Gordana M. Prelevic

A cross-sectional study of the effects of hormon replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women.

OBJECTIVE To assess risk factors for cardiovascular disease in healthy postmenopausal women who had been uninterruptedly on menopausal hormone replacement therapy (HRT) for at least 5 years or who had not received any HRT. DESIGN Cross-sectional study. SETTING The Royal Free Hospital and The Middlesex Hospital. PATIENT(S) A total of 256 healthy postmenopausal women were analyzed: 73 were taking tibolone, 60 were taking transdermal E(2), 58 were taking conjugated equine estrogens (E), and 65 were not taking any menopausal therapy. INTERVENTION(S) Cardiovascular disease risk factors measurement. MAIN OUTCOME MEASURE(S) Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprotein(a), insulin, glycated hemoglobin, high sensitivity C-reactive protein, fibrinogen, total antioxidants, and endothelin-1. RESULT(S) The different types of HRT induced disparate changes in the various markers of cardiovascular disease. Significantly higher high sensitivity C-reactive protein concentrations were found in women receiving conjugated equine E and tibolone than in women who were not taking any therapy. Glycated hemoglobin was significantly lower in women receiving transdermal E(2) and tibolone compared to women not on HRT. Women on tibolone had significantly higher systolic blood pressure. CONCLUSION(S) Because high sensitivity C-reactive protein has recently emerged as an important predictor of cardiovascular disease, the higher high sensitivity C-reactive protein levels observed in women on conjugated equine estrogens and on tibolone have potential important clinical implications.

Twenty-four-hour serum growth hormone, insulin, C-peptide and blood glucose profiles and serum insulin-like growth factor-I concentrations in women with polycystic ovaries

Raised insulin levels are now recognized as a characteristic feature of women with polycystic ovaries (PCO), and hyperinsulinism has been shown to stimulate androgen production in such women. We have, however, recently shown that hyperinsulinaemia is present only in the obese subjects with PCO in whom insulin concentrations correlate with those of luteinizing hormone. We therefore studied 24-hour blood profiles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in obese and non-obese women with PCO, for comparison with their levels of insulin, C-peptide and other hormones, such as androgens which are known to be disturbed in PCO. Mean 24-hour GH levels were higher overall in PCO than in control subjects, although the difference was not significant. When, however, a separate analysis was made in obese as compared with non-obese PCO patients, GH concentrations were significantly higher in the non-obese group than in the obese (p = 0.0005). There was a significant negative correlation between body mass index and mean 24-hour GH concentrations (r = -0.641; p = 0.0006). IGF-I concentrations were however similar in the PCO group overall and in controls, as well as in the obese and non-obese PCO patients. The 24-hour blood glucose profile pattern was significantly different in PCO women from controls (p = 0.009), with absence of post-prandial peaks in blood glucose concentrations. These changes were most marked in the non-obese PCO group, who also had significantly lower blood glucose levels than either controls or obese PCO subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum vascular endothelial growth factor concentrations in postmenopausal women: the effect of hormone replacement therapy

OBJECTIVE To assess serum vascular endothelial growth factor (VEGF) concentrations in healthy postmenopausal women in relation to hormone replacement therapy (HRT) and the presence or absence of a uterus. DESIGN Cross-sectional study. SETTING The Middlesex Hospital. PATIENT(S) A total of 199 postmenopausal women were enrolled: 132 had uterus in situ and 67 had had hysterectomies. Of the 67 women who had had hysterectomies, 6 received no HRT, 20 received tibolone, 25 received transdermal E2, and 16 received conjugated equine estrogens. Of the 132 women with uteri in situ, 34 received no HRT, 56 received tibolone, 24 received transdermal E2 with sequential norethisterone acetate, and 18 received conjugated equine estrogens with sequential levonorgestrel. INTERVENTION(S) Serum VEGF level measurement. MAIN OUTCOME MEASURE(S) Serum VEGF concentrations. RESULT(S) Women who received HRT had higher VEGF concentrations than those not receiving HRT. Among women who received no HRT, those with uterus in situ had higher VEGF levels than did those who had had hysterectomies. Among women who had had hysterectomies, VEGF concentrations were higher in those who received conjugated equine estrogens than in those who did not receive HRT and those who received tibolone or transdermal E2. Among women with uterus in situ, no difference was found between subgroups. CONCLUSION(S) Postmenopausal women with uterus in situ and those who received HRT had higher VEGF concentrations than did those who had had hysterectomies and who did not receive HRT. Among women receiving HRT, those who received conjugated equine estrogens alone had higher VEGF concentrations. This estrogen-mediated increase in serum VEGF concentrations may be a mechanism by which HRT benefits the cardiovascular system.

Menopausal hot flushes revisited

Vasomotor symptoms are generally recognized as one of the most common symptoms, or signs, of the menopause, together with menstrual cycle changes. The etiology of hot flushes is unknown, although several mechanisms have been implicated. The reduction in hot flushes with estrogen replacement therapy suggests a hormonal etiology. However, the levels of estrogens do not appear to correlate with hot flushes. It seems more likely that the rate of change of plasma estrogen concentrations influences the thermoregulatory system via the hypothalamus. During the past few decades, remedies for the treatment of hot flushes have advanced from simple sedatives and purgatives to the use of ovarian extracts and, finally, to pharmacological estrogen preparations. In view of the contraindications and side-effects of estrogens and progestogens in postmenopausal women, however, there is a need to consider treatments other than hormone replacement for the relief of hot flushes.

Elevated concentrations of retinol-binding protein-4 (RBP-4) in gestational diabetes mellitus: Negative correlation with soluble vascular cell adhesion molecule-1 (sVCAM-1)

Background. Retinol-binding protein-4 (RBP-4) may increase insulin resistance (IR) in animals, with elevated levels reported in humans with obesity and type 2 diabetes. There are, however, few data on concentrations of RBP-4 in gestational diabetes mellitus (GDM). Methods. We measured fasting serum levels of RBP-4, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 50 women at 28 weeks of gestation, divided according to the results of a 50 g glucose challenge test (GCT) and a 75 g oral glucose tolerance test (OGTT): (1) controls (n = 20), normal responses to both GCT and OGTT; (2) intermediate group (IG) (n = 15): false positive GCT, but normal OGTT; and (3) GDM group (n = 15), both GCT and OGTT abnormal. IR was assessed by homeostasis model assessment (HOMA-IR) and by insulin resistance index (IRI) based on glycemia and insulinemia during OGTT. Results. All groups were matched for age and body mass index (BMI). RBP-4 levels (μg/ml, mean±standard deviation) were higher in women with GDM vs. controls (53.9 ± 17.9 vs. 29.7 ± 13.9, p ≤ 0.001), with a trend towards higher RBP-4 in GDM compared with IG (38.0 ± 19.3, p = 0.07). There was no significant correlation between RBP-4 and age, BMI, insulin, IRI or HOMA-IR, but there was a moderate, significant negative correlation between RBP-4 and sVCAM-1 (r2 = 0.20, p = 0.001). Conclusions. RBP-4 levels are elevated in women with GDM, but do not correlate with IR indices and correlate negatively with sVCAM-1. The physiological significance of RBP-4 rise in women with GDM remains to be elucidated.

Cardiac flow velocity in women with the polycystic ovary syndrome

OBJECTIVE Women with the polycystic ovary syndrome (PCOS) often have several of the known risk factors for cardiovascular disease, including hyperinsulinaemia. We have therefore investigated variables of cardiac flow in young women with PCOS and related them to blood levels of reproductive hormones (LH, FSH, oestradiol and testosterone) and also of insulin.

Effects of a Iow-dose estrogen-antiandrogen combination (Diane-35) on lipid and carbohydrate metabolism in patients with polycystic ovary syndrome

This study was undertaken in order to evaluate the effect of an oral contraceptive containing 35 μg of ethinyl estradiol and 2 mg of cyproterone acetate (Diane-35) on carbohydrate and lipid metabolism in patients with polycystic ovary syndrome (PCOS).Twentythree patients with PCOS were treated with Diane-35 for between 9 and 18 cycles without interruption (a total of 318 treated cycles). Metabolic evaluations, which included measurements of fasting blood glucose, insulin, C-peptide, total cholesterol, triglyceride, total lipids, HDL-cholesterol, LDL-cholesterol and apolipoproteins (Apo A1, Apo A2 and Apo B), were performed before treatment and every 3rd cycle during the treatment period. In the case of 5 women an oral glucose tolerance test (oGTT) was performed before and after the 12th cycle of Diane-35 treatment, with blood samples taken for glucose, insulin and C-peptide measurements.Total cholesterol showed a significant increase after the 6th cycle (p < 0.001) and reached the mean maximal value after...

LH pulsatility and response to a single s.c. injection of buserelin in polycystic ovary syndrome

The present study was undertaken in order to determine whether patients with polycystic ovary syndrome (PCOS) have LH pulse frequency and/or amplitude higher than those in normal cycling women during the follicular phase, and, if so, to establish possible factors which might influence LH secretion in PCOS. The study was conducted on 14 PCO patients (aged 19-30 years), who were subdivided according to the data on their cycle abnormality into 2 groups: amenorrheic (Am-PCOS, n = 9) and oligomenorrheic (O-PCOS, n = 5). LH pulsatility was assessed in the early follicular phase in controls (n = 5) and O-PCOS and at any time in Am-PCOS. Blood samples were taken every 10 minutes for 4 hours. Pulse analyses of LH data were performed using the Munro program. The buserelin test was performed on the same day by injection of 40 micrograms of buserelin (blood samples were taken every 60 minutes for the following 10 hours). Eleven PCO patients and 12 control subjects had an oral glucose tolerance test (oGTT) (blood samples were taken every 60 minutes for glucose, insulin and C-peptide measurements). Both mean LH pulse frequency and mean pulse intervals were not distinguishably different in PCO women (Am and O) and controls. In contrast, the mean pulse amplitude was significantly higher in the Am-PCOS group than in O-PCOS women and controls (p less than 0.02 and p less than 0.001, respectively). A significant positive correlation was established between nadir LH concentrations and LH pulse amplitude (r = +0.966, p less than 0.001). The LH response to buserelin stimulation was significantly higher in Am-PCOS than in O-PCOS (p less than 0.004). A highly significant positive correlation was observed between LH pulse amplitude and insulin response during oGTT (p less than 0.001) in PCO subjects. Basal (prebuserelin) LH concentrations correlated significantly with fasting insulin levels (p less than 0.008) and insulin and C-peptide responses to oGTT. These results allow us to conclude the following: 1. An increased LH pulse amplitude and an exaggerated LH response to buserelin observed in amenorrheic PCO subjects compared to those in oligomenorrheic PCO subjects fail to support the hypothesis of an intrinsic hypothalamo-pituitary abnormality. 2. The relationship between fasting and glucose-stimulated insulin levels with LH nadir concentrations, pulse amplitude and response to buserelin suggests an etiological role of insulin in the pathogenesis of PCOS.

Effect of estrogen replacement therapy on cardiac function in postmenopausal women with and without flushes

Left ventricular heart function and its response to long-term estrogen replacement therapy was assessed in 30 postmenopausal women, 20 of whom had modest to severe hot flushes and 10 of whom had never had them. Continuous transdermal estradiol was given to women who had surgically induced menopause, and a combination of transdermal estradiol and sequential medroxyprogesterone acetate was given to those who had spontaneous menopause. Left ventricular systolic and diastolic function was evaluated by complete two-dimensional M-mode and pulsed Doppler echocardiography before and after 6 and 12 months of therapy. The parameters assessed were: systolic and diastolic blood pressure, heart rate, cardiac septal and posterior wall dimensions, left ventricular end-systolic and end-diastolic dimensions and volumes, ejection fraction (EF), ejection time, peak left ventricular outflow velocity (PFV), flow velocity integral (FVI), acceleration time (AT), mean acceleration of systolic flow (MA), duration of early and late filling phase, peak velocity of the early (E) and late (A) mitral flow, and A/E velocity ratio. Although no difference in chamber and wall dimensions between flushers and non-flushers was found, women with hot flushes had lower (not significantly) EF, PFV, FVI, MA, blood pressure and heart rate before therapy. Twelve-month estrogen replacement therapy significantly reduced cardiac wall dimensions and improved systolic function in both flushers and non-flushers. However, stroke volume, EF and MA were increased whereas systolic blood pressure and heart rate were decreased more in flushers. Also, the increase in E mitral flow and decrease in A/E were more pronounced in flushers. Thus, although estrogen replacement therapy significantly improves heart function in healthy postmenopausal women, there appears to be some minor differences in response between flushers and non-flushers.

INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME

Hyperinsulinaemia is found in 30% of slim and 75% of obese women with polycystic ovary syndrome. Despite resistance to insulin action in terms of glucose transport, increased insulin levels may cause hyperandrogenaemia by enhancement of androgen production in the ovaries where insulin acts as co-gonadotrophin. Recent interest in insulin resistance results from the recognition that it predisposes to various metabolic abnormalities, and could be involved in the pathogenesis of atherosclerosis. Women with polycystic ovary syndrome frequently have metabolic disturbances associated with insulin resistance, and recent long-term follow-up studies have indicated that they also have a higher incidence of diabetes and hypertension later in life compared with control populations. This review describes the association of hyperinsulinaemia with hyperandrogenism, metabolic and circulatory changes in women with polycystic ovary syndrome. Special emphasis is placed on recent studies of molecular mechanisms of insulin resistance in polycystic ovary syndrome and clinical implications of hyperinsulinaemia in these women.