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First Trimester Insulin Resistance and Subsequent Preeclampsia: A Prospective Study

Renal Unit, Departments of Medicine and Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Myles Wolf, M.D., Bulfinch 127, 55 Fruit Street, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: . mswolf{at}partners.org

Abstract

Insulin resistance is implicated in the pathogenesis of preeclampsia, but prospective data are limited. SHBG, a marker of insulin resistance among nonpregnant individuals, has not been studied in detail during pregnancy. We conducted a prospective, nested, case-control study to test the hypothesis that increased insulin resistance, marked by reduced first trimester SHBG levels, is associated with increased risk of subsequent preeclampsia. First trimester SHBG levels were measured in 45 nulliparous women who subsequently developed preeclampsia (blood pressure, 140/90 mm Hg; proteinuria, either 2+ by dipstick or 300 mg/24 h, after 20 wk gestation) and in 90 randomly selected normotensive nulliparous controls. Compared with controls, women who developed preeclampsia had significantly reduced first trimester SHBG levels (302 ± 130 vs. 396 ± 186 nmol/liter; P < 0.01). Every 100 nmol/liter increase in SHBG was associated with a 31% reduced risk of preeclampsia [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.55, 0.88; P < 0.01]. After adjusting for covariates in a multiple logistic regression model, the association between first trimester SHBG and preeclampsia remained significant (per 100 nmol/liter increase; OR, 0.66; 95% CI, 0.47, 0.92; P = 0.01). When subjects were stratified by body mass index (lean: body mass index, <25 kg/m²; overweight: body mass index, 25 kg/m²), overweight women had lower SHBG levels than lean women (286 ± 156 vs. 410 ± 166 nmol/liter; P < 0.01), and within each stratum, women with preeclampsia had lower SHBG levels than their respective controls. In a multivariable analysis, the association between SHBG and preeclampsia strengthened among lean women, such that every 100 nmol/liter increase in serum SHBG was associated with a 55% reduction in the risk of preeclampsia (OR, 0.45; 95% CI, 0.27, 0.77; P < 0.01), whereas in overweight women, the association was mitigated (OR, 1.02; 95% CI, 0.62, 1.69; P = 0.9). We conclude that increased early pregnancy insulin resistance is independently associated with subsequent preeclampsia. First trimester SHBG levels may be a useful biomarker for preeclampsia, especially among lean women who otherwise would be perceived to be at low risk.

PREECLAMPSIA, WHICH is characterized by pregnancy-induced hypertension and proteinuria, complicates 3–4% of pregnancies and thus is a leading cause of maternal and fetal morbidity and mortality (1). Currently, there are no early gestation screening tests available to predict the occurrence of preeclampsia, and the only effective therapy for established preeclampsia is delivery. Prophylactic strategies, including calcium supplementation and aspirin therapy, have been mostly unsuccessful (2, 3). Novel therapeutic targets, identified preferably during early gestation when there is time for therapeutic modification, are needed for future clinical trials aimed at preventing preeclampsia.

The insulin resistance syndrome is comprised of a cluster of metabolic abnormalities that confer increased risk of diabetes, hypertension, and cardiovascular disease (4). Several features of the insulin resistance syndrome, such as obesity (5), hypertension (6), dyslipidemia (7), systemic inflammation (8), and impaired fibrinolysis (9), are also associated with preeclampsia. In addition, women with polycystic ovary syndrome or gestational diabetes, two disorders characterized by insulin resistance, are at increased risk of preeclampsia (10, 11). Collectively, these data suggest that insulin resistance may contribute to the pathogenesis of preeclampsia (12). Most studies that examined insulin resistance in preeclampsia, however, were cross-sectional or retrospective, and as a result, it remains unclear whether insulin resistance is involved in the pathogenesis of preeclampsia or is a consequence of the disease.

SHBG is a glycoprotein synthesized by the liver that binds circulating estrogens and T. Hepatic SHBG production is inhibited by insulin (13), and thus reduced SHBG levels are a marker of hyperinsulinemia and insulin resistance (14, 15, 16, 17, 18, 19, 20, 21). The clinical utility of SHBG measurement as an index of insulin resistance was established by two prospective studies in which reduced SHBG levels were associated with increased risk of future type II diabetes in otherwise healthy women (22, 23). In normal pregnancy, SHBG levels rise steadily during the first and second trimesters, reaching a peak that is 4–6 times the normal nonpregnant range (24, 25). Whether altered early gestation SHBG levels are associated with preeclampsia is unknown. Therefore, we conducted a prospective, nested, case-control study to test the hypothesis that increased insulin resistance, marked by reduced first trimester SHBG levels, is associated with increased risk of subsequent preeclampsia.

Materials and Methods

The Massachusetts General Hospital Obstetric Maternal Study was developed in 1998 for the prospective study of early gestation risk factors for hypertensive disorders of pregnancy. The details of the design of this cohort have been described previously (8). In brief, women who receive prenatal care at Massachusetts General Hospital and its affiliated health centers are eligible for inclusion in the cohort. After providing informed consent, eligible women have first trimester serum samples collected and frozen at -80 C for future analysis. Baseline and intrapartum data are collected in a computerized record on all participants through the early postpartum period. Pregnancy outcome and other variables are verified using the hospital paper record and the hospital laboratory records.

For this study nulliparous women with singleton gestations resulting in delivery after 20 wk were eligible for inclusion. Forty-five consecutive cases of preeclampsia, defined by blood pressure elevation of 140/90 mm Hg or more after 20 wk gestation in association with proteinuria, either 2+ or more by dipstick or 300 mg/24 h or more in the absence of urinary tract infection, were selected (1). For each case two nulliparous controls were randomly selected. Controls were women who entered the Massachusetts General Hospital Obstetric Maternal Study cohort within 2 wk of each case and who remained normotensive and nonproteinuric throughout pregnancy. Women with a history of diabetes; thyroid, liver, or chronic renal disease; or preexisting chronic hypertension (defined as blood pressure 140/90 or need for antihypertensive medications before pregnancy or before 20 wk gestation) were excluded. This institution’s human subjects committee approved the study.

Frozen serum was sent on dry ice by overnight courier to Esoterix, Inc. (Calabasas Hills, CA) for assay of SHBG levels. Given the reported association between increased T levels and preeclampsia (26), total T and free T assays were also performed. All samples were handled identically during storage, transport, and processing. In a pilot study we performed first trimester E2 assays on 10 cases of preeclampsia and 10 randomly selected controls. Mean E2 levels did not differ among cases and controls (5.9 ± 0.9 vs. 5.3 ± 0.8 nmol/liter, respectively; P = 0.35). Based on these data and similar reports in the literature in which E2 levels did not differ among women with preeclampsia and controls (26, 27), E2 assays were not performed on the remaining study subjects.

SHBG was measured using an immunoradiometric assay that has an intraassay coefficient of variation (CV) less than 4%, and an interassay CV less than 7.8%. The sensitivity of the SHBG assay is 2 nmol/liter. Total T was measured by a specific RIA after extraction in hexane-ethyl acetate and column chromatography. The intra- and interassay CV are less than 8.1% and 8.5%, respectively. The free T concentration was determined by the product of the fraction of free T, measured by equilibrium dialysis, and the total T concentration. The lower limit of detection for the assay is 0.1 pmol/liter. The free T assay has an intraassay CV less than 6.9%, and an interassay CV less than 9.4%.

To assess glucose tolerance, participants underwent a 50-g oral glucose-loading test between 24–28 wk gestation. This routine prenatal test is used to screen for gestational diabetes. In the nonfasting state subjects consumed 50 g oral glucose. Glucose levels in 1 h postloading plasma samples were determined using standard glucose oxidase assays with intra- and interassay CV less than 2%.

Analyses were performed with SAS (SAS Institute, Inc., Cary, NC) and STATA (STATA Corp., College Station, TX) statistical packages. Continuous variables were compared using two-sample t tests or Wilcoxon rank-sum test, and categorical variables were compared using Fisher’s exact test. Logistic regression was used to adjust for potential confounding variables. In addition, to control for the effects of obesity, we performed a stratified analysis by body mass index (BMI; lean: BMI, <25 kg/m²; overweight: BMI, 25 kg/m²). Similar stratified analyses have been used to examine the effects of insulin resistance, independent of obesity, in polycystic ovary syndrome and in studies that related SHBG as a marker of insulin resistance and future type II diabetes (19, 22, 28). Two-tailed P < 0.05 was considered statistically significant. Results are reported as the mean ± SD.

Results

Baseline and delivery characteristics are presented in Table 1. Women who subsequently developed preeclampsia displayed significantly increased baseline BMI and systolic and diastolic blood pressures and were more likely to have undergone fertility treatment. Women with preeclampsia delivered smaller birth weight babies at younger gestational ages and were more likely to deliver by cesarean.

To further understand the effects of BMI on the relationship between SHBG and preeclampsia, subjects were stratified by BMI (lean: BMI, <25 kg/m²; overweight: BMI, 25 kg/m²). Overall, SHBG levels were lower (286 ± 156 vs. 410 ± 166 nmol/liter; P < 0.01) and 1 h postloading glucose levels were higher (6.9 ± 1.2 vs. 6.2 ± 1.4 mmol/liter; P < 0.01) among overweight women compared with lean women. Table 3 lists the indexes of insulin resistance stratified by BMI and pregnancy outcome. Within both the lean and overweight strata, SHBG levels were lower, and 1 h postloading glucose levels were higher among women who developed preeclampsia compared with their respective controls. The largest stratum-specific difference in SHBG levels was among lean women, in whom SHBG levels were 20% lower in cases compared with controls.

View larger version (12K): [in this window] [in a new window]   Figure 1. Probability of preeclampsia as a function of SHBG levels among lean (BMI, <25 kg/m2) and overweight (BMI, 25 kg/m2) women.

In this prospective study of nulliparous women we identified a significant association between first trimester insulin resistance and subsequent risk of preeclampsia. This association was independent of elevated blood pressure, BMI, and fertility treatment, which are established risk factors for preeclampsia (5, 29, 30). Although insulin resistance has been implicated in the pathogenesis of preeclampsia, until now, most of the evidence in support of this hypothesis was derived from cross-sectional and retrospective studies. To date, SHBG levels have not been examined prospectively in preeclampsia.

SHBG is a glycoprotein synthesized by the liver that binds circulating E2 and T (17). SHBG mediates the balance between inactive, bound sex hormones and biologically active, free sex hormones (17). Clinical and in vitro studies indicate that E2 and thyroid hormone are the principal stimuli for hepatic SHBG secretion, whereas insulin, PRL, androgens, and GH suppress SHBG (13, 14, 15, 31, 32). Increasing insulin levels suppress hepatic SHBG secretion even in the face of increasing E2 levels (13), an observation that is especially pertinent during pregnancy, when insulin, E2, and SHBG levels increase markedly (13, 24, 25, 33).

In studies of nonpregnant women, SHBG levels correlate inversely with glucose tolerance (18), insulin levels (19), and insulin resistance as determined by the euglycemic-hyperinsulinemic clamp (16). In each of these studies the correlations were independent of BMI and body fat distribution. The link between SHBG and insulin resistance has important clinical implications. In two separate prospective studies, reduced SHBG levels were independently associated with increased incidence of type II diabetes in otherwise healthy women (22, 23). In pregnancy, women with gestational diabetes displayed markedly lower SHBG levels compared with women without gestational diabetes (34). Furthermore, when insulin sensitivity is increased pharmacologically, SHBG levels rise (20, 21). Collectively, these data support a direct, physiological link between insulin resistance and SHBG in vivo. Importantly, unlike other markers of insulin resistance, SHBG is reliable in the nonfasting state (35), and it exhibits minimal diurnal variation (36). These features render SHBG a unique marker of insulin resistance that is especially useful in clinical situations when fasting blood samples are not routinely collected, such as during prenatal obstetric care.

During the first trimester of pregnancy, SHBG levels increase 3- to 5-fold above the normal range in healthy menstruating women (24, 25). This early gestation increase in SHBG levels mirrors the contemporaneous increase in E2 levels, which rise almost 20-fold during the first trimester alone (24, 25). E2 levels continue to rise through the end of pregnancy such that by delivery, levels reach greater than 100 times the normal, nonpregnant, early follicular phase range (24). In contrast, SHBG peaks at levels 4–6 times the normal nonpregnant range within 24 wk gestation and thereafter remain constant through the duration of pregnancy (24, 25). Insulin resistance and insulin levels also increase progressively during normal gestation, but the greatest increment occurs during the second half of pregnancy (33, 37). This physiological increase in insulin resistance during the third trimester may prevent further increases in SHBG levels that otherwise would be expected in the setting of progressive increases in E2 levels. Indeed, in a third trimester study, women with gestational diabetes were more insulin resistant and had significantly reduced SHBG levels compared with normoglycemic controls despite similar E2 and thyroid hormone levels (34).

Although insulin resistance is associated with preeclampsia, the majority of evidence comes from cross-sectional and retrospective studies. For example, in studies that examined surrogate markers of insulin resistance, women with established preeclampsia displayed elevated levels of glucose (38), uric acid (39), triglycerides (40), leptin (41), and plasminogen-activating inhibitor-1 (9) and reduced high density lipoprotein levels (40). In other cross-sectional studies, women with established preeclampsia had higher fasting and postglucose loading insulin levels and lower insulin sensitivity than controls (39, 42). Two prospective studies support an association between insulin resistance and subsequent preeclampsia (43, 44). Sowers et al. (43) showed that among African-American women, fasting insulin levels were significantly increased at 20 wk gestation in those who ultimately developed preeclampsia. In a large prospective study involving more than 3600 women, Joffe et al. (44) reported that increasing deciles of glucose levels during the 50-g oral glucose-loading test were associated with increased risk of subsequent preeclampsia. In the same study, however, the relative risk of preeclampsia among women with abnormal glucose tolerance or gestational diabetes compared with women with normal glucose tolerance was not significantly increased. Furthermore, in both studies subjects were examined during the second trimester, a time when the pathological changes of preeclampsia and the physiological insulin resistance of pregnancy may already be established (37, 45). Finally, neither study examined the independent association between insulin resistance and preeclampsia among lean and overweight women.

The association we identified between first trimester SHBG levels and preeclampsia in the unstratified univariate and multivariable analyses supports the hypothesis that insulin resistance contributes to the pathogenesis of preeclampsia. In the stratified analysis, the independent association between first trimester SHBG levels and preeclampsia strengthened in lean women, but was mitigated in overweight women. One possible interpretation of this observation is that insulin resistance contributes to the pathogenesis of preeclampsia only in lean women. Alternatively, insulin resistance may contribute to the pathogenesis of preeclampsia in all women, but in overweight women it is but one of several contributing factors, including inflammation (8). Our data suggest the latter possibility. Overweight women displayed significantly reduced SHBG levels compared with lean women, and as shown in Fig. 1, there was a trend toward reduced risk of preeclampsia as SHBG levels increased, even among overweight women. Furthermore, whereas SHBG levels were lower among overweight women who developed preeclampsia than their respective controls, the difference was markedly smaller than the difference within the lean stratum. Therefore, we may have had limited power to identify a significant, independent effect of insulin resistance within the overweight category of women. We conclude that insulin resistance itself, whether in association with obesity or not, is linked to increased risk of preeclampsia. Furthermore, reduced SHBG levels may be especially helpful in identifying lean insulin-resistant women who otherwise would not be considered to be at high risk for preeclampsia.

The results of this study differ from those of a prior cross-sectional study in which SHBG levels were somewhat lower, although not statistically significant, among cases of preeclampsia compared with controls (26). In that study Acromite et al. (26) examined women at 37 wk gestation, a time when the physiological insulin resistance of normal pregnancy peaks and thus may reduce the difference in SHBG levels among normotensive and preeclamptic women. Our T data also differ from Acromite’s findings. Whereas Acromite et al. (26) showed that third trimester free and total T levels were elevated among women with preeclampsia, in this study there was no difference in first trimester androgen levels. Longitudinal studies examining how androgens vary during pregnancy may further elucidate the pathogenesis of preeclampsia.

This study has certain limitations. First, we measured SHBG levels at one time point in pregnancy. This is the first study, however, to prospectively examine SHBG in detail in preeclampsia. In addition, we adjusted SHBG levels for gestational age at the time of the blood sampling to reduce the variability in SHBG levels for which duration of pregnancy accounts. Second, we were unable to measure E2 levels in all participants. There is no evidence, however, that E2 levels differ between preeclampsia and normal pregnancy (26, 27), and a pilot study within our population supported this. Third, since we collected nonfasting serum samples that were drawn as part of routine prenatal care, we were not able to correlate SHBG levels with first trimester fasting insulin or glucose levels. Sampling fasting blood, however, is not part of routine prenatal care, and if a nonfasting marker such as SHBG proves useful, it would have widespread use. Furthermore, SHBG samples were obtained from all subjects during their first prenatal visit, long before case or control status was ascertained. No subjects were instructed about the study before their visit, and none was instructed to fast. Therefore, the timing of the subject’s last meal was randomly and probably equally distributed among cases and controls. We expect that such a random distribution would impede, rather than facilitate, identification of a statistically significant difference among cases and controls, further validating our results.

The strength of this study is that we identified evidence of increased insulin resistance in the first trimester among women who subsequently developed preeclampsia, long before preeclampsia became clinically evident. This temporal relationship supports the hypothesis that insulin resistance may be in the "causal pathway" of preeclampsia. Furthermore, as the timing of this study precedes most of the physiological insulin resistance of pregnancy (37), it is possible that the excess insulin resistance we detected in cases may have been present at baseline, predating pregnancy. This point has important therapeutic implications. First, it is tempting to consider that improving insulin sensitivity in high risk women before and during early pregnancy may reduce the risk of preeclampsia. Second, if preeclampsia is associated with increased insulin resistance at baseline, then it represents a potentially modifiable risk factor for the excess long-term cardiovascular risk observed in women with a history of preeclampsia (46). Further intrapartum and postpartum studies are needed to expand our understanding of how insulin resistance contributes to the pathogenesis of preeclampsia so that potential strategies to reduce the risk of preeclampsia may be appropriately designed.

Acknowledgments

Footnotes

This work was supported by NIH Grants HL-03804 and HD-39223.

Abbreviations: BMI, Body mass index; CI, confidence interval; CV, coefficient(s) of variation; OR, odds ratio.

Received August 28, 2001.

Accepted January 10, 2002.

References

1. National High Blood Pressure Education Program Working Group 2000 Report on high blood pressure in pregnancy. Bethesda: NHLBI, NIH; NIH Publication 00-3029:1–38
2. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, DerSimonian R, Esterlitz JR, Raymond EG, Bild DE, Clemens JD, Cutler JA 1997 Trial of calcium to prevent preeclampsia. N Engl J Med 337:69–76[Abstract/Free Full Text]
3. Sibai BM, Caritis SN, Thom E, McNellis D, Rocco L, Paul RH, Romero R, Witter F, Rosen M, Depp R, for the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units 1993 Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 329:1213–1218[Abstract/Free Full Text]
4. Timar O, Sestier F, Levy E 2000 Metabolic syndrome X: a review. Can J Cardiol 16:779–789[Medline]
5. Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM, Goldenberg RL, Joffe G 1997 Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 177:1003–1010[CrossRef][Medline]
6. Thadhani R, Ecker J, Kettyle E, Sandler L, Frigoletto F 2001 Pulse pressure and risk of preeclampsia: a prospective study. Obstet Gynecol 97:515–520[CrossRef][Medline]
7. Thadhani R, Stampfer MJ, Hunter DJ, Manson JE, Solomon CG, Curhan GC 1999 High body mass index and hypercholesterolemia: risk of hypertensive disorders of pregnancy. Obstet Gynecol 94:543–550[CrossRef][Medline]
8. Wolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R 2001 Obesity and preeclampsia: the potential role of inflammation. Obstet Gynecol 98:757–762[CrossRef][Medline]
9. Estelles A, Gilabert J, Aznar J, Loskutoff DJ, Schleef RR 1989 Changes in the plasma levels of type 1 and type 2 plasminogen activator inhibitors in normal pregnancy and in patients with severe preeclampsia. Blood 74:1332–1338[Abstract/Free Full Text]
10. de Vries M, Dekker G, Schoemker J 1998 Higher risk of preeclampsia in the polycystic ovary syndrome: a case control study. Eur J Obstet Gynecol Reprod Biol 76:91–95[CrossRef][Medline]
11. Schmidt MI, Duncan BB, Reichelt AJ, Branchtein L, Matos MC, Costa e Forti A, Spichler ER, Pousada JM, Teixeira MM, Yamashita T, Brazilian Gestational Diabetes Study Group 2001 Gestational diabetes mellitus diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. Diabetes Care 24:1151–1155[Abstract/Free Full Text]
12. Solomon CG, Seely EW 2001 Brief review: hypertension in pregnancy: a manifestation of the insulin resistance syndrome? Hypertension 37:232–239[Abstract/Free Full Text]
13. 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]
14. Pasquali R, Vicennati V, Bertazzo D, Casimirri F, Pascal G, Tortelli O, Labate AM 1997 Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Virgilio-Menopause-Health Group. Metabolism 46:5–9
15. Hampl R, Starka L 1996 Sex hormone-binding globulin in endocrine regulation [Minireview]. Endocr Regul 30:57–65[Medline]
16. Sherif K, Kushner H, Falkner BE 1998 Sex hormone-binding globulin and insulin resistance in African-American women. Metabolism 47:70–74[CrossRef][Medline]
17. Anderson DC 1974 Sex-hormone-binding globulin. Clin Endocrinol (Oxf) 3:69–96[Medline]
18. Goodman-Gruen D, Barrett-Connor E 1997 Sex hormone-binding globulin and glucose tolerance in postmenopausal women. The Rancho Bernardo Study. Diabetes Care 20:645–649[Abstract]
19. Haffner SM, Katz MS, Stern MP, Dunn JF 1988 The relationship of sex hormones to hyperinsulinemia and hyperglycemia. Metabolism 37:683–688[CrossRef][Medline]
20. Crave JC, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M 1995 Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 80:2057–2062[Abstract]
21. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654[CrossRef][Medline]
22. Lindstedt G, Lundberg PA, Lapidus L, Lundgren H, Bengtsson C, Bjorntorp P 1991 Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM. 12-yr follow-up of population study of women in Gothenburg, Sweden. Diabetes 40:123–128[Abstract]
23. 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]
24. Kerlan V, Nahoul K, Le Martelot MT, Bercovici JP 1994 Longitudinal study of maternal plasma bioavailable testosterone and androstanediol glucuronide levels during pregnancy. Clin Endocrinol (Oxf) 40:263–267[Medline]
25. O’Leary P, Boyne P, Flett P, Beilby J, James I 1991 Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin Chem 37:667–672[Abstract/Free Full Text]
26. Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG 1999 Androgens in preeclampsia. Am J Obstet Gynecol 180:60–63[CrossRef][Medline]
27. Rosing U, Carlstrom K 1984 Serum levels of unconjugated and total oestrogens and dehydroepiandrosterone, progesterone and urinary oestriol excretion in pre-eclampsia. Gynecol Obstet Invest 18:199–205[CrossRef][Medline]
28. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
29. Hoy J, Venn A, Halliday J, Kovacs G, Waalwyk K 1999 Perinatal and obstetric outcomes of donor insemination using cryopreserved semen in Victoria, Australia. Hum Reprod 14:1760–1764[Abstract/Free Full Text]
30. Moore MP, Redman CW 1983 Case-control study of severe pre-eclampsia of early onset. Br Med J 287:580–583
31. Krotkiewski M, Holm G, Shono N 1997 Small doses of triiodothyronine can change some risk factors associated with abdominal obesity. Int J Obes Relat Metab Disord 21:922–929[CrossRef][Medline]
32. 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]
33. Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA 1991 Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 165:1667–1672[Medline]
34. Bartha JL, Comino-Delgado R, Romero-Carmona R, Gomez-Jaen MC 2000 Sex hormone-binding globulin in gestational diabetes. Acta Obstet Gynecol Scand 79:839–845[CrossRef][Medline]
35. Key TJ, Pike MC, Moore JW, Wang DY, Morgan B 1990 The relationship of free fatty acids with the binding of oestradiol to SHBG and to albumin in women. J Steroid Biochem 35:35–38[CrossRef][Medline]
36. Hamilton-Fairley D, White D, Griffiths M, Anyaoku V, Koistinen R, Seppala M, Franks S 1995 Diurnal variation of sex hormone binding globulin and insulin-like growth factor binding protein-1 in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 43:159–165[Medline]
37. Stanley K, Fraser R, Bruce C 1998 Physiological changes in insulin resistance in human pregnancy: longitudinal study with the hyperinsulinaemic euglycaemic clamp technique. Br J Obstet Gynaecol 105:756–759[Medline]
38. Innes KE, Wimsatt JH, McDuffie R 2001 Relative glucose tolerance and subsequent development of hypertension in pregnancy. Obstet Gynecol 97:905–910[CrossRef][Medline]
39. Kaaja R, Laivuori H, Laakso M, Tikkanen MJ, Ylikorkala O 1999 Evidence of a state of increased insulin resistance in preeclampsia. Metabolism 48:892–896[CrossRef][Medline]
40. Wakatsuki A, Ikenoue N, Okatani Y, Shinohara K, Fukaya T 2000 Lipoprotein particles in preeclampsia: susceptibility to oxidative modification. Obstet Gynecol 96:55–59[CrossRef][Medline]
41. Teppa RJ, Ness RB, Crombleholme WR, Roberts JM 2000 Free leptin is increased in normal pregnancy and further increased in preeclampsia. Metabolism 49:1043–1048[CrossRef][Medline]
42. Martinez Abundis E, Gonzalez Ortiz M, Quinones Galvan A, Ferrannini E 1996 Hyperinsulinemia in glucose-tolerant women with preeclampsia. A controlled study. Am J Hypertens 9:610–614[CrossRef][Medline]
43. Sowers JR, Saleh AA, Sokol RJ 1995 Hyperinsulinemia and insulin resistance are associated with preeclampsia in African-Americans. Am J Hypertens 8:1–4[CrossRef][Medline]
44. Joffe GM, Esterlitz JR, Levine RJ, Clemens JD, Ewell MG, Sibai BM, Catalano PM 1998 The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 179:1032–1037[CrossRef][Medline]
45. Roberts JM 1998 Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 16:5–15[Medline]
46. Hannaford P, Ferry S, Hirsch S 1997 Cardiovascular sequelae of toxaemia of pregnancy. Heart 77:154–158[Abstract/Free Full Text]

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				M. Tanaka, G. Jaamaa, M. Kaiser, E. Hills, A. Soim, M. Zhu, I. Y. Shcherbatykh, R. Samelson, E. Bell, M. Zdeb, et al. Racial Disparity in Hypertensive Disorders of Pregnancy in New York State: A 10-Year Longitudinal Population-Based Study Am J Public Health, January 1, 2007; 97(1): 163 - 170. [Abstract] [Full Text] [PDF]

				E. Parretti, A. Lapolla, M. Dalfra, G. Pacini, A. Mari, R. Cioni, C. Marzari, G. Scarselli, and G. Mello Preeclampsia in Lean Normotensive Normotolerant Pregnant Women Can Be Predicted by Simple Insulin Sensitivity Indexes Hypertension, March 1, 2006; 47(3): 449 - 453. [Abstract] [Full Text] [PDF]

				M. Wolf, C. A. Hubel, C. Lam, M. Sampson, J. L. Ecker, R. B. Ness, A. Rajakumar, A. Daftary, A. S. M. Shakir, E. W. Seely, et al. Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6239 - 6243. [Abstract] [Full Text] [PDF]

				M. Wolf, A. Shah, R. Jimenez-Kimble, J. Sauk, J. L. Ecker, and R. Thadhani Differential Risk of Hypertensive Disorders of Pregnancy among Hispanic Women J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1330 - 1338. [Abstract] [Full Text] [PDF]

				R. Thadhani, J. L. Ecker, W. P. Mutter, M. Wolf, K. V. Smirnakis, V. P. Sukhatme, R. J. Levine, and S. A. Karumanchi Insulin Resistance and Alterations in Angiogenesis: Additive Insults That May Lead to Preeclampsia Hypertension, May 1, 2004; 43(5): 988 - 992. [Abstract] [Full Text] [PDF]

				K. Shinohara, A. Wakatsuki, K. Watanabe, N. Ikenoue, T. Fukaya, N. Sattar, J. Ramsey, N. Jamieson, and I. A. Greer Plasma Adiponectin Concentrations in Women With Preeclampsia * Response: Adiponectin Concentrations in Preeclampsia Hypertension, April 1, 2004; 43(4): e17 - e17. [Full Text] [PDF]

				R. Thadhani, W. P. Mutter, M. Wolf, R. J. Levine, R. N. Taylor, V. P. Sukhatme, J. Ecker, and S. A. Karumanchi First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 770 - 775. [Abstract] [Full Text] [PDF]

				J. E. Ramsay, N. Jamieson, I. A. Greer, and N. Sattar Paradoxical Elevation in Adiponectin Concentrations in Women With Preeclampsia Hypertension, November 1, 2003; 42(5): 891 - 894. [Abstract] [Full Text] [PDF]

				R. Tamimi, P. Lagiou, L. J. Vatten, L. Mucci, D. Trichopoulos, S. Hellerstein, A. Ekbom, H.-O. Adami, and C.-C. Hsieh Pregnancy Hormones, Pre-eclampsia, and Implications for Breast Cancer Risk in the Offspring Cancer Epidemiol. Biomarkers Prev., July 1, 2003; 12(7): 647 - 650. [Abstract] [Full Text] [PDF]

				E. W. Seely and C. G. Solomon Insulin Resistance and Its Potential Role in Pregnancy-Induced Hypertension J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2393 - 2398. [Abstract] [Full Text] [PDF]

				M. Wolf, L. Sandler, R. Jimenez-Kimble, A. Shah, J. L. Ecker, and R. Thadhani Insulin Resistance But Not Inflammation Is Associated With Gestational Hypertension Hypertension, December 1, 2002; 40(6): 886 - 891. [Abstract] [Full Text] [PDF]

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