This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sowers, M. Articles by Pasternak, R. Search for Related Content PubMed PubMed Citation Articles by Sowers, M. Articles by Pasternak, R.

Insulin Resistance, Hemostatic Factors, and Hormone Interactions in Pre- and Perimenopausal Women: SWAN

Department of Epidemiology (M.F.S., M.L.J.), University of Michigan, Ann Arbor, Michigan 48109-2029; Department of Neurology (C.D.), Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461; Department of Obstetrics, Gynecology, and Women’s Health (J.I.T.), University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey 07103; and Department of Cardiology (R.P.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: MaryFran Sowers, Ph.D., University of Michigan, Department of Epidemiology, 109 Observatory Street, Room 2624, Ann Arbor, Michigan 48109-2029. E-mail: mfsowers{at}umich.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We evaluated the association of hemostatic factors with insulin resistance in relation to reproductive hormones including FSH, estradiol, testosterone, and SHBG. SHBG was used to calculate the free estradiol index and free androgen index. We studied 3,200 women, aged 42–52 yr, in the Study of Women’s Health Across the Nation, a prospective multiethnic study of the menopausal transition. We measured the hemostatic factors, fibrinogen, factor VIIc, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1), as well as glucose and insulin to calculate insulin resistance.

After adjustment for body mass index, site, and ethnicity, SHBG was correlated with PAI-1 (partial r = -0.30) and t-PA (partial r = -0.12). Although testosterone was associated with t-PA (partial r = 0.13) and PAI-1 (partial r = 0.07), free androgen index was strongly correlated with t-PA (partial r = 0.18) and PAI-1 (partial r = 0.26). SHBG modified the association of hemostatic factors with insulin resistance. Women with greater insulin resistance had lower SHBG and higher PAI-1. Estrogen measures were not associated with insulin resistance.

The influence of sex hormones on hemostatic factors and insulin resistance is poorly understood. SHBG, which influences the amount of bioavailable hormone, significantly modified the association of PAI-1 and t-PA with insulin resistance. The longitudinal Study of Women’s Health Across the Nation will help us discern whether this interaction contributes to heart disease and diabetes among postmenopausal women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IT IS UNCERTAIN whether hormonal influences on hemostatic factors contribute to the heart disease incidence in women by minimizing thrombosis (1, 2, 3, 4, 5, 6, 7, 8). Estelles et al. (9) found that, in comparison to postmenopausal women, plasminogen activator inhibitor type 1 (PAI-1) antigen was lower both in postmenopausal women using hormone replacement therapy and in premenopausal women. Yet, in premenopausal women, there is an inconsistent association of oral contraceptives use with fibrolytic and coagulation activity (10).

Insulin resistance may be one mechanism through which the hemostatic factors are associated with endogenous hormones and cardiovascular disease (CVD). The World Health Organization MONICA Project, monitoring CVD in 21 countries, suggested that the relationship between insulin concentration and coronary heart disease was potentially stronger in women than men. MONICA investigators found that insulin levels were correlated with PAI-1 activity; however, the strength of the relationship differed according to menopause status (11). A similar constellation of hormones and CVD risk factors may occur in selected premenopausal populations of women, including those with polycystic ovary syndrome (PCOS). In PCOS, hemostatic factors have been associated with insulin levels and insulin resistance, an association that is mitigated with treatment by metformin (12), which concomitantly induces resumption of normal menstrual cycles in amenorrheic women (13). Collectively, studies have not considered the interaction of hormones with hemostatic factors in relation to insulin resistance.

The Study of Women’s Health Across the Nation (SWAN) is a natural history study of the menopausal transition that has included measures of endogenous hormone concentrations and hemostatic factors. In SWAN, fibrinogen and factor VIIc were measured as markers of the extrinsic blood coagulation pathway, and tissue plasminogen activator (t-PA) and PAI-1 were measured as markers of the fibrinolytic system. To assess the role of sex hormones on hemostatic factors and insulin resistance, we first corroborated that hemostatic factors were correlated with insulin resistance in women with and without diabetes. Then, we addressed the following questions: 1) are hormone concentrations, including FSH, estradiol, and testosterone, or the SHBG carrier protein associated with hemostatic factors and insulin resistance; and, 2) do the levels of reproductive hormones modify the direction or magnitude of the associations between hemostatic factors and insulin resistance?

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Population

SWAN is a prospective, multiethnic, multidisciplinary study of the natural history of the menopausal transition located in Boston, Chicago, the Detroit area, Los Angeles, Newark, Pittsburgh, and Oakland, California. A two-stage recruitment process began with a 15-min cross-sectional survey to collect selected health, reproductive, demographic, and lifestyle data. Women identified for participation in the cross- sectional survey were 40–55 yr old and living in the geographic area defined by the clinic sites as their target areas. The listing of the 16,065 women in this screening survey served as the sampling frame for the second stage of recruitment. There were 3302 women formed into the longitudinal cohort with each clinical center recruiting at least 450 women in a proportion that included non-Hispanic Caucasian women and women from one race/ethnic group designated for each site (African-American, Caucasian, Chinese, Japanese, or Hispanic). The longitudinal cohort study enrollment criteria were: aged 42–52 yr, intact uterus and at least one ovary, no current use of exogenous hormone preparations that affect ovarian function, at least one menstrual period in the 3 months before enrollment, and self-identification with the site’s designated race/ethnic group. Additional information about the eligibility criteria, sampling frames, and characteristics of participants have been published (14). Data were collected via protocols reviewed and endorsed by an appropriate Institutional Review Board at each site. This report is based on the baseline examination of the cohort study.

Measures

Menstrual status was based on self-report and classified as: perimenopausal, indicating menses had occurred in the previous 3 months but had become less predictable; or premenopausal, indicating menses had occurred in the past 3 months with no decreased predictability. Postmenopausal women or women using oral contraceptives or hormone replacement were ineligible for enrollment in the longitudinal cohort.

Height (in centimeters) and weight (in kilograms) were measured with stadiometers and calibrated scales and used to calculate body mass index (BMI) [weight (kilograms)/height (square meters)]. Waist-to-hip ratio (WHR) was calculated using hip and waist circumference measures (centimeters). BMI was used in analysis because it explained more variation than waist circumference or WHR.

Assays

Phlebotomy was performed in the morning after an overnight fast (96% of participants). Women were scheduled for venipuncture on d 2–7 of a spontaneous menstrual cycle occurring within 60 d of recruitment. Two attempts were made to obtain the d 2–7 sample; however, if a timed sample could not be obtained, a random fasting sample was taken within the 90-d period of recruitment (14% of participants). Blood was assayed in laboratories at the University of Michigan (estradiol, testosterone, SHBG, FSH, or TSH) or at the Medical Research Laboratories (glucose, insulin, hemostatic factors, and lipids). Throughout the study, the Medical Research Laboratories participated in, and remained certified by, the National Heart Lung and Blood Institute, Centers for Disease Control Part III program (15).

Insulin was measured in serum by solid phase RIA (Coat-A-Count, Diagnostics Product Corp., Los Angeles, CA), and glucose was measured using a hexokinase-coupled reaction (Roche Molecular Biochemicals Diagnostics, Indianapolis, IN). From the measurement of glucose and insulin, an index was derived to reflect insulin resistance [(fasting insulin x fasting glucose)/ 22.5] (Ref.16). All lipid, lipoprotein, and apolipoprotein fractions were analyzed on EDTA-treated plasma (17, 18).

Hormone assays were conducted in the University of Michigan SWAN Endocrine Laboratory using the ACS-180 automated analyzer (Bayer Diagnostics Corp., Norwood, MA). The inter- and intraassay coefficients of variation are shown in brackets for each analyte. Serum FSH concentrations were measured with a two-site chemiluminometric immunoassay (12.0 and 6.0%). SHBG was a de novo two-site chemiluminescent assay (9.9 and 6.1%). Serum estradiol concentrations were measured with a modified, off-line ACS:180 (E₂-6) immunoassay (10.6 and 6.4%). Total estradiol was indexed to SHBG [free estradiol index (FEI) = 100 x total estradiol/272.11 x SHBG] to estimate nonbound estradiol activity. Testosterone (T) concentrations were evaluated with the ACS:180 total testosterone assay modified to increase precision in the low ranges (10.5 and 8.5%). The free androgen index (FAI) was (100 T/SHBG). TSH concentration was assessed using a two-site sandwich chemiluminescent assay (9.0 and 1.9%). The cutpoints of less than 0.5 mIU/ml and more than 5.0 mIU/ml were used to classify women as having subclinical hyperthyroid or subclinical hypothyroid, respectively. Diabetes was defined as having a blood glucose greater than 126 mg/dl, use of medication for diabetes, or self-report of diabetes diagnosis.

Statistical analysis

All continuous variables other than age were log-transformed for use in linear regressions, to satisfy model assumptions such as normally distributed residuals. A variable for the time of day of blood draw was included in regression models because t-PA, PAI-1, and estradiol had significant diurnal variation. A variable for the day of blood draw within the menstrual cycle was included in regression models because insulin resistance, t-PA, PAI-1, estradiol, and BMI have higher values in women whose blood was drawn outside of d 2–7 of the menstrual cycle. A variable representing seasonality was included in regression models because insulin resistance was greater in the fall season. Other covariates included BMI, site, race/ethnicity, and site x ethnicity interaction. Smoking and age, with its narrow range in this study (42–52 yr), were not included in the final regression models because these variables were not correlated with the exposures or the outcomes. Initial analyses (data not shown) indicated that there were marked differences in values for African-American and Caucasian women according to clinical site, so a site x race/ethnicity interaction term was also included in subsequent model building.

Women being treated with anticoagulants (n = 8) were excluded from analyses, although women who reported the use of aspirin were retained because the reason for aspirin use could not be explicitly discerned. Women with diabetes and without diabetes were evaluated as separate strata because of the reported associations between diabetes and hypercoagulability (19). Likewise, the consistency of the associations were evaluated when including or excluding those women with TSH values within the ranges of 0.5–5.0 µIU/ml, thereby acknowledging the potential confounding of clinical or subclinical thyroid disease with the associations being described.

Medians and interquartile ranges were used to describe the data, and a Wilcoxon test was used to evaluate group differences. Correlations and their 95% confidence intervals (CI) were used to show the strength and direction of associations. Multiple variable regression analyses were used to relate insulin resistance, hemostatic factors, and hormones, and results were reported with partial correlations. The association of insulin resistance with hemostatic factors according to perimenopause status was also evaluated with multiple variable regression analyses with an indicator variable for pre- vs. early perimenopause status as well as an interaction term. Model fit, including appropriateness of transformations, was assessed using residual analyses. Log transformations were returned to appropriate units using the technique of Duan (20). A P value <0.01 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Women with and without diabetes

As expected, those mid-aged, pre- and perimenopausal women in this cohort with diabetes (n = 94) had higher mean insulin values, greater insulin resistance, and higher mean BMI compared with women in the cohort without diabetes (Table 1). All hemostatic factors were significantly elevated in women with diabetes compared with women without diabetes, particularly the fibrinolytic markers, PAI-1 and t-PA. Although hypercoagulability is reported among persons with diabetes, the coagulation markers, fibrinogen and factor VIIc, were only modestly higher among women with diabetes, compared with women without diabetes. Testosterone values were similar in women with and without diabetes, but the significantly lower SHBG values seen in women with diabetes generated a significantly higher FAI compared with women without diabetes (P < 0.0001). African-American women were significantly more likely to have diabetes than the women of other race/ethnic groups (P < 0.0001).

Table 3 shows the unadjusted correlations between the hormones, hemostatic factors, and insulin resistance overall. In women without diabetes, SHBG was strongly and negatively correlated with insulin resistance [-0.28 (95% CI, -0.30, -0.25)]. Although FAI and FEI were also significantly associated with insulin resistance (r = 0.24 and 0.14, respectively), the correlations of estradiol and testosterone were very low, which suggested that in large measure, the correlations of FAI and FEI with insulin resistance reflected the contribution of SHBG.

Androgens were associated with the fibrinolytic factors. After adjustment for covariates, total testosterone was associated with t-PA (partial r = 0.13) and PAI-1 (partial r = 0.07). After adjustment for covariates, FAI remained strongly correlated with t-PA (partial r = 0.18) and PAI-1 (partial r = 0.26).

Although there were some statistically significant associations of estradiol and FSH with the hemostatic factors, after adjustment for covariates, the only significant partial correlation was between estradiol and fibrinogen (partial r = -0.09). FEI was significantly correlated with fibrinogen (partial r = 0.11).

These associations were consistent whether data included or excluded women with TSH values outside the 0.5–5.0 mIU/ml euthyroid range.

Interactions of hormones and hemostatic factors in relation to insulin resistance

Based on multiple variable regression, there were important interactions in the association of hemostatic factors with insulin resistance (Table 4), and these were not related to race/ethnicity. There was a negative interaction between SHBG and the hemostatic factors, PAI-1 and t-PA, in relation to insulin resistance. As seen in Fig. 1, there was a greater insulin resistance in those women whose t-PA was in the highest quintile. However, in women of the highest quintile of t-PA, insulin resistance was significantly higher in those women who had the lower SHBG concentrations compared with women with higher SHBG concentrations. Thus, these interactions indicated that the magnitude of the insulin resistance in relation to a given level of hemostatic factor was related to a specific level of SHBG.

View larger version (22K): [in this window] [in a new window]   FIG. 1. The interactions between lowest, middle, and highest quintiles of PAI-1 and t-PA with SHBG with respect to insulin resistance. A higher SHBG quintile is associated with a lower insulin resistance at each quintile of the hemostatic factors.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found a strong inverse association between SHBG concentrations and an index of insulin resistance in this large community-based study of pre- and perimenopausal women without diabetes. This finding is consistent with clinical studies of PCOS in which hyperinsulinemia was reported to have a direct inhibitory effect on hepatic SHBG production (21, 22). Likewise, there were strong associations of hemostatic factors, particularly PAI-1, t-PA, and fibrinogen, with insulin resistance. Importantly, SHBG and the SHBG-based indices for bioavailable testosterone and estradiol modified the association between hemostatic factors and insulin resistance; that is, the magnitude of insulin resistance in relation to a given level of PAI-1, t-PA, or fibrinogen was related to levels of SHBG or the testosterone/SHBG and estradiol/SHBG ratios. With higher SHBG concentrations, there was a dampening of the degree of insulin resistance with these hemostatic factors. These interactions suggest that, even in pre- and early perimenopausal women, the correlations of hemostatic factors with insulin resistance were modified by reproductive hormones and indicate that this may be a productive area for further investigation.

It is recognized that women have higher concentrations of SHBG because SHBG production is promoted by estrogen and inhibited by androgen. Although women with hirsutism or PCOS have elevated androgens and lower SHBG, this study links these characteristics into a broader population that was probably not enriched with women who had PCOS because of the entry criteria for regularity of menstrual bleeding. Finding that SHBG played a strong role in the relation between hemostatic factors and insulin resistance in a large community-based study of menstruating women suggests a potentially important menopausally related mechanism in the expression of heart disease.

In the San Antonio Heart Study, an inverse association between SHBG and insulin concentrations (23) and a decreased SHBG in incident type 2 diabetes has been reported (24). Investigations have shown that insulin decreased SHBG concentrations (25, 26). Additionally, we, like others (27, 28, 29), identified that t-PA and PAI-1 levels were higher in women with diabetes. Stoney et al. (28) and Brandenburg et al. (29) have speculated that women with diabetes may have a greater probability of hemostatic abnormalities than diabetic men. Recently, the Insulin Resistance Atherosclerosis Study identified that men and women with higher baseline levels of fibrinogen and PAI-1 were more likely to have incident diabetes 5 yr later; however, they showed that PAI-1 predicted the development of type 2 diabetes independent of insulin resistance and other known risk factors for diabetes (30). This suggests that exploiting the interaction of SHBG with insulin resistance and hemostatic factors may be a mechanism to address both diabetes and CVD in women.

SHBG could be acting to influence insulin resistance by several mechanisms. First, SHBG could be altering the amount of free testosterone and estradiol available for biological interaction in processes leading to insulin resistance (31). A better test of this would require the direct measurement of bioavailable hormone. Second, SHBG is an allosteric protein with both steroid and membrane-binding sites, so SHBG or one of its isoforms could enter the cells and the SHBG-membrane binding site could be internalized (32). Third, as a binding protein, SHBG may alter fatty acid metabolism profiles seen with insulin resistance (33).

This cross-sectional study of the associations between hemostatic factors and insulin resistance, which includes a documented effect modification by SHBG, cannot be used to determine direction or causality. For example, although an interaction is present, it could reflect that more severe insulin resistance contributed to the lower SHBG and higher PAI-1. It is known that SHBG and hemostatic factors are synthesized by the liver, there is some homology between factors that function in the blood clotting cascade (34), and their covariance could be derived from their being stimulated by similar mechanisms in hepatocytes. Likewise, circulating SHBG concentrations are the manifestation of a controlling factor in the balance between biologically active androgen and estrogens (35). However, the women being evaluated in this study are in the menopausal transition, and the balance is tipped increasingly in favor of increasing androgen relative to the amount of circulating estrogen. This provides a strong motivation for the collection of longitudinal data to compare the hormone and hemostatic factor profiles of women who become increasingly insulin resistant during the menopausal transition vs. those who retain insulin sensitivity and establish temporality of these events.

In summary, we confirmed the previously reported association of hemostatic factors and insulin resistance and diabetes. Additionally, in women without diabetes, we found that whereas hormones, particularly SHBG, were associated with hemostatic factors and insulin, the SHBG concentrations modified the association of the hemostatic factors relationship, particularly PAI-1 and t-PA, with insulin resistance. The biological implications of this interaction have yet to be elucidated. The ongoing observation of hemostatic factors, insulin resistance, and the changes in body composition and ovarian hormones in SWAN enrollees who transition to the postmenopause offers the opportunity to discern whether the interaction contributes to the burden of heart disease and diabetes in these women.

	Footnotes

 
The National Institute on Aging, the National Institute of Nursing Research, and the Office of Research on Women’s Health of the National Institutes of Health funded the Study of Women’s Health Across the Nation (SWAN) at clinical sites, laboratories, and a coordinating center.

Abbreviations: BMI, Body mass index; CI, confidence interval(s); CVD, cardiovascular disease; FAI, free androgen index; FEI, free estradiol index; PAI-1, plasminogen activator inhibitor type 1; PCOS, polycystic ovary syndrome; SWAN, Study of Women’s Health Across the Nation; t-PA, tissue plasminogen activator; WHR, waist-to-hip ratio.

Received February 28, 2003.

Accepted June 17, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Hoffmeister HS, Jur M, Wendel HP, Heller W, Seipel L 1995 Coronary artery disease/myocardial infarction: alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris. Circulation 91:2520–2527[Abstract/Free Full Text]
2. Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B 1987 Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2:3–9[CrossRef][Medline]
3. Tousoulis D, Bosinakou E, Tentolouris C, Apostolopoulos T, Copshari C, Kyriakides M, Toutouzas P 1996 t-Plasminogen activator and von Willebrand factor in patients with unstable angina. Int J Cardiol 54:89–92[CrossRef][Medline]
4. Wiman B, Andersson T, Hallqvist J, Reuterwall C, deFaire AAU 2000 Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEP) Study. Arterioscler Thromb Vasc Biol 20:2019–2023[Abstract/Free Full Text]
5. Gottsater A, Rendell M, Hulthen UL, Berntorp E, Mattiasson I 2001 Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors. J Intern Med 249:237–246[CrossRef][Medline]
6. Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler GH 1995 Association between increased estrogen status and increased fibrinolytic potential in the Framingham-Offspring Study. Circulation 91:1952–1958[Abstract/Free Full Text]
7. Scarabin PY, Allhencgelas M, Plubureau G, Taisne P, Agher R, Aiach M 1997 Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 17:3071–3078[Abstract/Free Full Text]
8. Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M 1993 Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk In Communities Study Investigators. N Engl J Med 328:1069–1075[Abstract/Free Full Text]
9. Estelles A, Cano A, Falco C, Espana F, Gilabert J, Grancha S, Aznar J 1999 Lipoprotein(a) levels and isoforms and fibrinolytic activity in postmenopause–influence of hormone replacement therapy. Thromb Haem 81:104–110[Medline]
10. Ferreira AC, Montes MB, Franceschini SA, Toloi MR 2001 Effects of two oral contraceptives, containing 30 or 20 microg of ethinyl estradiol in combination with gestodene, on blood coagulation and fibrinolysis in Brazilian women. Int J Fertil Womens Med 46:265–270[Medline]
11. Eliasson M, Asplund K, Evrin PE, Lindahl B, Lundblad D 1994 Hyperinsulinemia predicts low tissue plasminogen activator activity in a healthy population: the Northern Sweden MONICA Study. Metabolism 43:1579–1586[CrossRef][Medline]
12. Velazques EM, Mendoza SG, Wang P, Glueck CJ 1997 Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 46:454–457[CrossRef][Medline]
13. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L 1999 Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 48:511–519[CrossRef][Medline]
14. Sowers MF, Crawford S, Sternfeld B, Morgenstein D, Gold E, Greendale G, Evans D, Neer R, Matthews K, Sherman S, Lo A, Weiss G, Kelsey J 2000 SWAN: a multi-center, multi-ethnic, community-based cohort study of women and the menopausal transition. In: Wren J, Lobo RA, Kelsey J, Marcus R, eds. Menopause: biology and pathobiology. New York: Academic Press; 175–188
15. Myers GL, Cooper GR, Winn CL, Smith SJ 1989 The Centers for Disease Control–National Heart, Lung and Blood Institute lipid standardization program. An approach to accurate and precise lipid measurements. Clin Lab Med 9:105–135[Medline]
16. Haffner SM 1997 Progress in population analyses of the insulin resistance syndrome. Ann N Y Acad Sci 827:1–12[CrossRef]
17. Steiner P, Freidel J, Bremner W, Stein EA 1981 Standardization of micromethods for plasma cholesterol, triglyceride and HDL-cholesterol with the lipid clinics’ methodology. J Clin Chem Biochem 19:850
18. Wald NJ, Law M, Watt HC, Wu T, Bailey A, Johnson AM, Craig WY, Ledue TB, Haddow JE 1994 Apolipoproteins and ischaemic heart disease: implications for screening. Lancet 343:75–79[CrossRef][Medline]
19. Aso Y, Matsumoto S, Fujiwara Y, Tayama K, Inukai T, Takemura Y 2002 Impaired fibrinolytic compensation for hypercoagulability in obese patients with type 2 diabetes: association with increased plasminogen activator inhibitor-1. Metabolism 51:471–476[CrossRef][Medline]
20. Duan N 1983 Smearing estimate: a nonparametric retransformation method. J Am Stat Assoc 78:605–661[CrossRef]
21. Nestler JE 1993 Sex hormone-binding globulin: a marker for hyperinsulinemia and/or insulin resistance? J Clin Endocrinol Metab 76:273–274[CrossRef][Medline]
22. Nestler JE, Powers LLP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blanckard WG 1991 A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese with polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89[Abstract/Free Full Text]
23. Haffner SM 1996 Sex hormone-binding protein, hyperinsulinemia, insulin resistance and noninsulin-dependent diabetes. Horm Res 45:233–237[Medline]
24. Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP 1993 Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. J Clin Endocrinol Metab 77:56–60[Abstract]
25. Loukovaara M, Carson M, Adlercreutz H 1995 Regulation of production and secretion of sex hormone-binding globulin in HepG2 cell cultures by hormones and growth factors. J Clin Endocrinol Metab 80:160–164[Abstract]
26. Plymate SR, Matej LA, Jones RE, Friedl KE 1988 Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460–464[Abstract/Free Full Text]
27. Juhan-Vague I, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P 1989 Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients—relationship with plasma insulin. Thromb Haem 61:370–373[Medline]
28. Stoney RM, O’Dea K, Herbert KE, Dragicevic G, Giles GG, Cumpstom GN, Best JD 2001 Insulin resistance as a major determinant of increased coronary heart disease risk in postmenopausal women with type 2 diabetes mellitus. Diabet Med 18:476–482[CrossRef][Medline]
29. Brandenburg SL, Reusch JE, Felder KK, Nelson-Wong E, Lindenfeld J, Manco-Johnson M, Regensteiner JG 2002 Impaired fibrinolysis in premenopausal women and age-matched men with type 2 diabetes mellitus: a pilot study. J Invest Med 50:110–115[CrossRef][Medline]
30. Festa A, D’Agostino Jr R, Tracy RP, Haffner SM 2002 Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes 51:1131–1137[Abstract/Free Full Text]
31. Pugeat M, Crave JC, Elmidani M, Nicolas MH, Garscio-Cholet M, Leujene H, Dechaud H, Tourniarie J 1991 Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 40:841–849[CrossRef][Medline]
32. Rosner W, Hrub DJ, Kahn MS, Nakhla AM, Romas NA 1999 Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. J Steroid Biochem Mol Biol 69:481–485[CrossRef][Medline]
33. Reed MJ, Dunkley SA, Singh A, Thomas BS, Haines AP, Cruickshank JK 1993 The role of free fatty acids in regulating the tissue availability and synthesis of sex steroids. Prostaglandins Leukot Essent Fatty Acids 48:111–116[CrossRef][Medline]
34. Petra PH 1991 The plasma sex steroid binding protein (SBP or SHBG). A critical review of recent developments on the structure, molecular biology and function. J Steroid Biochem Mol Biol 40:735–753[CrossRef][Medline]
35. Barbieri RL, Ryan KJ 1983 Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 147:90–101[Medline]

This article has been cited by other articles:

				T Sathyapalan and S. L Atkin Investigating hirsutism BMJ, April 28, 2009; 338(apr28_1): b912 - b912. [Full Text]

				C. Maric Sex, diabetes and the kidney Am J Physiol Renal Physiol, April 1, 2009; 296(4): F680 - F688. [Abstract] [Full Text] [PDF]

				J. Chen, M. R. Sowers, F. M. Moran, D. S. McConnell, N. A. Gee, G. A. Greendale, C. Whitehead, S. E. Kasim-Karakas, and B. L. Lasley Circulating Bioactive Androgens in Midlife Women J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4387 - 4394. [Abstract] [Full Text] [PDF]

				K. A. Matthews, N. Santoro, B. Lasley, Y. Chang, S. Crawford, R. C. Pasternak, K. Sutton-Tyrrell, and M. Sowers Relation of Cardiovascular Risk Factors in Women Approaching Menopause to Menstrual Cycle Characteristics and Reproductive Hormones in the Follicular and Luteal Phases J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1789 - 1795. [Abstract] [Full Text] [PDF]

				E. L. Ding, Y. Song, V. S. Malik, and S. Liu Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis JAMA, March 15, 2006; 295(11): 1288 - 1299. [Abstract] [Full Text] [PDF]

				M. R. Sowers, M. Jannausch, J. F. Randolph, D. McConnell, R. Little, B. Lasley, R. Pasternak, K. Sutton-Tyrrell, and K. A. Matthews Androgens Are Associated with Hemostatic and Inflammatory Factors among Women at the Mid-Life J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6064 - 6071. [Abstract] [Full Text] [PDF]

				M. R. Sowers, K. A. Matthews, M. Jannausch, J. F. Randolph, D. McConnell, K. Sutton-Tyrrell, R. Little, B. Lasley, and R. Pasternak Hemostatic Factors and Estrogen during the Menopausal Transition J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5942 - 5948. [Abstract] [Full Text] [PDF]

				N. Santoro, J. Torrens, S. Crawford, J. E. Allsworth, J. S. Finkelstein, E. B. Gold, S. Korenman, W. L. Lasley, J. L. Luborsky, D. McConnell, et al. Correlates of Circulating Androgens in Mid-Life Women: The Study of Women's Health Across the Nation J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4836 - 4845. [Abstract] [Full Text] [PDF]

				K. Sutton-Tyrrell, R. P. Wildman, K. A. Matthews, C. Chae, B. L. Lasley, S. Brockwell, R. C. Pasternak, D. Lloyd-Jones, M. F. Sowers, J. I. Torrens, et al. Sex Hormone-Binding Globulin and the Free Androgen Index Are Related to Cardiovascular Risk Factors in Multiethnic Premenopausal and Perimenopausal Women Enrolled in the Study of Women Across the Nation (SWAN) Circulation, March 15, 2005; 111(10): 1242 - 1249. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sowers, M. Articles by Pasternak, R. Search for Related Content PubMed PubMed Citation Articles by Sowers, M. Articles by Pasternak, R.