Insulin resistance with hormone replacement therapy: associations with markers of inflammation and adiposity

doi:10.1016/j.ajog.2006.08.042

American Journal of Obstetrics and Gynecology

Volume 196, Issue 2, February 2007, Pages 123.e1-123.e7

https://doi.org/10.1016/j.ajog.2006.08.042 Get rights and content

Objective

This study was undertaken to determine whether insulin resistance associated with combination hormone replacement therapy (HRT) is mediated by changes in serum markers of inflammation or in serum adipocyte hormones.

Study design

Forty-five postmenopausal women, aged 55 ± 7 years, were examined from a randomized, double-blind placebo-controlled trial evaluating the effect of HRT on insulin-stimulated glucose disposal and body composition. Volunteers were randomly assigned to conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg vs placebo for 1 year. At baseline and at 1 year, body composition was assessed by dual photon x-ray absorptiometry scans; body fat distribution was measured by computed tomographic scans at the L4/L5 vertebral disk space; insulin sensitivity was measured by euglycemic hyperinsulinemic clamp; interleukin-6 (IL-6), leptin, and adiponectin were measured by enzyme-linked immunosorbent assay; and c-reactive protein (CRP) was measured by radioimmunoassay.

Results

HRT increased CRP by 121% compared with a 32% increase with placebo (P = .03); HRT decreased glucose disposal by 17% compared with no change with placebo (P = .04) as reported previously. HRT did not affect body composition, body fat distribution, IL-6, leptin, or adiponectin. The increase in CRP did not correlate with the decrease in glucose disposal in the HRT group (R = 0.11, P = .65).

Conclusion

Treatment with HRT for one year increases CRP, but does not alter IL-6, adiponectin, or leptin. The change in CRP was not, however, related to the decrease in glucose disposal with HRT treatment.

Section snippets

Subjects

Forty-five postmenopausal women, aged 55 ± 7 years (mean ± SD), were recruited as part of a randomized, double blind, placebo-controlled trial of the effect of HRT on insulin-stimulated glucose disposal and body composition. The effect of HRT on body composition and insulin-stimulated glucose disposal in early postmenopausal women has been reported previously by our group,⁷ and predictors of worsening insulin sensitivity (including age, years since menopause, lipids, family history of diabetes)

Results

Baseline characteristics and baseline and follow-up body composition data are shown in Table 1. There were no significant differences between HRT and placebo groups with regard to age, weight, fasting glucose, fasting insulin, or glucose disposal. Body composition over the course of the study did not differ significantly between or within the 2 groups at any point. Glucose disposal decreased in the HRT group compared with the placebo group over time. Food intake and leisure time physical

Comment

We report that HRT increased CRP in postmenopausal women, and that this increase was not correlated with the decrease in glucose disposal observed with HRT in this trial.⁷ Furthermore, IL-6, leptin, and adiponectin were not significantly altered with HRT, and change over time of these potential mediators did not explain the decrease in glucose disposal with HRT. To our knowledge, no previous study has examined circulating markers of inflammation or adipocyte hormones as possible mediators of

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Citation Excerpt :
Whilst acknowledging the potential for this finding to be due to the smaller sample size in the HT group and reduced statistical power, this finding may reflect a mediating effect of HT on inflammatory mechanisms. Indeed, previous literature investigating HT’s effect on metabolic and vascular inflammatory markers has suggested an upregulation and downregulation by HT, respectively (Lo et al., 2017; Tanimoto et al., 2013; Cooper et al., 2007; Goudev et al., 2002). HT may therefore attenuate any anti-inflammatory potential of an anti-inflammatory diet.
Low muscle mass is associated with reduced independence and increased risk for falls and fractures. Identification of modifiable risk factors for low muscle mass is thus imperative. This study aimed to examine the longitudinal relationship between both diet quality and patterns and lean mass in Australian women.
Data from n = 494 participants of the Geelong Osteoporosis Study’s 10- and 15-year women’s follow-ups were used (conducted in 2004–08 and 2011–14, respectively), and participants were aged 21–89 years. Self-reported lifestyle and demographics were collected, and food frequency questionnaire data informed the dietary exposure variables: the Australian Recommended Food Score (ARFS); the Dietary Inflammatory Index (DII); and a posteriori dietary patterns. The outcome, Skeletal Muscle Index (SMI), was calculated from DXA-derived appendicular lean mass (ALM) relative to height (ALM kg/m²). Analyses employed Generalised Estimating Equations.
A higher ARFS score positively predicted SMI over 5-years, and adjustments for age and physical activity did not attenuate this relationship (B:0.044, (95%CI 0.004, 0.084) kg/m²). Following adjustment, both an anti-inflammatory diet (B:-0.034, (95%CI −0.070, −0.002) kg/m²) and a ‘traditional’ dietary pattern predicted higher SMI (B:0.081, (95%CI 0.004, 0.158) kg/m²). No other associations were observed.
Our study reinforces the importance of diet quality for healthy, aging muscle mass. Furthermore, a less inflammatory diet and a diet comprising a wide variety of plant and animal foods may be conducive to maintenance of muscle mass in women. Further studies investigating diet quality’s impact on various muscle health measures over longer time periods are warranted.
Placental NRP1 and VEGF expression in pre-eclamptic women and in a homocysteine-treated mouse model of pre-eclampsia
2016, European Journal of Obstetrics and Gynecology and Reproductive Biology
To investigate the expression levels of neuropilin 1 (NRP1) and vascular endothelial growth factor (VEGF) in the placentas of women with pre-eclampsia (PE), determine whether homocysteine (Hcy) contributes to the development of PE in mice, and detect alterations in placental NRP1 and VEGF in Hcy-treated mice.
Placental tissue samples were obtained from 16 patients with and without PE. Using reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, the expression levels of NRP1 and VEGF in PE and control placental tissues were examined. Immunohistochemical (IHC) assay was used to detect the localization of NRP1 and VEGF proteins. Pregnant mice were treated with DL-Hcy on embryonic day 7.5. The symptoms of the treated mice were examined. The expression levels of Ddah1, Ddah2, eNos, Cbs and Cse were determined by quantitative RT-PCR to study the possible mechanism of hyperhomocysteinemia (HHcy). Nrp1 and Vegf expression levels in the placentas of treated mice were measured by quantitative RT-PCR, western blot analysis and IHC.
NRP1 and VEGF were expressed at lower levels in women with PE compared with control women. The immunoreactivity of NRP1 was detected in villous trophoblast cells and villous capillary endothelial cells (ECs). Immunoreactive VEGF was observed mainly in vascular ECs within the villi. The pregnant mice treated with DL-Hcy showed PE-like symptoms such as higher systolic blood pressure and proteinuria in late pregnancy. Compared with the control mice, Ddah1, Ddah2 and eNos mRNA were expressed at lower levels, and Cbs and Cse mRNA were expressed at significantly higher levels in the placentas of the Hcy-treated group. Expression levels of Nrp1 and Vegf in mice placentas were decreased in the Hcy-treated group.
DL-Hcy can induce PE-like symptoms in mice. Both placental NRP1 and VEGF were expressed at lower levels in women with PE and Hcy-treated mice, which may contribute to endothelial damage.
Hormone Replacement Therapy in Relation to Risk of Cataract Extraction. A Prospective Study of Women
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Citation Excerpt :
Proinflammatory cytokines like interleukin-6 and tumor necrosis factor-α52 and the hepatically derived CRP53 have been associated with cataract development. However, interleukin-6 and tumor necrosis factor-α have not been reported to be associated with HRT.44,46,51 The effect of oral estrogen on CRP may therefore be due to an upregulation of CRP in the liver rather than a generalized inflammatory response.43,45,46,51
To investigate the association between hormone replacement therapy (HRT) and the incidence of cataract extraction among postmenopausal women.
Population-based, prospective cohort study.
A total of 30 861 postmenopausal women participating in the Swedish Mammography Cohort, age 49 to 83 years, who completed a self-administered questionnaire in 1997 about hormone status, HRT, and lifestyle factors.
The women were followed from September 1997 through October 2005. The cohort was matched with registers of cataract extraction in the study area.
Incident operative extraction of age-related cataract.
We identified 4324 incident cases of cataract extractions during 98 months of follow-up. In multivariate adjusted analysis, ever use of HRT was associated with a 14% increased risk of cataract extraction (rate ratio [RR], 1.14; 95% confidence interval [CI], 1.07–1.21) compared with those who never used HRT. Current use of HRT was associated with an 18% increased risk of cataract extraction (RR, 1.18; 95% CI, 1.10–1.26). A significant linear trend was observed where increasing duration of HRT usage resulted in an increased risk of cataract extraction (P for trend = 0.006). Multivariate RR for current HRT usage for >10 years was 1.20 (95% CI, 1.06–1.36; P for trend = 0.001). Among women drinking on average >1 drink of alcohol per day, current HRT users had a 42% increased risk (RR, 1.42; 95% CI, 1.11–1.80) for cataract extraction, compared with women who neither used HRT nor alcohol. The risk of cataract extraction among current users of HRT was similar among current smokers and those who never smoked.
Our prospective, population-based study indicates that postmenopausal women using HRT for a long period of time may be at an increased risk for cataract extraction, especially those drinking >1 alcoholic drink daily.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Metabolic syndrome in gynecology
2009, Progresos en Obstetricia y Ginecologia
El síndrome metabólico (SM) se define por una constelación de múltiples factores de riesgo de enfermedad cardiovascular (ECV), entre los que se incluye la obesidad abdominal, la dislipemia aterogénica, la hipertensión y el aumento de la glucosa en ayunas. Este síndrome se considera como un importante problema de salud pública, ya que está asociado a un incremento de 5 veces en la prevalencia de diabetes tipo 2 y de 2-3 veces en la de ECV.
La resistencia a la insulina, o disminución de la sensibilidad a la insulina en la captación y el metabolismo de la glucosa en los tejidos periféricos, tiene una gran importancia en el desarrollo del SM. En el campo de la ginecología y la obstetricia, hay varias entidades clínicas en las que puede existir resistencia a la insulina con hiperinsulinemia compensatoria y, por consiguiente, ser más frecuente la presencia del SM: síndrome de ovarios poliquísticos, hiperandrogenismo, posmenopausia, disfunción sexual femenina, riesgo de recurrencia de cáncer de mama, hiperglucemia gestacional e hipertensión inducida por el embarazo. En este trabajo, se revisa la implicación del SM en estos frecuentes cuadros de nuestra especialidad.
Metabolic syndrome is defined by the constellation of multiple cardiovascular risk factors that include abdominal obesity, atherogenic dyslipidemia, hypertension and increased fasting glucose levels. This syndrome is an important public health problem, since it is associated with a 5-fold increase in the prevalence of diabetes type 2 and a 2-3-fold increase in that of cardiovascular disease.
Insulin-resistance, or reduced insulin sensitivity in the uptake and metabolism of glucose in peripheral tissues, plays a major role in the development of metabolic syndrome. In obstetrics and gynecology, insulin resistance with compensatory hyperinsulinism can occur in several entities, in which the presence of metabolic syndrome is therefore more frequent. These entities include polycystic ovary syndrome, hyperandrogenism, postmenopausal status, female sexual dysfunction, risk of recurrence of breast cancer, gestational hyperglycemia and pregnancy-induced hypertension. In this review, the involvement of metabolic syndrome in these frequent gynecological and obstetric conditions is discussed.
Effects of estrogen versus estrogen and progesterone on cortisol and interleukin-6
2008, Maturitas
The purpose of this study was to compare the effects of 3 months of estrogen replacement therapy, estrogen plus progesterone replacement therapy and a placebo, on the resting cortisol and interleukin-6 (IL-6) levels in post-menopausal women.
Forty-three women were randomised to one of three treatment arms: estradiol 2 mg/day (ERT), estradiol 2 mg/day plus medroxyprogesterone acetate 5 mg/day (HRT), or a placebo that was administered orally for 3 months.
Cortisol levels showed a significant condition by intervention interaction. Post hoc tests showed that ERT significantly increased cortisol levels after treatment compared to baseline, while in the HRT group a trend toward increased cortisol was found. No changes were observed in IL-6 levels.
Estrogen administration elevated cortisol levels, but this effect may be moderated by progestins. IL-6 was not altered by ERT or HRT, future studies should consider the interaction of cortisol increases on change in IL-6 expression.
Estrogen replacement therapy decreases plasma adiponectin but not resistin in postmenopausal women
2008, Metabolism: Clinical and Experimental
Citation Excerpt :
In the present study, neither treatment affected the BMI (Table 1). In other studies, PE treatment has been combined with progesterone, resulting in either no change [20,27] or decrease [28] in plasma adiponectin concentrations; but the use of progesterone prevents a reliable comparison with our results. In our study, no correlations were seen between estradiol, estrone, and adiponectin.
The effects of estrogen replacement therapy (ERT) to cardiovascular disease risk are still unclear. Low adiponectin and high resistin plasma concentrations are reported to be associated with atherosclerosis. However, it is not known how ERT affects plasma adiponectin and resistin concentrations. Seventy-three hysterectomized, nondiabetic, postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate or transdermal 17β-estradiol gel for 6 months. Biochemical measurements were determined from samples taken before and after the therapy. Peroral estradiol valerate therapy decreased adiponectin concentrations from 13.6 to 11.6 mg/L (P = .008), whereas transdermal 17β-estradiol gel had no effect (12.7 vs 12.2 mg/L). Neither treatment changed the resistin concentrations significantly. Plasma concentrations of estradiol and estrone did not correlate with adiponectin or resistin concentrations before or after therapy. The change in adiponectin concentration correlated significantly with the changes in waist-hip ratio, very low-density lipoprotein triglycerides, and insulin-like growth factor 1 in the peroral estradiol valerate group. The changes in these variables and the change in estradiol concentration explained 43.1% (P = .001) of the variability in the change of plasma adiponectin, the change in very low-density lipoprotein triglycerides being the strongest determinant (β = −.407, P = .011). The results show that peroral ERT can decrease plasma adiponectin levels. However, ERT does not seem to influence plasma resistin concentrations.

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This work was supported by NIH grants K24 RR19705, R29 AG 15121, and M01 RR109.

Reprints are not available from the authors.

Cite this article as: Cooper BC, Burger NZ, Toth MJ, et al. Insulin resistance with hormone replacement therapy: Associations with markers of inflammation and adiposity. Am J Obstet Gynecol 2007;196;123.e1-123.e7.

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ResearchGeneral gynecologyInsulin resistance with hormone replacement therapy: associations with markers of inflammation and adiposity

Objective

Study design

Results

Conclusion

Section snippets

Subjects

Results

Comment

J Clin Epidemiol

Am J Clin Nutr

Metabolism

Am J Obstet Gynecol

Fertil Steril

Lancet

Maturitas

Maturitas

Maturitas

Mech Ageing Dev

Fertil Steril

Metabolism

Fertil Steril

J Nutr

Metabolism

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women

Diabetes Care

Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study

Diabetes Care

Effect of menopausal status on body composition and abdominal fat distribution

Int J Obesity

The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double blind, placebo-controlled trial

J Clin Endocrinol Metab

Influence of continuous combined estradiol-norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women

Menopause

A comparison of the effects of oral and transdermal estrogen replacement on insulin sensitivity in postmenopausal women

J Clin Endocrinol Metab

Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women

J Clin Endocrinol Metab

The effect of estragiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women

J Clin Endocrinol Metab

Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion

Eur J Endocrinol

Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women

Horm Metab Res

The effects of sequential combined oral 17 beta-estradiol and norethisterone acetate on insulin sensitivity and body composition in healthy postmenopausal women: a randomized single blind placebo-controlled study

Menopause

C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

N Engl J Med

Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease

JAMA

Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot defference and regulation by glucocorticoid

J Clin Endocrinol Metab

Hormone replacement therapy and increased plasma concentration of C-reactive protein

Circulation

Effects of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study

Circulation

Research
General gynecology
Insulin resistance with hormone replacement therapy: associations with markers of inflammation and adiposity