{"paper_id":"22515543-c574-4359-9263-b09c78892130","body_text":"1 \n \n \nSex hormone-binding globulin, testosterone and type 2 diabetes risk in middle-aged African women: 1 \nexploring the impact of HIV and menopause 2 \n 3 \nJulia H. Goed ecke 1,2,3 , Clement Nyuyki Ku fe 2, 4 , Maphoko Masemola 2 , Mamosilo Lic haba 5 , Ikanyeng D. 4 \nSeipone 1 , Amy E Mendh am 2,6,7 , Hylton Gibson 8 , James Hawley 9 , David M. Selva 10 , I tai Magodo ro 11 , Andr e 5 \nPascal Kengne 12 , Tinashe Chikowore 2 , Ni gel J. Crowthe r 13 , Shane A Norris 2,14 , Fred rik Karpe 15,16 , Tommy  6 \nOlsson 3 , Karl-Heinz St orbeck 8 ,  Lisa K. Micklesfield 2   7 \n 8 \nAffiliations:  9 \n1 Biomedical Resea rch and Inn ovation Pla tform, South African Medic al Resea rch Council, Cape Town, 10 \nSouth Africa  11 \n2 South African Medica l Resea rch Council/WITS Developmental Pa thways for Heal th Rese arch Unit 12 \n(DPHRU), Departmen t of Paediat rics, Fac ulty of Health Scienc es, Universi ty of the Witwat ersra nd, 13 \nJohann esburg, Sou th Africa  14 \n3 Department of Public Heal th and Clinica l Medicine, M edicine, Um eå Universi ty, Umeå, Swede n.  15 \n4 Department of An aesth esiology, School  of Clinical Medicine, Faculty of Heal th Sciences, Universi ty of 16 \nthe Wi twate rsrand , Joh annesbu rg, South  Africa.  17 \n5  Department of Ex ercise Scienc e and Sp orts Medicin e, Facul ty of Health Scienc es , University of the 18 \nWitwat ersra nd, Jo hannesbu rg, Sout h Afr ica 19 \n6 Riverland Malle e Coorong Local Heal th Netwo rk, South A ustr alia Heal th, B erri , South Aus tralia , 20 \nAustrali a  21 \n7 Health th rough Physical Activity, Lifestyle and Spor t Rese arch Cent re (HPALS), FIMS Inte rna tional 22 \nCollaborati ng Centre of Spo rts Me dicine,  Division of Physiological Sciences, Depar tment of 23 \nHuman Biology, Faculty of Heal th Scienc es, University of Cape Town  24 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n \n2 \n \n \n8 Department of Bioch emistry, St ellen bos ch University, Stell enbosch, So uth Africa  25 \n9  Department of Clinical Biochemis try, U niversity Hospital of Sou th Manch este r, Manchest er, Uni ted 26 \nKingdom 27 \n10 Diabetes and Me tabolism Depar tmen t,  Vall d'Hebron R esea rch Insti tut e, Ba rcel ona, Spain  28 \n11 Department of Medicin e, Universi ty of Cape Town, Cape Town, South Africa  29 \n12 Non-Communicable Diseases Research  Unit, Sou th African Me dical Rese arch Co uncil, Cape Town, 30 \nSouth Africa  31 \n13  Department of Chemical Pathology, N a tional He alth Labo rat ory Service and Uni versity of the 32 \nWitwat ersra nd Faculty of Heal th Science s, Johann esburg, Sou th Africa.  33 \n14  School of Human Development and He alth, Unive rsity of the Sou thampt on, UK  34 \n15 Oxford Centre for Diabet es, Endocrinol ogy and Metab olism, U niversity of Oxfo r d, Oxford , UK and  35 \n16 National Ins titu te for He alth R esea rch, Oxford Biom edical Res earch Cen tre, Oxf ord Radcliffe Hospitals 36 \nTrust, OCDEM, Churchill Hospital , Oxfor d , UK   37 \n 38 \nCorrespondence: Julia H. Goedecke  39 \nBiomedical Res earch and Innovati on Plat form, South African M edical Res earch Co uncil 40 \nFrancie van Zijl Drive, Parow Valley 41 \n7505, Cape Town, South Africa  42 \nEmail: Julia.go edecke@mrc. ac.za  43 \nPhone: +27 (021) 9380862  44 \n 45 \nRunning head : SHBG's Protective Effects on T2D Risk in HIV  46 \nWord count : 3459 words 47 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n3 \n \n \nKeywords: Sex hormo ne-binding globuli n, androgens , to tal t estost eron e, fre e tes toste rone , oes trogen , 48 \nHIV, postmeno pausal, p remeno pausal, A frica  49 \n50 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n4 \n \n \nAbstract  51 \nObjectives:  Sex hormone-binding globuli n (SHBG) and testos te rone a re differen ti ally associated with 52 \ntype 2 diabe tes (T2D) risk.  We investigat ed whethe r th ese associa tions differ by HIV and menopausal 53 \nstatus in Black Sou th African women livin g with (WLWH) and without HIV (WLWOH).   54 \nDesign: Cross-sectional obse rvation al.   55 \nMethods : Eighty one prem enopausa l (57 WLWOH, 24 WLWH) and 280 postmen o pausal (236 WLWOH, 56 \n44 WLWH) women from the Middle-Age d Soweto Cohor t (MASC) completed th e following measures:  57 \ncirculating SHBG and sex ho rmones, bod y composition (dual energy x-ray ab sor pt iometry), oral glucose 58 \ntoler ance t est t o estima te insulin sensi tivity (Matsuda inde x), secre tion (insulinog enic index , IG I) and 59 \nclearance , and be ta-cell function (disposi tion inde x, DI). Dysglycaemia was defined as eithe r impaired 60 \nfasting or postpr andial glucose o r T2D.  61 \nResults : SHB G was higher and tot al and free t estos ter one wer e lower in pos tmen opausal WLWH t han 62 \nWLWOH (all p< 0.023). I rresp ective of HI V serostat us, SHBG was posi tively associated with M atsuda 63 \nindex, insulin cle aranc e and DI and invers ely with HOMA-IR (all p<0 .011). The asso ciation be tween SH BG 64 \nand Matsud a inde x was stronger in p rem enopausal than pos tmenop ausal women  (p=0.043 for 65 \ninter action). Fr ee t estos ter one (and no t t otal t estos ter one) was only negatively as sociated with bas al 66 \ninsulin clearanc e (p=0.021), and positivel y associated with HO MA-IR in pr emenop ausal and not p ost-67 \nmenopausal women (p=0.015 for in ter ac tion).  68 \nConclusions : We show for the first time t hat midlife African WLWH have high er S HBG and lowe r to tal 69 \nand free t estos ter one th an WLW OH, which correspond ed to their high er be ta-cell  function, suggesting a 70 \nputative p rot ective effect of SHB G on T2D risk in WLWH.  71 \n 72 \n  73 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n5 \n \n \nSignificance statement:  74 \nThis study in midlife Black African women suggest that high er sex h ormone bin di ng protein (SHB G) and 75 \nlower free t estos te rone in women living with HIV (WLWH) may be associated wit h reduced risk of type 2 76 \ndiabet es (T2D) compared to women living without HIV. Fur the r, this study pr ovides a puta tive 77 \nmechanism underlying the low er preval e nce of T2D in WLWH and obesity compar ed to women living 78 \nwith obesity but with out HIV . However, l ongitudinal stu dies ar e requi red to unde r stand th e clinical 79 \nimplications of thes e findings. 80 \n 81 \n 82 \n83 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n6 \n \n \nIntroduction 84 \nType 2 diabetes (T2D) has reached epid e mic proportio ns globally and is associate d with obesity and 85 \nageing 1 . Sub-Sahar an Africa  (SSA) is the r egion with the high est projec ted r elat ive increase in T2D (129% 86 \nby 2045) 1 , with  South Africa (SA) 2  having the highest number of peopl e living with T2D in SSA 3 .  Midlife 87 \nSA women are dispr opor tiona tely affecte d by T2D 4 , with putative drive rs being HI V, the menopa usal 88 \ntransi tion, and the high pr evalence of obesity 5  6 . Hormonal changes em erge as a k ey factor connecti ng 89 \nthese h ealth chal lenges, with s tudies sug gesting tha t sex ho rmones play a critica l role in th e 90 \ndevelopmen t and progr ession of T2D 7-11 . 91 \n 92 \nThe menopausal transi tion is charac teris ed by an increase in the and rogen t o E2 ratio, which reflec ts the 93 \nsubstanti al decline in o estr ogen (E2) production and a slowe r rat e of decline in a ndrogen biosynth esis 9 . 94 \nHigher tes tost eron e in women has bee n associated with inc reas ed risk for T2D 7, 11-13 . However, the re is 95 \nevidence to suggest tha t the associ ation betwee n tes tost eron e and T2D risk may be driven (directly or 96 \nindirectly) by the effects of sex ho rmone binding globulin (SHBG) 7, 14 . Indeed, rec e nt Mend elian 97 \nrandomisati on studi es showed an indep e ndent associa tion betwee n SHBG a nd T2D 7, 8, 15 .  98 \n 99 \nGiven the impac t of SHBG and androge ns on the risk of T2D, it is important to inve stigate their p oten tial 100 \nindepend ent r oles in th e preval ence of d ysglycaemia among two high-risk groups; women living with 101 \nHIV (WLWH) and postmenopausal wome n. On aver age, SHB G decr eases over the menopausal p eriod 16 , 102 \nwith SHBG being significantly lower in po stmenopaus al compared to pr emenopa u sal women 17 . Results 103 \nfrom the Women ’s Int erag ency HIV study (WIHS) have shown that WLWH have lo wer E2 and tot al 104 \ntestos te rone, but higher SH BG compa red  to women living without HIV (WLWOH) 18-21 . However, this 105 \nstudy did not e xplor e the r ole of SHB G a nd androgens on insulin dynamics (i.e . insulin sensitivity, insulin 106 \nresponse a nd bet a-cell function), which is integral t o the d evelopmen t of T2D 22 . We rec ently showed 107 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n7 \n \n \nthat SHB G was associat ed with inciden t T2D, insulin sensitivity and bet a-cell functi on in a cohort of 108 \nmiddle-aged Black SA men withou t HIV 23 .  This may be because the alr eady el evate d SHBG levels in men 109 \nliving with HIV (MLWH) may have reache d a satura tion poin t, limiting furt her effe cts 23 . Since women 110 \nhave higher SHB G levels tha n men 24 , it is importan t to und erst and how eleva ted S HBG affects insulin 111 \ndynamics and T2D risk in WLWH. This is especially rel evant for African women w ho presen t with a 112 \nphenotyp e of low insulin sensitivity and hyperinsulina emia 25 . 113 \n 114 \nWe hypoth esised th at highe r SHBG an d lower to tal and fre e tes tost eron e in SA W LWH before and aft er 115 \nthe menop ause will be associa ted with f avourable insulin dynamics th at may pro tect agains t th e 116 \ndevelopmen t of T2D. Accordingly, the ai m of the study was to investigat e associa tions betw een 117 \nandrogen ho rmones, SH BG and T2D risk in pre- and post-meno pausal Black SA wo men living with and 118 \nwithout HIV.   119 \n 120 \nMethods  121 \nDesign, study population and setting. 122 \nRecruitm ent a nd da ta collec tion we re c onducted betwe en Janua ry 2017 and Au gust 2018 at the S out h  123 \nAfrican Medical Res earch Council/Wits Developmental Pat hways for Health Res earch Unit a t th e Chris  124 \nHani Baragwana th Hospit al in Soweto , J ohannesbu rg, South Africa . The sta rting  sample for this cross-125 \nsectional s tudy included women (n=50 1) selected from t he Middl e-Aged So weto Cohor t (MASC) 26 . 126 \nExclusion crit eria i ncluded using m enop ausal hormon e ther apy (n=7), hormon al  contrac eptives (n=30),  127 \nhad a hyster ectomy (n=47), had no HIV d ata (n=1) or blood sampl es (n=1), were p erimenop ausal (n=54), 128 \nresulting in  a final sampl e of 361 pa rtici pants. Th e final sampl e included  81 pre menopausal wome n (57  129 \nWLWOH, 24 WLWH), and 280 postm eno pausal women (236 WLWOH, 44 WLWH).  130 \n 131 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n8 \n \n \nThe study, conducte d in accordance wit h  the decla rati on of Helsinki, was approve d by the Human 132 \nResearch E thics Committee (HREC) (Medical) of the University of the Wi twat ersra nd (clearance 133 \ncertificat e No . M160604). Informed writ t en consent was obtaine d from all partici pants.  134 \n 135 \nTesting procedures  136 \nAdministered questionnaires 137 \nInte rviewer-administ er ed qu estionn aire s were cap tur ed on to REDCap (Version 14.6.7 , Vande rbil t  138 \nUniversity, 2024). Data collected includ e d age, housing density (number of people per room) and asset  139 \nindex (percen tage from a possible 1 2 assets), current med ication us e, smoking status (curren t  140 \nsmoker/non-smoker) and alcohol  consu mption (curr ently consum es/does n ot c onsume). M enopaus al  141 \nstatus was classified using the d at e of final menstr ual pe riod . Pre-menopa use w as defined as cu rren tly  142 \nhaving a regular menstrual cycle and post-menopause was defined as cessation of the menstrual cycle  143 \nfor > 12 months 27 .  144 \n 145 \nHIV testing and CD4 count 146 \nWomen wit hout  a previous  HIV posi tive diagnosis  complet ed a HIV  antibody t est (On e S tep  HIV–1/2 ,  147 \nGuangzhou  Wondfo  Biot ech, China).  In WLWH, venous  blood  was analysed  for  CD4 count using flow  148 \ncytometry (Beckman Coulte r, Be rea , CA, USA). The number of years since HIV dia gnosis, number of years  149 \non HIV tre atmen t and th e medica tion us ed were r ecorde d.  150 \n 151 \nBody composition  152 \nWeight and h eight wer e measu red using standar d techniq ues. Waist circumfer enc e was measured in the  153 \nmid–axilla ry line at the midpoin t betwe en the lower margin of the last palpabl e rib and the top of th e  154 \niliac cres t a t the  end  of no rmal expi r ation,  and  hip ci rcumference  was me asured  as the  grea tes t  155 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n9 \n \n \nprotrusi on of the but tocks 28 . Subto tal  fat mass (FM) and regional  fat distribu tio n were m easur ed usin g  156 \ndual en ergy x-ray abso rpti omet ry (DXA; Hologic Discovery-A  (S/N 86254), Be dford, M A, USA,  APEX  157 \nsoftware versi on 13.4 .2:3). Regional  fat distribut ion includ ed trunk a nd leg FM r eport ed rela tive (%) t o  158 \nFM 29 . Abdominal visceral (VAT) and subcutane ous adipose tissue (SAT) were esti mated 30 . Fa t mass inde x  159 \n(FMI) was calculated as FM (kg) divided by height squared (m 2 ). 160 \n 161 \nFasting venous blood and oral glucose tolerance test (OGTT) 162 \nAt ~0800 h and following an overnigh t fast (10–12 h), baseline venous blood was drawn for the 163 \ndete rminati on of HbA1c, glucose, insulin,  C-peptide, SHB G, follicle stimula ting hor mone (FSH), and 164 \nluteinizing ho rmone (LH), E2 and testos t erone conc ent ratio ns.  Participan ts th en completed a s tanda rd 165 \n120-minute OGTT. Af ter inges tion of glucose (75 g), venous blood samples (~5 mL)  were drawn at 30, 60, 166 \n90 and 120 minutes for the d et erminat io n of glucose, and insulin, and C-peptid e concentr atio ns. 167 \nParticipants with known diabet es (on medication) did not comple te the O GTT. Ho meostasis model 168 \nassessment of insulin resis tance (HOM A-IR) was calculated 31 . Basal insulin cle aran ce was estimate d 169 \nusing the ra tio of fasting C-peptide t o insulin 32  and peripher al insulin sensitivi ty was estimat ed using the 170 \nMatsuda Inde x 33 . Insulin resp onse and se cretion we re es timate d using the insulin ogenic index (I GI, 171 \n(∆Insulin 0-30 /∆Glucose 0-30 )) 34  and C-peptide index (∆C-pep tide 0-30 /∆Glucose 0-30 ) 35 , respectively . 172 \nDisposition index (DI), which is an estima te of bet a-cell function, was calculat ed (I GI/Ma tsuda inde x) 34 . 173 \nWorld He alth O rganiza tion (WHO) crit eri a were for th e classification of glucose to lerance s tatus 36 . The 174 \nparticipan ts were classified as n ormal glu cose tole rance (N GT), impaired glucose metabolism (IG M) 175 \nincluding those with impair ed fasting glu cose (IFG) and/or impaired glucos e tole r ance (IGT), or T2D 36 . 176 \nDysgly caemia was defined as the combin ation of I GM and T2D.  177 \n 178 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n10 \n \n \nBiochemical analysis 179 \nPlasma glucose was analysed on the Ra ndox RX Daytona Chemistry An alyzer us ing enzymatic method s  180 \n(Randox Labora tori es Ltd. , Londo n, UK).  Serum i nsulin an d C-peptid e was analy sed on the  Immulit e®  181 \n1000 Immunoassay Syst em (Siemens  Chemiluminescent  He althca re GmbH,  Henk estr,  G ermany). Hb A1c  182 \nlevels were me asured on whole blo o d samples using the D-10™ Hemoglo bin Analyzer (Bio-R ad  183 \nLaborat ories,  Inc. , CA, USA). S erum foll icle stimula ting hormo ne (FSH), lu teiniz ing hormone  (LH) and  184 \nSHBG we re a nalysed using ch emilumin escent micr opar ticle immuno assays (Ar chitect assays, Abb ott  185 \nLaborat ories, IL, USA) and albumin was analysed using colorimetric (Bromcresol Gre en) assay (Alinity c,  186 \nAbbot t Labora tori es, IL, US A). Endogeno us steroid ho rmones (E2 and to tal t estos teron e) were quan tifie d  187 \nby ultra-high perform ance liquid chr o matography t andem mass spect rome t ry (LCMS)  37, 38 . Free 188 \ntestos te rone was calcula ted 39 .  189 \n 190 \nStatistical Analysis  191 \nStatis tical analysis was performe d using STATA version 18 (StatCorp , College Sta ti on, Texas). The 192 \nShapiro –Wilk tes t was used to ass ess the  distributi on of continuous varia bles. Un adjusted 193 \nmean6i08±6i08st andard d eviation (SD), media n and (25 th  to 75 th  perc entil e), or count ( %) are present ed for 194 \nnormally distribu ted, skewe d or cat egori cal data, r espec tively. Withi n menopaus a l groups, differences 195 \nbetwee n WLWOH an d WLWH were asse ssed using unpaired t- tests , two-sample Wilcoxon r ank sum test 196 \nor Fisher’s e xac t tes t for normally distri buted, skewed a nd catego rical da ta, r espe ctively. Logistic (or 197 \nmultinomial logistic), linea r or quan tile r egressions wer e used to explo re th e over all effects of HIV and 198 \nmenopause in the combined sampl e, incl uding an HIV x menopausa l inte ractio n t erm. Ove rall group 199 \ndifferences in sex ho rmones as well as gl ycaemia and insulin param ete rs were adj usted for age . 200 \nAssociations betwee n androg ens and SH BG, and p revalen t dysglycaemia were e x plored using logistic 201 \nregression , adjusting for age and FM I. Da ta rep ort ed as odds ra tio (OR) (95% confi dence int erval (CI).  In 202 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n11 \n \n \nwomen living without T2D associations between SH BG, and to tal and fre e t estost erone wit h continuo us 203 \nglycaemic and insulin paramet ers, wer e explo red using quan tile r egression a t the  50 th  percen tile, 204 \nadjusting for age and FMI . Data r epor ted  as beta coefficient (β) (95% CI). In all logistic and quantil e 205 \nregressions we e xplor ed wheth er HIV or menopausal st atus al ter ed th ese re latio n ships by including 206 \ninter action t erms with se x hormon es in t he models sepa rat ely.  Age was included in all models to 207 \nexplo re th e effect of menopaus al sta tus independ ent of chron ological age. Fo r bo th the logis tic and 208 \nquantile regressi on models, ro bust Z-scores, calculat ed from th e m edian and scal ed median absolu te 209 \ndeviation (MAD), were de rived for SHB G,  total an d free t estos ter one and the glycaemic and insulin 210 \nmeasures t o facilitat e comparisons of th e magnitude of th e associati ons using a standa rdised measu re. 211 \nThe robust Z-scores rep rese nt th e numb er of MADs that a d ata p oint lies from th e median. The M ADs 212 \nwere scaled by a constan t facto r of 1.4826 so that th e robus t Z-scores are mor e di rectly comparabl e to a 213 \ntradi tional Z-score, with 1 r obust Z-score indicating a value ~1 SD from the medi an . As missing data was 214 \nminimal (<10%) and missing  at random (no differences be tween grou ps), pairwise dele tion was used 215 \nwhen handling missing data.  216 \n 217 \nResults  218 \nParticipant characteristics 219 \nCharacte ristics of particip ants st ratified by HIV and menopausal sta tus ar e described in Tab le 1. 220 \nPostmenopausal women we re old er tha n premenop ausal women, and wit hin th e postmeno pausal 221 \ngroup, WLWH wer e younger th an WLWO H. Socioeconomic st atus, cha ract erised by housing density and 222 \nasset inde x, did no t differ by HIV or men opausal group . Postmenopa usal women were less likely to drink 223 \nalcohol and smoke cigare tt es than p rem enopausal women . Dieta ry intake and p h ysical activity did not 224 \ndiffer between H IV and menopa usal gro ups (data not shown). A gre ate r prop orti on of postmenopa usal 225 \nwomen repor ted taking anti-hyper tensiv e medication comp ared to prem enopaus al women, while 226 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n12 \n \n \ndiabet es and lipid loweri ng medications did not differ by menopause o r HIV. In W LWH, 81% of women 227 \nwere taking an tire trovir al the rapy (ART), with the majori ty (73%)  using non-nucleoside revers e 228 \ntranscrip tase inhibito rs (NNRTIs) and this , togeth er with CD4 count, did no t differ b y menopausal group.  229 \n 230 \nDifferences in body composition  231 \nTotal body fatness (BMI o r body fat %) and body fat distribu tion (waist circumfer ence, t runk and leg fat 232 \nmass, VAT and SAT areas) betwe en th e menopausal and H IV groups are repo rte d in Table 1. The only 233 \ndifference be tween the groups was body  fat percen tage which was higher in post menopausal compa red 234 \nto prem enopausa l women. Wh en excludi ng participan ts with T2D, weight and FMI  were significantly 235 \nlower in WLWH th an WLWOH (p=0 .037 a nd 0.028, respec tively, dat a not shown).  236 \n 237 \nDifferences in SHBG and sex hormones  238 \nIn age-adjusted a nalyses LH and FSH wer e higher and E2 was lower in postm enop ausal compared to 239 \npremenop ausal women (Table 2). While LH and FSH did not differ by HIV status, E 2 was lower in 240 \npostmenop ausal WLWH t han WLW OH (HIV x menopaus e inte ractio n; p<0 .001), while SHBG was higher 241 \nin postmenop ausal WLWH th an WLW OH . In contr ast, tot al and free tes toste ron e were lower in pr e- and 242 \npostmenop ausal women WLWH compa r ed to WLW OH. Tot al tes tost eron e was lo wer in postmenop ausal 243 \ncompared t o premen opausal women , bu t free t estos ter one and SH BG did no t differ by menopausal 244 \nstatus . The findings did not differ when e xcluding particip ants with T2D.  245 \n 246 \nDifferences in glycaemic and insulin parameters  247 \nOverall, 70.7% of par ticipan ts prese nted with NGT, 14.8% with I GM and 14.5% wit h T2D, and did not 248 \ndiffer by HIV or menopausal sta tus (Table 2). The overall preval ence of dysglycaemia was 29.2 (95% CI: 249 \n24.6-34.3)%, with 32% of WLWOH prese nting with dysglycaemia compared to 20 % of WLWH.    250 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n13 \n \n \n 251 \nDifferences in fasting parame ters wer e o nly evident when exclu ding those with T 2D (n=309). In 252 \npostmenop ausal women withou t T2D, th e IG I, C-peptide in dex a nd DI were highe r  in WLWH compared 253 \nto WLWOH .  254 \n 255 \nThe association between SHBG, and total and free testosterone with glycaemic and insulin parameters 256 \nIn the tot al sample each ~1SD increase in  SHBG was associate d with 40% lower od ds of dysgly caemia 257 \n(Table 3), with the associatio n being significant in WLWOH (OR (95% CI): 0.50 (0.3 5–0.71), p<0.001) but 258 \nnot in WLWH (OR (95%CI): 0.90 (0.62–1.31), p=0.592)(SHBG x HIV inte ractio n p=0 .055; Figure 1). The 259 \nassociation betwee n SHBG a nd dysglycaemia did not differ b y menopausal st atus .  260 \n 261 \nSHBG was positively associat ed with Ma t suda index , DI and basal insulin clea ranc e, and nega tively 262 \nassociated with fas ting glucose, insulin, a nd HOMA-IR , irr espective of HIV sta tus, a ge, and FMI (Table 3).  263 \nNotably, the associa tion betwe en SHBG and Matsud a inde x differed b y menopau sal status (p=0.043 for 264 \nSHBG x men opause , Figure 2A), with th e association st ronger in p remen opausal (standa rdised ß (95%CI): 265 \n0.46 (0.22-0.70) p<0.001) compared to p ostmenopa usal women (standa rdised ß (95%CI): 0.29 (0.16-266 \n0.43), p<0.001).  267 \n 268 \nTotal tes tost eron e was not associa ted wi th dysglycaemia or any glycaemic or insulin parame ters (Table 269 \n3). The association be tween fr ee t estos t erone and HOM A-IR was only signficiant in the pr emenopa usal 270 \nwomen (standardised ß (95%CI): 0.40 (0. 13-0.67), p=0.005) and not th e postmen opausal women 271 \n(standardised ß (95%CI):0.05 (-0.02 – 0.12), p=0.200). Free test oste rone was nega tively associated with 272 \nbasal insulin clear ance, ind epend ent of a ge, HIV status , and FMI .  273 \n 274 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n14 \n \n \nDiscussion 275 \nThis is the first study to r epor t sex ho rmones in Black African women at differ ent stages of the 276 \nmenopausal t ransi tion, e xplor e differenc es by HIV serosta tus, and t o investigat e h ow SHBG and 277 \ntestos te rone leve ls rela te t o T2D risk. We showed tha t SHBG was highe r in postm enopausal WLWH 278 \ncompared t o WLWOH . No tably, higher S HBG was associat ed with a T2D-protec tive pheno type, including 279 \nhigher insulin sensitivity, beta-cell functi on, and b asal insulin cle aranc e, as well as  lower fasting glucose, 280 \ninsulin, and HOM A-IR, r egardl ess of HIV status . In cont rast , to tal and fre e tes tost e rone wer e lower in 281 \nboth pr e- and postmen opausal WLWH th an WLWOH . Lower free t estos te rone wa s linked to higher basa l 282 \ninsulin clearanc e, and lower H OMA- IR in premenop ausal, bu t not pos t-menopa usal women. These 283 \nfindings support our hypot hesis tha t high er SHBG and lower fre e tes tost eron e in WLWH compared to 284 \nWLWOH may be associat ed with r educe d risk of T2D.  This  study also provides a putative mech anism 285 \nunderlying the lowe r preval ence of T2D in WLWH and obesi ty compared t o wome n living with obesity 286 \nbut withou t HIV 40 . However, longit udinal  studies are requi red t o unders tand t he c linical implications of 287 \nthe findings, par ticularly as prem enopau sal women transi tion int o post-menop au se.  288 \n 289 \nHigher SHBG l evels have bee n consisten t ly and causally associated with lowe r risk for T2D in both men 290 \nand women 7, 8, 12, 14-16, 23, 41, 42 . Accordingly, one may hypothesise tha t the high er SH BG in post-291 \nmenopausal WLWH may confer r educed risk for T2D compared to WLWOH . Inde e d, higher SHB G levels 292 \nin postmenop ausal WLWH wer e linked t o great er be ta-cell function compa red t o  WLWOH. Fur the r, 293 \nSHBG was also associat ed with lowe r risk of T2D-related trai ts, such as lower fasti ng glucose and insulin, 294 \nand higher insulin sensi tivity, with th ese associations bei ng independ ent of fat ma ss and unaffected by 295 \nHIV serosta tus. Simila r alt era tions in SHB G and andr ogens have be en obse rved in middle-aged African 296 \nmen, along with significant associat ions betwee n SHBG , insulin dynamics and incident T2D. However, 297 \nthese associa tions wer e only significant in men without HIV and no t th ose living with HIV 23 . The reasons 298 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n15 \n \n \nfor these differ ences ar e unclear , but t he  association be tween SH BG and T2D risk is stronger in women, 299 \nsuggesting sexually dimorphic effects 13 . F urthe r, rec ent r esults from th e KORA st u dy report ed higher 300 \nSHGB levels in women compar ed to me n  contribut ed to s ex differenc es in fasting glucose and incident 301 \nT2D 24 .  302 \n 303 \nHigher SHBG l evels in postmen opausal WLWH than WLW OH is consisten t with p revious studies 18-20 .  304 \nHigher SHBG h as previously been link ed t o chronic viral infections including HIV, e specially in women 305 \nand those with H IV RNA >400 copi es/mL 20 . The regulati on of SHBG is comple x, but  proinflammatory 306 \ncytokines like inte rleukin-1 and tumou r n ecrosis factor alph a reduc e SHBG mR NA expr ession by 307 \ndownregulati ng its main transc ription fac tor, h epat ocyte nucle ar factor 4 (reviewe d previously 43, 44 ). We 308 \ncan only speculate that elevat ed SHB G le vels in WLWH may be a compensato ry mechanism to pro tec t 309 \nagainst systemic inflammation associa te d with HIV 20 . SHBG is also regula ted by h epatic de novo  310 \nlipogenesis, adip onecti n and sex h ormon es 43-45 . Mendelian ran domisatio n studies have shown that 311 \nhigher SHBG l evels are associ ate d with lo wer free t estos ter one, bu t not tot al tes t oster one levels 7 . 312 \nIndee d, our stu dy shows that higher SH B G in the pos tmenop ausal WLWH was acc ompanied with lowe r 313 \nfree tes tost eron e concen tra tions, which corrobo rat es the findings of WIHS 18 . Whi le E2 is positively 314 \nassociated with SH BG 44 , we showed lowe r E2 levels in postmenopa usal WLWH co mpared to WLWOH, 315 \nsuggesting that H IV and/or ARVs may directly increase SH BG . Since most of th e women were bei ng 316 \ntrea ted with NNRT I’s it is difficult to diffe renti ate the effect of HIV from thos e of A RVs on endocrine 317 \nfunction. Fur ther rese arch is need ed to bett er und ersta nd the m echanisms underl ying this endocrine 318 \ndysregulation in WLW H over th e menop ausal tra nsition .  319 \n 320 \nNone thel ess, our study showed that the association betwee n SHBG a nd preval ent  dysglycaemia was 321 \nonly significant in WLWOH. W e postul ate  that th e lower tot al and free test oste ron e concentr atio ns in 322 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n16 \n \n \nWLWH may confer reduced risk for T2D, with higher levels of SHBG h aving no additional be nefit . In 323 \ncontras t, in WLWOH who p resen t with hi gher to tal and fre e tes tost eron e levels co mpared to WLWH, 324 \nhigher SHBG may re duce T2D risk by low ering the bi oavailabili ty of testos ter one. This is supported by 325 \nour findings, which showed that the asso ciation be tween SH BG and insulin s ensiti vity was stronger in 326 \npremenop ausal women, who have highe r tot al tes tost eron e levels compar ed to p ostmenopa usal 327 \nwomen (Figure 2A). A recen t Mend elian randomisati on study showed a causal lin k between t he 328 \nbioavailability of tes tost eron e and incr ea sed risk of T2D in women 7 . Similar to our study and oth ers 14, 16, 329 \n21, 42, 46 , the Mendeli an rand omisation s tu dy showed no association be twee n tot al testos te rone an d T2D 330 \nrisk, suggesting that the associa tions be t ween SHBG a nd bioavailabl e tes tost eron e is likely driven by 331 \nSHBG, ei the r direc tly or in combinatio n with free t estost eron e 7 . The e xact mech anisms by which SHBG 332 \nmay influence T2D risk are not fully understood . However, SH BG has been shown to act as a he pat okine, 333 \nmediating th e link betwe en int rahep atic lipids, insulin sensitivity and T2D status, with stronge r effects in 334 \nwomen than men 47, 48 . Further , SHBG bin ds to GPRC6A, stimula ting insulin rel ease  in a dose depend ent 335 \nmanner 49 , providing a pot enti al mechani sm for the observed r ela tionships be twe en SHBG an d bet a-cell 336 \nfunction.  337 \n 338 \nOur study showed th at fre e tes tost eron e  was associated with lower basal insulin clearanc e and higher 339 \nHOMA-IR , with this associa tion only signi ficant in premeno pausal women . This could be due to the 340 \nlower to tal andr ogen load af ter men opa use. These r esults a re suppor ted by ot he r studies showing tha t 341 \nhigher free test oste rone in pr emeno pau sal women is associated with r educed h e patic insulin clear ance 342 \nand lower insulin sensi tivity, but no t wit h obesity-rela ted insulin s ecre tion 50 . Ot h er studi es also suggest 343 \nthat the r elati onship be tween fre e tes tos teron e and incide nt T2D is mediated by a diposity and insulin 344 \nresistanc e 42 . Taken toge the r, our r esults i ndicated that high er SHB G, couple d with lower free 345 \ntestos te rone leve ls may confer reduced r isk for T2D in WLWH than WLWOH.  346 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n17 \n \n \n 347 \nDespite significantly lower E2 in the pos t menopausal women, n o differences in body composition or T2D 348 \nrisk were observed b etwe en th e menopa usal groups, findings contra ry to oth ers 51 . However, o thers 349 \nhave shown that Bl ack African women may not gain as much abdominal adiposi ty across the menop ause 350 \ntransi tion due to both high er abd ominal adiposity and smalle r fluctuati ons in sex steroid h ormones in 351 \nthe years l eading up to men opause 52 . I n our study, th e majority (67.1%) of the women were living with 352 \nobesity, limiting th e pot enti al for furth er increases in body fat and rela ted chang e s in glycaemic and 353 \ninsulin parame ters . A compar ative study conducted in SSA reveal ed no significant differences in 354 \nanthro pomet ric and cardiom eta bolic risk factors betwe en pre- and p ost-menop au sal women from South 355 \nand East Africa who pres ent ed with a hig h prevalence of obesity (32-66%) 5, 53 . In contras t, women from 356 \nWest Africa , with a lower pr evalence of obesity (1-5%), showed distinct variations in cardiomet abolic 357 \nrisk between men opausal s tages 5 .   358 \n 359 \nStrengths and limitations 360 \nThis study comprehensively pheno types Black African women, including OGTT-de rived measures of 361 \nglycaemic and insulin paramet ers, as wel l as detaile d charact erisa tion of sex h orm ones measur ed using 362 \nLCMS. The study is however limited by th e cross-sectional d esign tha t preclud es inferences abou t 363 \ncausality. Fr ee t estos ter one was not me a sured, and we r elied on calcul ate d free t estost eron e 39 . In 364 \naddition , the r ela tively small sample of premenop ausal women and WLWH limi ts our analysis and 365 \ninterp re tati on of the r esults. Fu rth er, se x  hormone measu remen ts in preme nopau sal women were not 366 \ntaken a t a set time during th e menst rual cycle, however we do not bel ieve th at th e phase of menstr ual 367 \ncycle influenced the and rogen r esults as differences in thes e hormon es by HIV ser ostatus we re 368 \nconsistent a t each me nopausal s tage.  369 \n 370 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n18 \n \n \nConclusion 371 \nFor the firs t time, we show th at midlife B lack African WLWH have higher SHB G, an d lower to tal and fre e 372 \ntestos te rone conce ntr ations compa red t o WLWOH, which may confer reduc ed ris k for T2D. These 373 \nfindings offer valuable insights into th e complex r elati onships betw een and rogeni c hormones, HIV, 374 \nmenopause , and T2D risk. However, long itudinal stud ies ar e requi red t o unders ta nd the clinical 375 \nimplications of thes e associatio ns.  376 \n 377 \nConflict of interest: The authors decla re no conflict of interes t.   378 \n 379 \nFunding: 380 \nThis study was jointly funded by the S outh African Medical Rese arch Council (SAMRC) via the Sout h  381 \nAfrican Na tion al Depar tmen t of He alth,  t he UK Me dical Res earch Council  (via the Newton Fund) and th e  382 \nGSK Africa Non-Communicable Disease Open Lab (grant projec t number ES/N01 3891/1) and the South  383 \nAfrican Nati onal Rese arch Founda tion (grant numbe r UID:99108). The AWI-G en Collaborative Cen tre is  384 \nfunded by the Na tional H uman G en ome Rese arch I nstitu te (NH GR I), the  Nati onal I nstitu te of  385 \nEnvironmental H ealt h Sciences (NIEHS), the Office of AIDS r esea rch (OAR) and t he Na tional Insti tut e of  386 \nDiabetes  and  Digestive and Kidn ey Dise ases (NIDDK), of th e Nat ional  Inst itu tes  of He alth  (NIH) und er  387 \naward numbe r U54H G006938, as p art  o f the H3Afric a Consor tium, and  by th e Departmen t of Sci ence  388 \nand Innovati on, Sout h Africa, award nu mber DST/CON 0056/2014. IDS is  also s upport ed by the Unit e d  389 \nStat es Na tion al Ins titu tes of He alth (N I H)/Fogarty Inte rna tional Cen tr e (FIC) grant N o. D43TW010937  390 \n(University of Pittsbu rgh HIV Como rbidi ties R esea rch Training  Program in  Sou th  Africa – Pitt-HRTP-SA,  391 \nPIs: Prof. Jean B. Nachega and Prof. S oraya Seed at) and th e Departm ent of Science and Innova tio n  392 \n(DSI)/National Res earch  Found ation  (NR F) Professional Developme nt Pr ogramme. JHG , APL and  IDS ar e  393 \nsupport ed by the SAMRC. The con ten ts of this publication are sol ely the resp o nsibility of the autho rs  394 \nand do not r epr esent the official views of the sponsors .  395 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n19 \n \n \n 396 \nAcknowledgements:  397 \nWe a re gr at eful to  th e pa rticipan ts of th e Middl e-Aged S oweto  Cohort  and  the  r esearch  staff who wer e  398 \ninvolved in this study.  399 \n 400 \nData availability : Data is available from a uthors upon reason able r eques t  401 \n 402 \n . 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Ra c ia l dif f erenc es in body \nco mpositio n and c ar diomet abol ic ris k du ring  the meno p ause  t r a nsiti on: a pr ospe c tive , obs er v a tional  coh ort \nst u dy .  A m  J  O b s te t Gyn e c o l  2019.  \n53. Jaf f  NG ,  Norris  SA , Sn yman T , Toman  M & C row t he r  N J . Body  com position  in the S t udy  of  Women E nt e r i ng \nand in Endoc rine Tran si tion ( S W E ET) : A pers pectiv e of  Af rica n women  who ha ve a  high p r ev alen ce of  ob esi ty  \nand H IV  i nf ection. M e ta bolis m 2015  64  103\n1- 1041. \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n23 \n \n \nTable 1.  Pa r t ic ipant c ha ract eri stic s  \n Pr e men opausa l  P ostm eno pau s a l  P V al u e  \n WLW OH  (n = 5 7 ) WLWH  (n= 24 ) P valu e  WL WOH  (n=2 36) WL WH (n=4 4 ) P  V alue  HI V  M e n o  H I V  x  \nMe n o  \nSo ci od em ogr aph i c and  l i fe s ty l e  f ac t o r s  \nA ge ( y ears)  48 ( 4 6 - 5 1)  46 ( 45- 4 9) 0 . 0 65 58 ( 5 4 - 6 1)  5 4 ( 5 0- 59)  <0 . 001  0. 2 0 8  <0 .00 1 0. 4 8 4  \nHo usi ng  de nsit y  ( pe ople  per \nroo m )  \n1 .2  (0 .9 -1 .5 ) 1 .0  (0 .8 -1 .3 ) 0 .271  1 .2  (0 .8 -1 .6 ) 1 . 1  (0 . 6 -1 .6 ) 0 . 44 7  0 .277 0 .7 6 7 0 .36 8  \nAss e t  i ndex ( %  of 1 2 )  7 5 . 0 ( 66. 7-83. 3)  75. 0 ( 5 8. 3 -9 1. 6 )  0 . 6 64 75 . 0 ( 58. 3-83. 3)  75.0 ( 5 8 . 3-8 3 . 3)  0.8 7 1  >0 . 9 99  > 0. 9 99  > 0. 9 99  \nCurrent sm o k e r ,  n  ( %) 7 (12 .3 ) 0  0 .07 9  1 0  (4 .2 ) 2  (4 .5 ) 0 . 93 1 0 .93 1  0 .026   \nCurrent alco hol  co ns ume r , n (% )  24 ( 4 2 . 1)  1 3 ( 54. 2)  0 . 3 20 53 ( 2 2 . 5)  1 1  ( 2 5.0)  0.712  0 . 3 21 0 .003  0. 5 78  \nMe d ic atio n us e ,  n(% ) \nDiab ete s m e dicat i o n s  4 ( 7.0)  1 ( 4 . 2)   25 ( 1 0 . 6)  6 ( 1 3.6)   0 . 6 30 0 . 4 21 0 . 5 01 \nHy p ert e nsi on medicat ion s   10 ( 1 7. 5)  5 ( 21. 7 )   99 ( 4 1 . 9)  2 2  ( 5 0.0)   0. 6 6 4  0 .001  0. 9 4 2  \nL i p id  me d i c at io n s  3  (5 . 3 ) 1  (4 .4 )  2 1  (8 .9 ) 2  (4 .5 )  0 .86 5  0 .371  0 .7 1 0  \nHIV i n f or m at ion           \nEs ta b li sh e d  on  A R T, n (%)   1 8 ( 75. 0)    3 7  ( 8 4.1)    0 . 2 21  \nPIs, n (%)   0   1  ( 2. 3 )    0 . 4 66  \nNNR TIs,  n ( %)   1 3 ( 7 2. 2)    2 7  ( 73.0)    0 . 721  \nCD 4 c oun t (cel l / mm 3 )  4 74 ( 36 1- 619)    6 1 1 ( 4 1 6 - 85 8)    0 . 1 28  \nCD 4 WC C (ce l l/m m 3 )  5 ( 4 - 6)    5  ( 4- 7)   0 . 8 62  \nC D4  ly m poh cy te s  ( ce l l / mm 3 )  33 ( 21- 4 0)   3 4 ( 2 3- 40)    0 . 4 63  \nB ody  co m pos itio n  \nH e i gh t ( c m ) 158 . 1 (15 4 . 1 - 162 . 5 ) 157. 1 (1 53 . 0 -160 .2 ) 0 .26 7  158 . 2  ( 1 54.4-1 6 2.0)  15 6.3 ( 1 53.3- 16 0. 4 )  0.1 08  0 . 5 06 0 . 9 15 0 . 8 44 \nWeig ht  ( k g )  8 1 . 8 ( 77. 0-97. 4)  75. 6 ( 6 3. 7 -8 8. 3 )  0 . 0 65 81. 3 ( 7 2. 4 – 9 5 .1 )  79.9 ( 6 4 . 3-9 2 . 8)  0.1 06  0 . 755 0 . 8 7 3 0 . 8 46 \nBMI ( k g / m 2 )  3 3 . 3 ( 29. 4-37. 7)  31. 6 ( 2 6. 8 -3 5. 7 )  0 . 1 21 3 3 . 1 ( 29. 1-37. 8)  3 3.1 ( 2 6 . 6-3 6 . 5)  0.1 84  0 . 1 73 0 . 8 68 0 . 2 71 \nWais t circu mfe re nce (c m)  9 5.5 ( 8 9 . 6-10 3. 0 )  9 5 . 5 ( 77. 5-10 6.0)  0 . 4 32 9 6.5 ( 8 9 . 6-10 5. 6 )  9 6. 6  ( 8 5.1-1 03. 8)  0.3 84  0 . 8 06 0 . 6 86 0 . 9 73 \nSub to tal bo dy f a t  m a s s  (%)  4 3 . 8 ( 41. 8-46. 7)  43. 8 ( 3 9. 0 -4 5 . 6 )  0 . 3 64 4 6 . 2 ( 42. 2-49. 0)  4 4.3 ( 3 8 . 6-4 9 . 3)  0.1 70  0 . 9 90 0 .014  0. 3 3 5  \nFMI (kg/m 2 )  1 4 . 2±3. 5  12. 5±3. 7 0 . 0 59 1 4 . 5±4. 3  1 3.5± 4 . 8  0 . 15 1 0. 1 0 2  0. 6 8 3  0. 5 70  \nLeg f at  mass  (% )  4 4 . 7±7. 1  43. 9±7. 2 0 . 6 81 4 4 . 2±6. 4  4 4.1± 7 . 2  0 . 972 0. 8 0 3  0. 77 5  0. 9 5 9  \nTru nk f a t  m a s s  (%)  4 2 . 7±6. 3  42. 8±6. 1 0 . 9 24 4 3 . 2±6. 0  4 3.2± 6 . 3  0 . 973 0. 8 6 9  0. 9 9 7 0. 70 3  \nVA T (c m 2 ) 10 2  (60 -12 8 ) 77 (59 -108 ) 0 .22 3  10 8  (7 8 -14 0 ) 109  (64 -1 3 2) 0 . 38 5 0 .12 8  0 .51 8  0 .19 6  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n24 \n \n \nSAT  (cm 2 )  4 6 4  ( 3 72- 51 5 )  4 13 ( 30 9- 535)  0 . 2 74 4 8 3  ( 3 92- 58 2 )  4 4 3 ( 2 9 6 - 58 0)  0.1 58  0 . 2 22 0 . 5 29 0 . 7 23 \nVA T / SA T  0. 21 ( 0 . 1 6-0 . 2 6)  0 . 2 0 ( 0. 1 5 -0. 2 5 )  0 . 6 28 0. 22 ( 0 . 1 8-0 . 2 7)  0. 22 ( 0.1 8-0.3 0)  0.8 14  0 . 9 12 0 . 2 77 0 . 8 49 \nValue s  a r e  medi an (inter q uar til e rang e) or  mean ± s t anda r d devia ti on. WLWO H, women li ving without HIV; WLWH, wome n livi ng wi th HIV; PI, pr ot ea se inhi bi tors , NN RT I s , \nnon-nuc l eoside r ev erse transcripta s e inhibitors; WCC, white ce ll count.   BMI, body  mass  i ndex, W HR, wai st-hi p-ratio; FFS TM, fa t - fre e s oft ti s s ue  ma ss; F MI , fa t ma s s  index ; \nV A T , vis c e r a l ad ip os e  tis s ue ; SA T , s u b c uta n eo us  ad ipo se  tis s u e.  \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n25 \n \n \n \nTable 2.  Dif fer enc e s  i n SHBG, s e x hormones a nd fa sting  and OGTT-derive d par amete rs betwe e n menopausal  and HI V groups.  \n Pr e men opausa l  P o s tm e n o pa us al  P  V alue  a d just ed  f o r  ag e  \n WLWOH  ( n= 52)  WL WH (n = 2 1)  P \nva l u e  \nWL WOH  (n=2 25) WLWH  (n= 41 ) P v a lue  HI V  M e n o  H I V  x  \nMe n o  \nS e x hormo n e s  \nLH (IU/L ) 6. 7 ( 4. 0-1 4.5)  4 . 5 ( 3 . 1- 1 2 .0 )  0 . 2 75  2 1.8 ( 16. 0-29. 3)  22. 7  (1 7 . 3 -3 1. 1 )  0. 218  0 . 4 9 5  <0 .001  0. 4 4 8  \nF SH  (IU/L ) 1 1. 9  ( 6. 0 - 23. 6 )  8 . 3 ( 4 . 7- 1 8 .9 )  0 . 2 1 2  5 5.3 ( 40. 8-69. 3)  63. 8 (4 3. 8 -7 5. 3 )  0. 092  0 . 3 8 0  <0 .001  0. 1 2 8  \nE 2  ( p mo l/L )  1 98.0  ( 77 .5 - 5 6 0 . 5)  3 3 3. 0  ( 96.0- 48 3. 0 )  0 . 9 9 1  2 4 . 0 ( 15. 0-39. 0 )  8. 0 ( 4. 3- 19. 5)  <0. 00 1  < 0. 0 01  <0 . 0 0 1 <0 . 0 0 1 \nSH BG  ( n m o l / L ) 55. 4 ( 4 3.4-8 1.7)  6 4.2 ( 5 1 . 3-1 11. 3 )  0 . 1 7 6  5 0 . 6 ( 37. 8-65. 2 )  7 2 . 1 ( 54. 2-10 3. 0)  <0. 00 1  0 .32 6 0 .370  0 .18 0  \nT o ta l te s tos ter one ( nm ol/L) 0. 4 5  ( 0. 25-0 .56 )  0. 24 ( 0 . 1 8-0.3 4 )  0 . 0 0 8  0 .3 5  (0 .21 - 0 . 57) 0 .25  (0 .09 - 0. 48 ) 0 .0 23 0 .02 6 0 .038  0. 2 9 4  \nF r e e tes to ster o n e (p mol/L) 5. 4  ( 3. 5 - 6. 9)  2. 5 ( 1 . 3- 4.3)  0 . 0 12  4. 8 ( 2 . 5- 8.0)  2. 0 ( 1. 0- 3 . 6)  <0. 00 1  0 . 0 11  0. 9 0 7 0. 9 2 1  \nGl y c aem ic  stat us ,  n  ( % ) \nNGT  4 6 ( 8 0. 7 )  19 ( 8 6 . 4)  0 . 7 0 3  1 54 ( 65. 8)  34 ( 77. 3)  0. 0 6 5  Ref  Ref  Ref  \nIGM 5 ( 8. 8)  2 ( 9.1)  44 ( 1 8 . 8)  2 ( 4 . 5)  0 . 8 70  0 . 6 39 0 . 1 88 \nT 2D  6 ( 10. 5)  1 ( 4.5)  36 ( 1 5 . 4)  8 ( 1 8 . 2)  0 . 4 8 6  0 . 764 0 . 4 49 \nD ys g l ycaemia  1 1 (1 9. 3 )  3  ( 1 3.6)  0 . 5 5 5  80 ( 3 4 . 2)  10 ( 22. 7)  0. 136  0 . 7 1 1  0 . 6 03 0 . 8 61 \nFasti n g p ar a m e te rs  inc l ud i n g part i c ipa nts w ith T 2 D  \nn  57 2 2  2 3 2 4 4     \nHb A 1 c  (% A 1c)  5. 7  ( 5. 3 - 6. 3)  5 . 7 ( 5 . 3- 5.9)  0 . 5 6 9  6 . 0 ( 5 . 6- 6.6)  6. 1 ( 5. 7- 6 . 6)  0. 543  0 . 6 9 8  0 . 5 29 0 . 3 26 \nF as ti ng  gl u c os e ( m mo l/L )  5. 0  ( 4. 5 - 5. 5)  5 . 0 ( 4 . 7- 5.5)  0 . 5 7 7  5 . 0 ( 4 . 5- 5.7)  5. 2 ( 4. 5- 5 . 8)  0. 592  0 . 7 5 3  0 . 2 62 0 . 6 04 \nF as ti ng  i ns ul i n  ( mmol/L)  8. 5  ( 5. 2-1 4.0)  1 0 . 3 ( 6 . 3- 14 . 0)  0 . 6 9 7 9 . 0 ( 4 . 9- 1 4 .4 )  9 . 9 ( 5 . 6- 16.2 )  0. 497 0 . 3 9 2  0 . 6 27  0 . 756 \nF as ti ng  C- pe pti de  ( nm ol / L) 1. 6  ( 1. 3 - 2. 3)  1 . 8 ( 1 . 4- 2.2)  0 . 71 0  1 . 8 ( 1 . 3- 2.5)  1. 9 ( 1. 3- 2 . 7 )  0. 457 0 . 5 1 2  0 . 5 22 0 . 8 28 \nHOM A-I R  1. 7  ( 1. 2 - 3. 6)  2 . 3 ( 1 . 3- 3.4)  0 . 70 6  2 . 0 ( 1 . 1- 3.6)  2. 4 ( 1. 3- 4 . 2)  0. 430  0 . 2 5 7 0 . 8 43 0 . 706 \nBa s a l  ins u li n c l e ara n c e 0 . 2 0 ( 0. 15-0. 26)  0. 18 ( 0.1 6-0 . 2 7)  0 . 9 6 9  0. 20 ( 0.1 6-0 . 2 7)  0.2 0 (0. 1 5 -0. 2 7 )  0. 602  0 . 2 9 7  0 . 5 99 0 . 4 46 \nFasti n g a nd  OG TT - d eri ve d p ar a mete rs exc lu di ng pa rtici p a nts  w ith T 2D  \nn  51  2 2  1 9 9 3 7     \nHb A 1 c  (% A 1c)  5. 6  ( 5. 2 - 6. 1)  5 . 6 ( 5 . 3- 5.8)  0 . 77 5  6 . 0 ( 5 . 6- 6.3)  6. 1 ( 5. 6- 6 . 4)  0. 635  0 . 9 9 0  0 . 1 7 4 0 . 5 39 \nFa s t i n g  g l uc o s e  ( m m ol / L )  4. 8  ( 4. 4 - 5. 3)  5 . 0 ( 4 . 7- 5.4)  0 . 5 7 7  4 . 9 ( 4 . 4- 5.4)  5. 1 ( 4. 5- 5 . 6)  0. 492  0 . 4 8 1  0 . 4 85 0 . 6 38 \nF as ti ng  i ns ul i n  ( mmol/L)  8. 0  ( 5. 1-1 3.8)  1 0 . 2 ( 6 . 3- 13 . 4)  0 . 6 2 3  8 . 1 ( 4 . 7 - 1 3 .2 )  9 . 6 ( 5 . 4- 15.7)  0. 357 0 . 3 0 1  0 . 5 18 0 . 8 14 \nF as ti ng  C- pe pti de  ( nm ol / L) 1. 6  ( 1. 3 - 2. 3)  1 . 8 ( 1 . 4- 2.1)  0 . 6 9 6  1 . 7 ( 1 . 3- 2.3)  1. 7 ( 1. 3- 2 . 7)  0. 667  0 . 3 1 8  0 . 5 23 0 . 4 85 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n26 \n \n \nHOM A-I R  1. 7 ( 1. 1 - 3. 0)  2 . 3 ( 1 . 3- 2.8)  0 . 5 3 7  1 . 7  ( 1 . 0- 3.2)  2. 2 ( 1. 2- 3 . 4)  0. 354  0 . 2 0 9  0 . 6 60 0 . 8 94 \nBa s a l  ins u li n c l e ara n c e 0 . 2 1 ( 0. 15-0. 27)  0. 18 ( 0.1 6-0 . 2 7)  0 . 8 4 0  0. 21 ( 0.1 6-0 . 2 8)  0.2 1 (0. 1 6 -0. 2 6 )  0. 390  0 . 4 7 7  0 . 5 33 0 . 6 96 \nMa t s u da in dex  5. 7 ( 3. 1 - 8. 1)  4 . 4 ( 3 . 0- 8.4)  0 . 7 6 3  5 . 3 ( 3 . 2- 8.1)  4. 9 ( 2. 8- 8 . 0)  0. 869  0 . 3 9 0  0 . 4 62 0 . 4 35 \nIns ul i n o g e ni c  in dex  32. 7 ( 1 7.5-5 6.2)  3 9.8 ( 19. 6-56. 5)  0 . 8 2 4  2 3 . 4 ( 13. 0-42. 3 )  38. 4 ( 1 9. 5 -6 5. 5)  0. 00 2  0 .58 2 0 .49 0  0 .35 7 \nC - p e pt id e  in d e x 3 .2  (1 .8 -5 .6 ) 3 .6  (2 .5 -4 . 3 ) 1 .00 0 2. 8 ( 1 . 6- 4.4)  4. 0 ( 2. 4- 6 . 6)  0. 01 9  0. 4 4 4  0 .77 7  0 .36 0  \nDis p osi tio n i ndex  1 69.0  ( 73.5 - 2 5 3 . 2)  1 3 9. 7 ( 63.3- 23 2. 5 )  0 . 76 0  126 .2  (5 7. 1 -2 15 .4 ) 21 4 .2  (9 0. 6 - 461 . 9) 0 .0 07 0 .41 8 0 .62 2  0 .019  \nValue s  a re  medi an (interq uar til e rang e ). W L WO H, women liv ing without H IV; WL WH ,  women living  with HIV; NGT, norma l  gluc os e  tol e r ance  ( fa sting  pla sma gl ucose <6. 1 \nmmol/L &  120 minute post gl ucos e loa d <7.8 mmol/ L ) ; IFG, impaired fa s ting g lucos e  (f as ting pl a s ma gluc ose: 6.1–6.9 mmol/L); IGT,  impai red glucose t ole ra nce (120 minute \npos t-g luco s e l oad: 7 .8– 11.0 mmo l / L ); T2D, type 2 dia bet es  (fa s ting pla sma gl ucos e > 7. 0 mmol/L a nd/ or 12 0 minut e po s t -g luc os e  l oad ≥ 11 .1 mmol / L  and/ or on dia bete s  \nmedi cation. IGM, i mpair ed g lucos e met a bolism  ( IFG and/or IGT ); Dy sglyc aemi a: I GM and/or type 2 diabe te s. S I , insulin sensit ivity; AIR g , acute insulin respons e t o glucos e ; \nDI, di sposi tion index; Sg, gluc ose ef fec tiv enes s .  \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n27 \n \n \n \nTable 3.  Ass ocia tion s  be tween SH BG, an drogen hormon e s  and glycaemic and in sulin parame ter s   \nParameter SHBG  \n(Scaled robust Z-score) \nTotal testosterone  \n(Scaled robust Z-score) \nFree testosterone  \n(Scaled robust Z-score) \n Odds ratio (95% CI) P value Odds ratio (95% CI) P value Odds ratio (95% CI) P value \nD ys glycaemia  0.60 \n(0.45 – 0.79)# <0.001 0.95 \n( 0.80 – 1.12 ) 0.540 1.20 \n( 0.12 – 11.97 ) 0.876 \nStandardised values  \n(scaled robust Z-scores) Beta (95% CI)  P value Beta (95% CI)  P value  Beta (95% CI)  P value  \nHbA1c -0 . 0 8  \n( - 0 .18- 0 .02) 0.106 -0 . 0 6  \n( - 0 .12 to 0.01 ) 0.106 -0 . 0 5  \n( - 0 .12 to 0.02 ) 0.195 \nFasting Gluco s e  -0.13  \n(-0.22 to -0.04) 0.003 -0 . 0 2  \n( - 0 .09 to 0.05 ) 0.541 -0 . 0 1  \n( - 0 .09 to 0.06 ) 0.673 \nFasting insulin  -0.12  \n(-0.21 to -0.03) 0.011 0.07 \n( - 0 .003 to 0.14 ) 0.060 0.06 \n( - 0 .01 to 0.12 ) 0.079 \nHOMA - IR  -0.14  \n(-0.23 to -0.05) 0.003 0.06 \n( - 0 .02 to 0.13 ) 0.132 0.05 \n(-0.02 to 0.11) *  0.176 \nBasal in s ulin clear ance  0.14 \n(0.04 to 0.24) 0.005 -0 . 0 6  \n( - 0 .14 to 0.02 ) 0.147 -0.09  \n(-0.16 to -0.01) 0.021 \nIns u linogenic index  -0 . 0 3  \n( - 0 .15 to 0.09) 0.592 0.0002 \n( - 0 .08 to 0.08 ) 0.995 0.03 \n( - 0 .05 to 0.11 ) 0.535 \nC - p eptid e index  0.10 \n( - 0 .03 to 0.22 ) 0.139 -0 . 0 5  \n( - 0 .14 to 0.03 ) 0.204 0.001 \n( - 0 .08 to 0.08 ) 0.977 \nMat s uda ind ex  0.31 \n(0.21 to 0.41) * <0.001 -0 . 0 4  \n( - 0 .12 to 0.04 ) 0.354 -0 . 0 4  \n( - 0 .13 to 0.04 ) 0.289 \nD i s po s itio n index  0.29 \n(0.16 to 0.42) <0.001 -0 . 0 2  \n( - 0 .11 to 0.08 ) 0.690 -0 . 0 1  \n( - 0 .11 to 0.78 ) 0.770 \nResult s  f r om logis tic and quan tile r egre ss ion model s  adju s t ed f o r age, f a t mass  i ndex  and HIV  stat us. Robu s t Z-s co re s , ca lculat ed from the m edia n and median  \nabs o lute  devia tion ( MA D ), wer e de rive d f or  SHB G, tot al and f r ee te sto s t eron e and the  glycaemic and in s ulin  mea sure s  t o facilita te c ompari s on s  of  th e  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n28 \n \n \nmagnitude o f  the a s sociati on s . The  rob us t  Z-s cor e s  rep re s e nt the n umber of  M ADs  t hat a da ta p oint li e s  from t he med ian of th e v ariabl e in the d ata set . Th e  \nMADs  wer e s ca led by a con s tan t factor o f  1.4826 so tha t th e robu s t Z - s c ore i s  mo re direc tly comparable to a t radit ional Z-s cor e .  \n #  s ex  hormon e x  HIV  int erac tion; *sex  hormone x  menopau s al s t atu s  int erac tion.  \n \n  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n \n \n \n \n \nFigure 1 . The a s sociati on betwe en SHB G  and prevalen t dys gla emia by HIV  stat us  (P =0.055 f or SHB G  x  HIV  in ter action ) . Hig her SHB G  was  a ss ocia ted with \nodds  o f  dys glycaemi a in WLWOH ( OR ( 95% conf idence in terval ( C I ) : 0 .50 ( 0.35 – 0 . 71) , P<0.001)  bu t not in WLWH ( O R ( 95% C I ) : 0.90  ( 0 .62 – 1.31, P =0 .59 2\nModel adju s t ed f o r age and FM I. SHB G  p re s en ted a s  s caled robu s t Z-s co re s , calcul ated f rom th e m edian a nd median ab s ol ute devia tion (MA D ) , with M A\nby a cons ta nt facto r of  1.4826 s o that th e robu s t Z-s co re i s  compara ble to a tra dit ional Z-s core .  \n         \n29 \nlo w e r  \n2 ).  \nD  s cal ed \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n30 \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint \n\n \n \n \nFigure 2 . The a s sociati on betwe en SHB G  and f r ee t e s to ster one and in s ulin p aram ete rs  by menop au s al s ta tu s , adju s ti ng f o r age, HI V  sta tu s  and fat ma ss  i\nA)  The a ss ocia tion be tween SH BG  and in s ulin s en s i tivity ( Ma t s uda ind ex )  diff e rs  b y menopausal sta tu s  ( p=0 .043 f o r SHBG  x  menopa u s e ) , with th e a ss oci a\nbeing stronge r in preme nopau s al (s tan da rdised ß ( 95%CI): 0.46 ( 0 .22- 0 .70)  p<0 .00 1)  compared to po s tm enopau sal women ( stand ardi s ed ß ( 95%C I ) : 0 .2 9\n0.43) , p<0 .001). B)  The a ss oci ation b etw een free te sto s t eron e and HOM A-IR di f fe rs  by menopa usal sta tu s  (P =0.015 f or f re e te s t o s te rone x  menopa use), \nass ocia tion only s ignf icia nt in th e prem e nopau s al women (standa rdi s ed ß ( 95%C I ) : 0.40 ( 0 .13- 0 .67), p=0.005 )  and no t the post- m e nopau sal women \n( stand ardi s ed ß ( 95%C I ) :0 .05 (- 0.02 – 0.1 2) , p=0.200 ) .  \n31 \n \ni ndex .  \na ti on \n9  ( 0.16 -\nwith the \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted December 29, 2024. ; https://doi.org/10.1101/2024.12.25.24319619doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}