Gonadotropin and Sex Steroid Levels in HIVinfected Premenopausal Women and Their Association with Subclinical Atherosclerosis in HIVinfected and -uninfected Women in the Women s Interagency HIV Study (WIHS) ROKSANA KARIM, MBBS, PHD UNIVERSITY OF SOUTHERN CALIFORNIA LOS ANGELES, CA
Background Prolonged amenorrhea in HIV-infected women Early onset of menopause in HIV-infected women Observations suggestive of altered gonadotropin and sex hormone levels Gonadal hormones not studies thoroughly in HIV infected women
Background Endogenous sex hormones associated with atherosclerosis, cardiovascular disease (CVD) and CVD risk factors Risk of CVD elevated in HIV-infection Impact of these endocrine disruptions on atherosclerosis has not been evaluated in women living with, or at risk for HIV infection
Objectives To compare gonadotropin and sex hormone levels between HIV-infected and HIV-negative premenopausal women To investigate the association of gonadotropin and sex hormone concentration with subclinical atherosclerosis in HIV-infected and HIV-negative premenopausal women
Methods Study design: Cross-sectional Study population: Women participating in the Women s Interagency HIV Study (WIHS) Premenopausal No history of oophorectomy No breast feeding Not taking exogenous hormones in past 12 months Sex hormones measured at or before Carotid artery ultrasound visit
Methods Subclinical atherosclerosis: Assessed by B-mode ultrasound scan of the carotid artery measuring Intima-media thickness (CIMT) Distensibility : [{2(D S -D D )/D D }/PP] x 106/133.3 D S = diameter at systole; D d = diameter at diastole; PP = pulse pressure Measured once between WIHS visits 20 and 22 (April 2004 and September 2005)
Methods Hormone analytes: Gonadotropin and female sex hormones: FSH, E2, and inhibin B Sample from 584 women (414 HIV+, 170 HIV-) collected on one of days 2 through 4 of mensutrual cycle Androgens and SHBG: T, DHEAS, and SHBG Random sample from 1094 women (771 HIV+, 323 HIV-) Assessed between WIHS visits 18 and 20 (April 2003 and October 2004)
Statistical analysis Median concentrations of the hormones were compared between HIV+ and HIV- women using Wilcoxon non-parametric test Similar testing done for comparison between current HAART users vs. non-haart users Multiple linear regression models were used to correlate the hormones with each of the atherosclerosis outcomes
Table 1. Demographic and clinical characteristics by HIV status E2, FSH and inhibin-b sample Androgen and SHBG sample HIV-uninfected HIV-infected HIV-uninfected HIV-infected P-value (n = 170) (n = 414) (n = 323) (n = 771) P-value Age, years` 38.2 (8.5) 39.1 (6.7) 0.25 37.0 (8.7) 39.8 (7.1) <.0001 Race African Am 111 (65.3) 252 (60.9) 0.51 182 (56.4) 460 (53.7) 0.69 Hispanic 46 (27.1) 120 (29.0) 105 (32.5) 261 (33.8) White/others 13 (7.6) 42 (10.1) 36 (11.1) 96 (12.5) Smoking No 69 (40.6) 213 (51.5) 0.03 146 (45.2) 403 (52.3) 0.048 Yes 101 (59.4) 198 (47.8) 177 (54.8) 365 (47.3) Alcohol Abstainer 55 (32.4) 214 (51.7) <.0001 112 (34.7) 417 (54.1) <.0001 <3 drinks/wk 77 (45.3) 144 (34.8) 142 (44.0) 267 (34.6) 3 drinks/wk 38 (22.3) 53 (12.8) 69 (21.3) 84 (10.9) Missing 0 (0) 3 (0.7) 0 (0) 3 (0.4) BMI, kg/m 2 30.7 (8.3) 29.0 (8.2) 0.02 30.6 (7.9) 28.5 (7.4) <.0001 Diabetes No 147 (86.5) 376 (90.8) 0.12 286 (88.5) 681 (88.3) 0.92 Yes 23 (13.5) 38 (9.2) 37 (11.5) 90 (11.7) Missing 0 (0) 0 (0) 0 (0) 0 (0) Education high school 107 (62.9) 298 (72.0) 0.04 212 (65.6) 558 (72.4) 0.04 > high school 62 (36.5) 116 (28.0) 109 (33.8) 212 (27.5) Missing 1 (0.6) 0 (0) 2 (0.6) 1 (0.1) Injection drug use No 164 (96.5) 405 (97.8) 0.15 314 (97.2) 748 (97.0) 0.52 Yes 6 (3.5) 6 (1.5) 9 (2.8) 20 (2.6) Non-injection drug use No 109 (64.1) 306 (73.9) 0.02 205 (63.5) 605 (78.5) <.0001 Yes 61 (35.9) 105 (25.4) 118 (36.5) 163 (21.1)
Table 1 (continued) HIVuninfected (n = 170) HIV-infected (n = 414) P-value HIV-uninfected (n = 323) HIV-infected (n = 771) P-value Anti-retroviral therapy None 159 (38.4) n/a 282 (36.6) n/a Mono or combo 7 (1.7) 15 (1.9) HAART 248 (59.9) 474 (61.5) Ever diagnosed with AIDS Yes 128 (30.9) n/a 276 (35.8) n/a No 286 (69.1) 495 (64.2) HIV RNA, copies/ml 80 177 (42.9) n/a 334 (43.3) n/a 81 999 63 (15.3) 103 (13.4) 1,000 9,999 70 (16.9) 146 (18.9) 10,000+ 103 (24.9) 184 (23.9) CD4 count, cells/µl <200 156 (37.9) n/a 279 (36.2) n/a 200 349 102 (24.8) 174 (22.6) 350 499 98 (23.8) 185 (24.0) 500+ 56 (13.6) 123 (15.9) n (%) for categorical measures; mean(std) for continuous Chi-square test and T-test for categorical and continuous variables, respectively
Table 2: Median (25 th, 75 th percentile) concentrations of sex hormones, FSH, and SHBG by HIV status E2, FSH and inhibin-b sample Androgens and SHBG sample HIV Uninfected (n = 323) HIV-infected (n = 771) HIV Uninfected (n = 170) HIV-infected (n = 414) *pvalue FSH, 5.6 (4.4, 7.7) 5.9 (4.6, 8.3) 0.35 miu/ml E2, pg/ml 43.5 (31.0, 58.0) 37.0 (27.0, 51.0) 0.001 *pvalue Inhibin-B, pg/ml 64.0 (17.0, 109.0) 59.0 (23.0, 104.0) 0.60 DHEAS, 106.0 (65.0, 165) 73.3 (34.0, 122.5) <.0001 mcg/dl T, ng/dl 37.3 (22.7, 53.1) 22.7 (10.0, 36.9) <.0001 SHBG, nmol/l 47.0 (32.0, 70.0) 58.5 (41.0, 88.0) <.0001 *p-values from Wilcoxon two sample test; Abbreviations: FSH = follicle-stimulating hormone; E2 = total estradiol; DHEAS = dehydroepiandrosterone sulfate; T = total testosterone; SHBG = sex hormone-binding globulin
Table 3: Adjusted associations of sex hormones, FSH and SHBG (dependent variable) with HIV status (independent variable) Sex hormones and SHBG ± N Estimate p-value FSH, miu/ml 573-0.03 0.56 E2, pg/ml 571-0.13 0.01 Inhibin-B, pg/ml 560-0.07 0.68 DHEAS, mcg/ml 1174-0.61 <.0001 T, ng/dl 1041-0.89 <.0001 SHBG, nmol/l 1174 0.11 0.004 Abbreviations: FSH = follicle-stimulating hormone; E2 = total estradiol; DHEAS = dehydroepiandrosterone sulfate; T = total testosterone; SHBG = sex hormone-binding globulin ± FSH, E2 and SHBG were log transformed; Inhibin-B, DHEAS and T were categorized with measures below lower limit of quantification as the referent group, and the measures above LLQ into tertiles All estimates are β parameters (multiple regression model used for FSH, E2 and SHBG; ordinal logistic regression model used for Inhibin-B, DHEAS and T). All models adjusted for age, BMI, smoking, use of injection drug, non-injection drug, cocaine and opiate
Table 4: Association of sex hormones, FSH, and SHBG with measures of subclinical atherosclerosis HIV-infected HIV-uninfected Fully adjusted model Fully adjusted model Hormones Outcome N Estimate P-value N Estimate P-value FSH CIMT 414 0.0004 0.40 170-0.0002 0.77 DIST 0.026 0.57-0.006 0.94 E2 CIMT 412 0.0002 0.14 170-0.00007 0.73 DIST -0.006 0.60-0.003 0.89 Inhibin-B CIMT 402 0.00007 0.42 167-0.0001 0.30 DIST 0.010 0.19 0.022 0.10 DHEAS CIMT 771-0.00007 0.19 323-0.00004 0.49 DIST 0.002 0.71 0.002 0.80 T CIMT 670-0.0002 0.33 290-0.0003 0.12 DIST 0.042 0.0005 0.011 0.59 SHBG CIMT 771-0.000006 0.94 323-0.00004 0.67 DIST -0.001 0.85-0.010 0.35 All estimates are β parameters from linear regression models Adjusted for age, race, BMI, smoking, alcohol, diabetes, injection drug use, non-injection drug use Models for HIV positive subjects also adjusted for anti-retroviral therapy and HIV viral load
Table 5: Multivariate association of sex hormones and SHBG with subclinical atherosclerosis among HIV-infected women stratified by CD4 count All estimates are β parameters from linear regression models Adjusted for age, race, BMI, smoking, alcohol, diabetes, injection drug use, non-injection drug use, anti-retroviral therapy, and HIV viral load
Summary results Compared to HIV-uninfected, E2, T and DHEAS concentrations were significantly lower and SHBG was higher in HIV-infected women. T was significantly positively associated with distensibility among HIV-infected women and the magnitude of association did not differ by CD4 cell count. E2 was significantly positively associated with distensibility among HIV-infected women with CD4 count <350 cells/µl.
Conclusions HIV-infected women had estrogen and androgen insufficiency compared to HIV-uninfected premenopausal women. T deficiency is linked with carotid artery stiffness regardless of immune suppression. E2 deficiency is linked with carotid stiffness among immunocompromised HIV-infected women. Further research is warranted to understand the impact of endocrine dysregulation on the accelerated CVD risk in HIV-infected women.
Acknowledgement Wendy J Mack, PhD University of Southern California, Los Angeles, CA Naoko Kono, Ms University of Southern California, Los Angeles, CA Phyllis C Tien, MD University of California, San Francisco, CA and Medical Service, Veterans Affairs Medical Center, San Francisco, CA Kathy Anastos, MD Montefiore Medical Center, Bronx, NY Jason Lazar, MD State University of New York Downstate Medical Center, Brooklyn, NY Mary Young, MD Georgetown University Medical Center, Georgetown University, Washington, DC Mardge Cohen, MD Stroger Hospital and Rush University, Chicago, IL Elizabeth Golub, PhD Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Ruth M Greenblatt, MD University of California, San Francisco, CA Robert Kaplan, PhD Albert Einstein College of Medicine, Bronx, NY Howard N Hodis, MD University of Southern California, Los Angeles, CA