Goudsmit J, et al. Dehydroepiandrosterone as predictorfor progression to AIDS in asymptomatic human im-munodeficiency virus-infected men. l Infect Dis 1992;165:413-8.

25 Christeff N, Benassayag C, Carli-Vielle C, Carli A, NunezEA. Elevated oestrogen and reduced testosterone levelsin the serum of male septic shock patients. Y SteroidBiochem 1988;29:435-40.

26 Christeff N, Auclair MC, Benassayag C, Carli A, NunezEA. Endotoxin-induced changes in sex steroid hormonelevels in male rats. J Steroid Biochen 1987;26:61-71.

518

on May 20, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.48.6.513 on 1 June 1995. Dow

nloaded from