The effects of micronutrient supplementation on vasomotor symptoms in postmenopausal women.

OBJECTIVE: Estrogen is the most effective treatment for vasomotor symptoms. Given its potential risks, herbal preparations and nutritional supplements have been developed as alternative remedies. The main aim of this double-blind, randomized, placebo-controlled trial was to assess any impact of a nutritional supplement containing 12 vitamins and nine minerals on the frequency and severity of hot flushes in postmenopausal women over a 3-month period. SUBJECTS AND METHODS: Ninety-one postmenopausal women were randomized to either the placebo (n = 45) or the treatment arm (n = 46). Seventy out of the 91 women completed the study (36 from the treatment group and 34 from the placebo group). At baseline and the 14-week post-intervention assessments, study participants completed questionnaires on the frequency and severity of hot flushes and night sweats, the Profile of Mood State questionnaire, the World Health Organization Quality of Life Questionnaire, the National Adult Reading Test and the Rey Auditory-Verbal Learning Test. Between assessments, the women also completed hot flush diaries. RESULTS: There was a significant decrease (p < 0.01) in the number (±standard error of the mean) of hot flushes experienced per week for treatment (pre 31.3 ± 4.7; post 23.1 ± 4.8) and placebo groups (pre 28.1 ± 4.7; post 17.3 ± 4.0). A significant decrease (p < 0.001) in the number of night sweats experienced per week was also observed in the treatment (pre 6.1 ± 1.0; post 4.2 ± 0.7) and placebo groups (pre 5.9 ± 0.7; post 3.7 ± 0.7). CONCLUSIONS: This study demonstrates a significant placebo effect on hot flushes and night sweats, as consistent with other studies. The micronutrient supplement containing 21 vitamins and minerals was not superior over placebo in effects on hot flushes and night sweat experiences.

Increased circulating levels of matrix metalloproteinase-2 and -9 in women with the polycystic ovary syndrome.

INTRODUCTION: Matrix metalloproteinases (MMPs) have been implicated in various pathological processes including inflammatory response, cardiovascular disease, and recently also in ovarian dysfunction. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and is characterized by chronic anovulation, insulin resistance, and increased prevalence of cardiovascular risk factors. Circulating levels of MMPs and their tissue inhibitors (TIMPs) so far have not been assessed in the PCOS. MATERIALS AND METHODS: Serum levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured in 23 women with PCOS [age (mean +/- sd), 30.5 +/- 6.7 yr; body mass index, 35.8 +/- 7.5 kg/m2] and 22 healthy, regularly menstruating women (age, 29.4 +/- 5.6; body mass index, 31.7 +/- 9.2 kg/m2). RESULTS: Women with PCOS had significantly higher concentrations of MMP-2 (999.8 +/- 155 vs. 521.8 +/- 242 ng/ml; P < 0.001), MMP-9 (592.4 +/- 279 vs. 345 +/- 309; P = 0.007), and TIMP-1 levels (823.8 +/- 145 vs. 692 +/- 210 ng/ml; P = 0.02) than control healthy women. There was no difference in TIMP-2 levels (47.3 +/- 30 vs. 44.4 +/- 39.7 ng/ml; P = 0.21) between women with PCOS and controls. CONCLUSIONS: Obese women with PCOS have elevated serum concentrations of MMP-2 and -9. It might be hypothesized that elevated MMP concentrations may be related to increased cardiovascular risk in PCOS and/or menstrual irregularities associated with this syndrome.

Hormone replacement therapy in postmenopausal women.

From the endocrine point of view, menopause is considered a deficiency state and menopausal hormone replacement therapy (HRT) regarded as restoring the premenopausal endocrine milieu. Millions of healthy postmenopausal women were taking HRT in late 1990's many in the absence of menopausal symptoms. The major benefit from HRT was considered to be cardiovascular protection and also protection against osteoporosis and Alzheimer's Disease. The Women's Health Initiative (WHI) trial and other studies published since 2002 fundamentally changed our understanding of risks and benefits associated with HRT. This review discusses the effects of HRT on menopausal symptoms, cognitive function, cardiovascular disease, osteoporosis and also breast and bowel cancer.

The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes.

GH hypersecretion in insulin-dependent diabetes (IDDM) is well documented. Although it has recently been shown that residual insulin secretion determines the magnitude of this GH hypersecretion, the underlying mechanisms of the disorder have not yet been clarified. The 24-h GH and blood glucose profiles, insulin-like growth factor I (IGF-I) concentrations and GH responses to GRF were analyzed in 21 insulin-dependent diabetics and 4 healthy subjects before and after 7 days treatment with recombinant human GH (rhGH) (4 IU given sc at 0800 h). According to C-peptide response to glucagon IDDM patients were subdivided into C-peptide negative (CpN, n = 12) patients without endogenous pancreatic beta-cell activity and C-peptide positive (CpP, (n = 9) patients with endogenous insulin secretion. No significant difference could be observed between the mean 24-h blood glucose profile before and after rhGH treatment in any treated group. Before and on rhGH treatment the highest 24-h GH values were observed in CpN patients when compared to CpP and controls. The rhGH treatment induced a similar increase in the mean 24-h GH concentrations in all groups studied which was statistically significant only in CpP diabetics. Mean pretreatment serum IGF-I concentrations were not significantly different between CpN, CpP patients and controls. The net increase in IGF-I concentrations after rhGH treatment was however, significantly lower in CpN patients than in CpP and control subjects. GRF-induced GH response before and after rhGH treatment was significantly greater in diabetics than in controls. The response of GH to GRF in CpN diabetics was however, almost unchanged after treatment whereas it became lower in CpP diabetics and controls. The dose of 4 IU of rhGH increased significantly GH levels in diabetics with preserved beta-cell function with consequent increase in IGF-I levels and attenuation of GRF induced GH response. In contrast, the same dose of rhGH failed to induce significant increase in GH levels in diabetics without residual beta-cell activity, most probably due to already high pretreatment levels. In addition, neither increase in IGF-I levels nor suppression of GH response to GRF on rhGH treatment was observed in CpN diabetics. The results are in keeping with an important role of portal insulin in GH-induced hepatic IGF-I secretion.

Effects of the somatostatin analogue, octreotide, in polycystic ovary syndrome.

In view of the association of hyperinsulinemia with elevated luteinizing hormone (LH) levels and hyperandrogenism in polycystic ovary syndrome (PCOS), the effect of octreotide was investigated in women with PCOS. Twelve amenorrheic women were treated with 100 micrograms octreotide twice a day for 7 days; 13 infertile women unresponsive to clomiphene citrate were treated either with octreotide (100 micrograms twice a day from day 1 of the menstrual cycle until corpus luteum formation) in addition to human menopausal gonadotropins (HMG) or with HMG alone. Octreotide significantly reduced the 4-hour integrated LH concentrations. LH pulse amplitude and nadir concentrations, and LH, testosterone, androstenedione, and estradiol responses to a gonadotropin-releasing hormone (GnRH) analogue in amenorrheic PCOS women. Octreotide treatment also resulted in a more "appropriate" hormonal milieu at the time of human chorionic gonadotropin (HCG) injection in the infertile women, with LH and testosterone levels being reduced while follicle-stimulating hormone (FSH) levels increased. Orderly follicular growth occurred, with one or two mature follicles being present at the time of HCG injection in cycles in which octreotide was given together with HMG. There were no cases of hyperstimulation, even in women who had previously hyperstimulated after HMG alone. Octreotide thus inhibits LH and androgen secretion and may improve ovulatory performance in infertile women with PCOS.

Testosterone levels after bromocriptine treatment in patients undergoing long-term hemodialysis.

Seventeen out of 34 male patients undergoing long-term hemodialysis had increased basal plasma prolactin levels (mean = 1344 +/- 1158.76 mU/L). Seven of these 17 patients having the greatest degree of erectile impotence were treated with 3.5 to 7.5 mg/day of bromocriptine. After a 4-week treatment period, basal plasma prolactin levels in all seven patients were within normal limits (mean = 210.2 +/- 66.97 mU/L). The treated patients reported an improvement in both libido and potency. At the same time, an increase in plasma testosterone levels was observed, while plasma LH and FSH levels were essentially unchanged.

The effect of oestrogen and progestogen replacement therapy on systolic flow velocity in healthy postmenopausal women.

The effects on left ventricular systolic outflow velocity of 3 months' treatment with either continuous transdermal oestradiol or cyclical transdermal oestradiol with medroxyprogesterone acetate were assessed in 34 healthy postmenopausal women. Cardiac flow was measured by pulsed wave Doppler echocardiography in 14 of these women and by continuous wave Doppler echocardiography in 20. Control studies were made in ten premenopausal women using pulse wave Doppler and in ten with continuous wave Doppler. The indicators assessed were: ejection fraction (EF), preejection time (PEP), ejection time (ET), peak systolic flow velocity over the aortic valve (PFV), acceleration time (AT), flow velocity integral (FVI) and mean acceleration (MA). Postmenopausal women had significantly lower EF, PFV, FVI, MA but longer AT and ET compared to premenopausal women. After 3 months' transdermal oestradiol significant increases in EF, PFV, FVI and MA were observed whilst AT decreased. The response in all cardiac flow indicators was similar with added progestogen. Blood pressure, however, increased after the addition of progestogen. Nevertheless the addition of progestogen does not attenuate the effect of oestrogen therapy on left ventricular systolic flow velocity.

Cause of vaginal bleeding in postmenopausal women taking tibolone.

OBJECTIVE: To determine the cause of vaginal bleeding in postmenopausal women treated with tibolone. SUBJECTS: Forty seven consecutive unselected women who bled in the course of treatment with tibolone between 1986 and 1995. STUDY METHODS: Clinical evaluation and pelvic ultrasound scanning in all women and additional Doppler flow assessment in 12. Hysteroscopy was performed in 20 women and D and C in nine. RESULTS: An endometrial polyp was found responsible for the bleeding in 11 women and uterine fibroids in seven. Thickened endometrium was seen on ultrasound in six women; there was no histological abnormality in three of these women, two had benign simple hyperplasia and the remaining woman had an early carcinoma in situ. Carcinoma in situ was also found in another woman as an incidental finding in the endometrial curettings taken at hysteroscopy in the course of polypectomy. In over half, however, (24 women), no intrauterine cause could be found to account for vaginal bleeding. The occurrence of vaginal bleeding after tibolone clustered in two groups; 30 women who bled within 4 months of starting tibolone (of whom 17 had recently taken oestrogens) and 17 who bled after at least a years' therapy. CONCLUSION: Bleeding after tibolone requires investigation. A morphological abnormality may be present even in women who have recently taken oestrogens and experienced cyclical bleeding. Despite full investigation, no cause for bleeding was however found in over half the group. The majority (37 women) of those who reported bleeding nevertheless continued on tibolone after completion of investigations with no recurrence of bleeding.

The effect of tibolone on cardiac flow in postmenopausal women with non-insulin dependent diabetes mellitus.

OBJECTIVE: Postmenopausal women with non-insulin dependent diabetes (NIDDM) are frequently obese, hypertensive and hyperlipidaemic and hence at particular risk of coronary heart disease (CHD). They might therefore benefit from menopausal therapy. In view of the fact that oestrogen replacement increases cardiac flow but not limb flow whilst tibolone dilates forearm flow in healthy postmenopausal women, a study was undertaken to evaluate the effects of tibolone on cardiac flow in postmenopausal women with NIDDM. DESIGN: A prospective 12 months before/after intervention study. PATIENTS: 15 postmenopausal women (mean age 58.36 +/- 1.25 years; mean duration of menopause 115.20 +/- 13.97 months; mean BMI: 26.22 +/- 1.02) with NIDDM (mean duration of diabetes 106.07 +/- 15.66 months). MEASUREMENTS: Cardiac flow was measured every 6 months for 1 year by pulsed Doppler echocardiography. The parameters assessed were: stroke volume (SV), cardiac output (CO), ejection fraction (EF), pre-ejection time (PEP), ejection time (ET), peak systolic flow velocity (PFV), acceleration time (AT), flow velocity integral (FVI), mean acceleration (MA), early diastolic filling time (Ei), atrial filling time interval (Ai), peak velocity of the early diastolic filling (E) and peak velocity of the early atrial filling (A). Blood pressure was also recorded during Doppler echocardiography. RESULTS: Stroke volume, cardiac output and ejection fraction increased significantly after 6 months. There was also a significant increase in peak flow velocity (PFV), flow velocity integral (FVI) and mean acceleration (MA) together with a significant increase in early diastolic filling time (Ei) and peak velocity of the early diastolic filling (E). Blood pressure was unchanged throughout the 12-month study period. CONCLUSION: The significant increase in stroke volume, cardiac output and flow velocity over the aortic valve parallel the effects of oestrogens in healthy postmenopausal women. The fact that tibolone improved left ventricular relaxation suggests the drug might help prevent or at least defer the development of cardiac dysfunction in diabetic women.

Effects of physical activity and menopausal hormone replacement therapy on postural stability in postmenopausal women--a cross-sectional study.

OBJECTIVES: Poor postural stability and muscular strength in postmenopausal women are associated with increased risk of falls and fractures. This study examined whether these risk factors for falls differed according to habitual physical activity and menopausal hormone replacement therapy (HRT) use. METHODS: Subjects were 117 postmenopausal women (mean age 65.3+/-6.0 years); of whom 70 had taken HRT for at least 5 years (42 tibolone and 28 transdermal oestradiol), whilst 47 had not received HRT. Duration of physical activity was assessed with monitors worn on a waist belt. Subjects were grouped into low (LPA; < or = 15 min day(-1)) or high (HPA; >15 min day(-1)) physical activity. Postural stability was assessed using a swaymeter which measured displacement at the waist. Maximal isometric strength of knee flexors was determined in 23 of the tibolone group, 26 of the oestrogen group and 12 of the no therapy group. RESULTS: Stature and body mass did not differ according to physical activity participation or HRT use, although the more active women were on average 2.5 years younger than the less active women. Body sway was lower in more physically active women in three of the four measurement conditions (P<0.05) and this effect persisted after inclusion of age as covariate. Body sway tended to be highest in the no therapy group, although not significantly so. Mean knee extensor strength was higher in women taking tibolone and oestrogen than in those not on therapy (115.3 (5.2), 118.2 (7.2) and 97.6 (9.3) Nm, respectively), although again this difference was not statistically significant. CONCLUSIONS: The more physically active postmenopausal women had significantly better postural stability than less active women, whilst HRT had no significant effect. Physical activity might thus have a role in reducing the risk of fracture through reducing the risk of falling.

Metabolic effects of tibolone in postmenopausal women with non-insulin dependent diabetes mellitus.

OBJECTIVE: Postmenopausal women with non-insulin dependent diabetes (NIDDM) are frequently obese, hypertensive and hyperlipidaemic and hence at particular risk of coronary heart disease (CHD). They might therefore benefit from menopausal therapy. In view of the improvement in insulin sensitivity and the reduction in triglyceride levels induced by tibolone in healthy postmenopausal women we evaluated the effects of 12 months of tibolone on glycaemic control, serum insulin and lipid levels in postmenopausal women with NIDDM. DESIGN: A prospective 12 months before/after intervention study. PATIENTS: Fourteen postmenopausal women (mean age 58.14 +/- 1.25 years; mean duration of menopause 121.21 +/- 13.42 months; mean BMI: 26.55 +/- 0.97) with NIDDM (mean duration of diabetes 113.79 +/- 13.89 months). MEASUREMENTS: Fasting and postprandial blood glucose levels were assessed monthly, serum fructosamine, fasting and postprandial insulin every 3 months and serum lipids (total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol) every 6 months. RESULTS: Changes in blood glucose, both fasting and postprandial, were not statistically significant during the treatment period. Serum fructosamine concentration increased significantly after 9 months. A significant decrease in fasting and postprandial insulin concentrations was observed after 9 months. A non-significant decrease was observed in total cholesterol, LDL cholesterol and triglyceride but no change in HDL cholesterol. Body weight did not change during the period of observation. CONCLUSION: A slight deterioration in glycaemic control, a fall in insulin concentration and no change in serum lipids were observed in women with NIDDM during 12 months treatment with tibolone.

The effect of hormone replacement therapy on diastolic left ventricular function in hypertensive and normotensive postmenopausal women.

OBJECTIVES: To evaluate the effect of hormone replacement therapy (HRT) on left ventricular diastolic function in a group of hypertensive and normotensive postmenopausal women. METHODS: Left ventricular diastolic function at rest was evaluated by M-mode, two-dimensional and Doppler echocardiography in 19 postmenopausal women with normal blood pressure and 11 postmenopausal women with mild hypertension, before treatment and during 12 months of HRT. Transdermal estradiol was used in women with a surgical menopause and a sequential regimen of transdermal estradiol and peroral medroxyprogesterone acetate in women with a spontaneous menopause. The parameters assessed were: body mass index, heart rate, ejection fraction of the left ventricle (EF), septal (SW) and posterior wall (PW) dimensions, left ventricular end-systolic (LVsd) and end-diastolic (LVdd) dimensions and volumes (ESV, EDV), total diastolic time (DT), duration of the early (Ei) and of the late (Ai) filling phase, peak velocity of the early (E) and late mitral flow (A), A/E velocity ratio and systolic and diastolic blood pressure. Quantitative data were analyzed using unpaired t-test, MANOVA and multiple regression analysis where appropriate. RESULTS: Hypertensive postmenopausal women had significantly higher SW (P < 0.05), PW (P < 0.05), A/E (P < 0.05) and A (P < 0.001) than normotensive postmenopausal women, before therapy. After 12 months of HRT a significant decrease in SW, PW, LVsd, ESV and increase in EF, DT, Ei and E was observed in both hypertensive and normotensive postmenopausal women. Heart rate slowed and systolic pressure decreased significantly only in normotensive postmenopausal women on HRT. CONCLUSION: HRT of 12 months' duration does not deteriorate left ventricular diastolic function of both hypertensive and normotensive postmenopausal women. Improvement in some parameters of diastolic function could be partially explained by the decrease in heart rate and systolic pressure, induced by therapy.

The influence of physical activity on the response of bone mineral density to 5 years tibolone.

OBJECTIVES: Menopausal hormone replacement therapy (HRT) maintains bone mineral density (BMD) and reduces risk of fracture in postmenopausal women. It has been suggested that sex steroids and loading may have synergistic effects on bone. We therefore investigated whether habitual physical activity influences the response of BMD to tibolone in postmenopausal women. METHODS: The subjects were 42 postmenopausal women aged mean (SE) 65.8+/-6.2 year who had taken tibolone for prevention/ treatment of osteoporosis over 5 years. Bone mineral density was measured annually by dual X-ray absorptiometry and physical activity was assessed using accelerometers after 5 years therapy. RESULTS: Twenty-six women were classified as having low physical activity (LPA; <15 min day(-1)) and sixteen as high physical activity (HPA; >15 min day(-1)). Spine BMD did not differ significantly between groups at baseline and increased significantly by 2 years of treatment with further increase to 5 years. The magnitude of increase did not differ between groups. Hip BMD at baseline was 7.3% higher in HPA women (P=0.07). Hip BMD increased over 2 years tibolone treatment in LPA women (+5.6%, P<0.01) whilst no significant change occurred in the HPA group (-0.5%). This difference in response between groups was statistically significant (P=0.002) and persisted after adjustment for age and body mass (P=0.002). Hip BMD was maintained in both groups over the subsequent 3 years of treatment. CONCLUSIONS: Spine BMD increased significantly in response to tibolone irrespective of physical activity participation. The more physically active women had higher hip BMD at baseline but the response to tibolone was greater in the less physically active women. The difference in response between groups may be due to physically active women having lower resorption at the hip and hence reduced response to anti-resorptive effects of HRT.

Effect of recombinant human growth hormone treatment on insulin-like growth factor (IGF-I) levels in insulin-dependent diabetic patients.

Basal and recombinant human growth hormone (rhGH)-stimulated insulin-like growth factor (IGF-I) levels were studied in 19 insulin-dependent diabetic patients and 4 healthy subjects. Diabetic patients were divided according to glucagon test result into CpN (10 patients without residual beta cell activity) and CpP (9 patients with preserved beta-cell activity) and CpP (9 patients with preserved beta-cell activity) groups, and according to age into three groups (A = 21-30 years; B = 31-40 years; C = 41-50 years). All control subjects belonged to group B. Blood glucose and growth hormone were measured at hourly intervals and IGF-I every 6 h during 24 h before and after 7 days treatment with 4 IU of rhGH given subcutaneously at 8 p.m. The age-related decrease in basal IGF-I levels was evident in both CpN and CpP groups of diabetic patients. IGF-I net increase with rhGH treatment was variable and insignificant in comparison with basal value without age-related differences in CpN diabetics. Progressively larger, age-related increases in IGF-I concentrations were observed in CpP diabetic patients. This study indicates impairment of hepatic IGF-I generation capacity in diabetic patients without residual beta-cell activity and the importance of simultaneous actions of portal insulin and GH on hepatic IGF-I production.

The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study.

The objective of this open, longitudinal, controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 microg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 microg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials.

Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance.

AIMS/HYPOTHESIS: Concentrations of visfatin are increased in insulin-resistant conditions, but the relationship between visfatin and insulin and/or insulin resistance indices in pregnancy remains unclear. Insulin resistance in pregnancy is further accentuated in women with gestational diabetes mellitus (GDM). Thus we assessed serum levels of visfatin in pregnant women with varying degrees of glucose tolerance. MATERIALS AND METHODS: Fasting visfatin levels were measured at 28 weeks of gestation in 51 women divided according to their response to a 50-g glucose challenge test (GCT) and a 75-g OGTT: control subjects (n = 20) had normal responses to both a GCT and an OGTT; the intermediate group (IG; n = 15) had a false-positive GCT, but a normal OGTT; the GDM group (n = 16) had abnormal GCTs and OGTTs. RESULTS: There were no age or BMI differences between analysed groups. Across the subgroups there was a progressive increase in glucose and insulin at 120 min of the OGTT (p < 0.01). This was accompanied by an increase in visfatin, from 76.8 +/- 14.1 ng/ml in the control subjects, to 84.0 +/- 14.7 ng/ml in the IG group and 93.1 +/- 12.3 ng/ml in the GDM group (p < 0.01 for GDM vs control subjects). There was a positive correlation between visfatin and fasting insulin (r = 0.38, p = 0.007) and insulin at 120 min of the OGTT (r = 0.39, p = 0.006). CONCLUSIONS/INTERPRETATION: An increase in fasting visfatin, the levels of which correlate with both fasting and post-glucose-load insulin concentrations, accompanies worsening glucose tolerance in the third trimester of pregnancy. However, the significance of these findings, and in particular the role of visfatin in the regulation of insulin sensitivity during pregnancy, remains to be elucidated.