Effect of hormone replacement therapy on intervertebral disc height.

OBJECTIVE: Intervertebral discs act as shock absorbers, thereby helping to reduce the risk of vertebral body fractures. Previous studies have shown that estrogen loss following menopause is associated with disc height reduction whereas treatment with hormone replacement therapy (HRT) helps to maintain disc height. This study reports the effect of HRT on disc height from a post hoc analysis of a prospective randomized clinical trial of the effect of HRT on bone density. METHODS: A total of 355 healthy postmenopausal women aged (mean ± standard deviation) 55.4 ± 4.8 years were randomized to HRT with oral 1 mg or 2 mg estradiol plus dydrogesterone or placebo. Dual-energy X-ray absorptiometry measurements (Lunar DPX) were obtained at baseline and following 2 years of treatment. Intervertebral disc height was measured in discs between T12 and L3 using the bone densitometer ruler. RESULTS: Compared with baseline, treatment with HRT resulted in a significant increase in total disc height with 1 mg estradiol (0.16 ± 0.65 cm, p = 0.015) and with 2 mg estradiol (0.21 ± 0.86 cm, p = 0.006) whilst there was no significant increase with placebo (0.13 ± 0.65 cm, p = 0.096). Between-group differences were not statistically significant. CONCLUSIONS: These results are consistent with previous findings of a beneficial effect of estrogen on discs. This may be in part responsible for the anti-fracture efficacy of HRT on vertebral fractures.

Cardiometabolic health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is an increasing public health problem with a prevalence now approaching 4%. POI results in adverse effects on the skeleton and central nervous system as well as disturbances of metabolic and cardiological factors that predispose to a major increased risk of cardiovascular disease (CVD). This article reviews the effects of the premature loss of ovarian function on lipids and lipoproteins, glucose and insulin metabolism, body composition, hemostasis and blood pressure, together with effects on the development of metabolic syndrome and diabetes mellitus. The article examines the effects of POI on vascular endothelial function and inflammation that result in arterial disease, and reviews the effects of hormone replacement therapy (HRT) on these various metabolic processes and on cardiovascular outcomes. It is essential that women with POI receive hormonal treatment to help prevent the development of CVD, and that this treatment is continued at least until the normal age of menopause. It appears that HRT has a more favorable effect than the combined oral contraceptive, but larger clinical trials are needed to establish the optimal treatment. Other therapeutic measures may need to be added to correct existing metabolic abnormalities and, in particular, attention to lifestyle factors such as diet and exercise must be encouraged.

The menopausal hot flush: a review.

The hot flush is the most characteristic and often the most distressing symptom of the menopause. It is a unique feature and yet the mechanism and health implications are still not fully understood. This review summarizes some of the current thoughts on factors contributing to flushing, the physiological, vascular and neuroendocrine changes associated with flushing and the possible cardiovascular and other health implications for women experiencing hot flushes. Therapy is not discussed.

Cardiovascular risk assessment in women - an update.

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Although it is a disease of aging, vascular disease initiates much earlier in life. Thus, there is a need to be aware of the potential to prevent the development of the disease from an early age and continue this surveillance throughout life. The menopausal period and early menopause present an ideal opportunity to assess cardiovascular risk and plan accordingly. Generally in this period, women will be seen by primary health-care professionals and non-cardiovascular specialists. This review addresses female-specific risk factors that may contribute to the potential development of cardiovascular disease. It is important for all health-care professionals dealing with women in midlife and beyond to be cognisant of these risk factors and to initiate female-specific preventative measures or to refer to a cardiovascular specialist.

Bisphosphonate drug holidays--when, why and for how long?

Bisphosphonates are first-line agents used for the treatment of osteoporosis in postmenopausal women and men. Although their efficacy in the reduction of vertebral, non-vertebral and hip fracture risk has been established, some concerns have arisen associated with their long-term use. These include osteonecrosis of the jaw and atypical (subtrochanteric and femoral shaft) fractures. The latter may result from accumulation of fatigue damage due to oversuppression of bone turnover in susceptible individuals. In this respect, the concept of a 'drug holiday' after completion of a reasonable period of bisphosphonate therapy has emerged. Theoretically, this allows bone turnover to increase and permits normal skeletal maintenance and repair, although there is as yet no good evidence that bisphosphonate discontinuation will reduce the risk of these adverse events. Current data derive from studies in postmenopausal women and support a beneficial effect of alendronate or zolendronate continuation in high-risk groups, such as those with T-score < -2.5 or prevalent vertebral fractures after completion of 5 or 3 years, respectively. The optimal length of a 'drug holiday' has not been established but existing data suggest up to 5 years with alendronate, 3 years with zoledronate and 1 year with risedronate. A decision to recommence therapy should then probably be based on regular reassessment of bone mineral density and fracture risk.

Conflicts of interest, smoke and mirrors.

Commercial funding of research studies may potentially influence or bias the findings and interpretation of results. An editorial on conflicts of interest suggested that funding from non-commercial sources, such as government agencies, may also represent a conflict of interest, and uses the Women's Health Initiative (WHI) as an example of how this might be. Two WHI investigators responded by claiming that the arguments put forward in the editorial were largely 'red herrings' and were aimed at disparaging the WHI results. But there is evidence of bias in the presentation and interpretation of WHI findings by some investigators which may be due to conflicts of interest. It is probably wise to declare all sources of external research funding, including industries, governments and charities, as conflicts of interest so that reviewers of such research studies are alerted to give them full scrutiny for evidence of external influences.

Validation of three geolocation strategies for health-facility attendees for research and public health surveillance in a rural setting in western Kenya.

Understanding the spatial distribution of disease is critical for effective disease control. Where formal address networks do not exist, tracking spatial patterns of clinical disease is difficult. Geolocation strategies were tested at rural health facilities in western Kenya. Methods included geocoding residence by head of compound, participatory mapping and recording the self-reported nearest landmark. Geocoding was able to locate 72·9% [95% confidence interval (CI) 67·7-77·6] of individuals to within 250 m of the true compound location. The participatory mapping exercise was able to correctly locate 82·0% of compounds (95% CI 78·9-84·8) to a 2 × 2·5 km area with a 500 m buffer. The self-reported nearest landmark was able to locate 78·1% (95% CI 73·8-82·1) of compounds to the correct catchment area. These strategies tested provide options for quickly obtaining spatial information on individuals presenting at health facilities.

Risks and benefits of hormone therapy: has medical dogma now been overturned?

BACKGROUND: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'. OBJECTIVES: To evaluate those claims. METHODS: Epidemiological criteria of causation were applied to the evidence. RESULTS: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor. CONCLUSIONS: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

The WHI: the effect of hormone replacement therapy on fracture prevention.

The Women's Health Initiative (WHI) randomized, controlled trial was the first study to prove that hormone replacement therapy (HRT) reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture. The study authors concluded that the bone-friendly aspect of HRT was limited in clinical practice as possible adverse effects outweighed possible benefit. On the strength of these publications, regulatory authorities downgraded the use of HRT for the prevention of fracture to second-line therapy. This article examines the original and subsequent evidence presented by the WHI study and concludes that the restrictions placed on HRT as a bone-specific drug by regulatory bodies have not withstood the test of time and are not supported by the data of the WHI.

HRT and breast cancer risk: a realistic perspective.

A new analysis from the Women's Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a significant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen?progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.

Type and route of estrogen administration.

Hormone replacement therapy (HRT) can be administered orally and non-orally. Providing equivalent doses are given, all forms of HRT can equally relieve menopausal symptoms and prevent bone loss and osteoporosis. Different routes of administration will have differing metabolic effects, with oral HRT producing a hepatic first-pass effect not seen with non-oral HRT. The first-pass effect can produce benefits including larger reductions in low density lipoprotein cholesterol, lipoprotein(a) and insulin resistance, and larger increases in high density lipoprotein cholesterol. Unwanted effects are seen in increases in triglycerides and in coagulation activation. Cardiovascular effects of oral and transdermal HRT appear to be fairly similar, with improvements in vascular endothelial function, angiotensin-converting-enzyme activity, and in most markers of inflammation. There is a paucity of studies on the effects of transdermal HRT on cardiovascular outcomes, but the few data available suggest similar effects to oral HRT, and dose rather than route of administration is probably more important in this respect. Oral HRT may be preferred in women with evidence of insulin resistance, such as in metabolic syndrome or maturity-onset diabetes mellitus. Transdermal HRT may be preferred in women with coagulation disturbances. But, for the majority of women, personal preference should determine their choice of HRT route.

Attention deficit/hyperactivity disorder (ADHD) symptoms and digit ratios in a college sample.

Diagnosticians recognize three subtypes of attention deficit/hyperactivity disorder (ADHD) if there are developmentally inappropriate levels (six or more symptoms) of Hyperactive-Impulsive behavior, or Inattentive behavior, or both (Combined), respectively. ADHD may partly reflect androgen dysfunction, and an arguable proxy for prenatal androgen exposure is the 2D:4D finger ratio set at least as early as week 9 in the fetus; this is lower in men than in women. We examined the relationship between digit ratios and ADHD symptoms representing the three phenotypes: ADHD/Combined as measured by "summarized" (Rasched) scales, i.e., 1) the short version of the Wender Utah Rating Scale (WURS) and a total symptom list derived from the DSM IV, and the subdivided DSM IV into 2) ADHD/Inattentive and 3) ADHD/Hyperactive-Impulsive inventories, in a sample of European-descent college students (135 female, 52 male) not selected for ADHD. All digit ratios were calculated excluding the thumb. There were significant sex differences for the 2D:4D digit ratios of both hands (RH and LH), and between the RH 3D:4D and between the LH 2D:3D ratio. In females, the more masculine the LH 2D:4D ratio, the more the ADHD/Combined symptoms (both WURS and DSM) and the more the ADHD/Inattentive symptoms and ADHD/Hyperactive-Impulsive symptoms. More masculine ratios also correlated between the total WURS and RH 2D:3D, RH 2D:4D, and LH 2D:3D; and between the inattentive DSM symptoms and LH 2D:5D, and between the ADHD/Hyperactive and Impulsive symptoms and RH 3D:4D.

Attention-deficit hyperactivity disorder and fluctuating asymmetry in another college sample.

Attention deficit/hyperactivity disorder (AD/HD) represents a developmental lag that may be reflected in fluctuating asymmetry (FA), i.e., differences from perfect symmetry in traits that display bilateral symmetry. Burton et al. (2003 Am. J. Hum. Biol. 15:601-619) found a statistical trend for FA to increase (as dermatoglyphic index or as total index) as the behavioral measure for AD/HDness (Rasch logit values derived from the Wender Utah Rating Scale, or WURS) increased in males but not in females. The objective here was to do a similar study in an independently collected sample of college students (n = 222; 61 male, 161 female) not selected for AD/HD, looking at FA vs. symptoms for AD/HD based on Rasch versions of responses to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) (Barkley and Murphy 1998 Attention-Deficit Hyperactivity Disorder, New York: Guilford Press, p. 95-96) and the more comparable shortened WURS. FAs were lowest for body and ear height, and highest for eye width and nose width, and ranged from 0.01 +/- 0.001 (mean +/- SE) for foot and ankle widths to 0.13 +/- 0.01 in eye and nose widths for both sexes; the sexes did not differ significantly. Males displayed higher AD/HD symptom rates overall. There was a significant correlation between body FA and the WURS measure in females after Bonferroni correction (P = 0.002, r(2) = 0.058). Thus, AD/HD symptoms levels increased with an increase in body FA in female college students not selected for AD/HD.

1 and 2 mg 17beta-estradiol combined with sequential dydrogesterone have similar effects on the serum lipid profile of postmenopausal women.

OBJECTIVES: The aim of this study was to assess the effects of 1 and 2 mg 17beta-estradiol on serum lipid profile. Beneficial effects have been clearly established in previous studies with a 2 mg dose; further evidence was required to confirm the beneficial effects of a 1 mg dose. METHODS: This double-blind, placebo-controlled study involved 579 postmenopausal women randomized to oral treatment with placebo, 1 mg/day 17beta-estradiol sequentially combined with 5 or 10 mg/day dydrogesterone for the last 14 days of each 28-day cycle, or 2 mg/day 17beta-estradiol sequentially combined with 10 or 20 mg/day dydrogesterone for the last 14 days of each 28-day cycle. Treatment was continued for 26 cycles. RESULTS: High density lipoprotein (HDL) cholesterol levels were significantly (p<0.05) increased after 26 cycles in all active treatment groups compared with placebo. In addition, low density lipoprotein (LDL) cholesterol and lipoprotein(a) levels were significantly reduced, and apolipoprotein A1 and triglyceride levels were significantly increased, in all active treatment groups after 13 and 26 cycles. CONCLUSIONS: The results of this study clearly indicate that sequential combinations of either 1 or 2 mg 17beta-estradiol with dydrogesterone are associated with long-term, favorable changes in the serum lipid profile. There was no evidence that dydrogesterone compromised the 17beta-estradiol-induced improvements in lipid profile.

Hemostatic risk factors and insulin sensitivity, regional body fat distribution, and the metabolic syndrome.

Disturbances in the thrombotic and fibrinolytic systems are a feature of insulin resistance, obesity, and the metabolic syndrome. However, there are few studies in which these relationships have been explored in mainly asymptomatic individuals using sophisticated measures of insulin sensitivity and regional adiposity. Variables of the hemostatic system were measured in 106 men (aged 32-68 yr; body mass index, 20-34 kg/m(2)). Insulin sensitivity was measured by minimal model analysis and regional adiposity by dual energy x-ray absorptiometry. Clustering of intercorrelated variables was assessed by the statistical technique of factor analysis. Plasma levels of procoagulant factors VII and X, anticoagulant proteins C and S, and plasminogen activator inhibitor-1 correlated positively with total and percent central body fat (r = 0.25-0.38; P < 0.05) and negatively with insulin sensitivity (except protein S; r = -0.24 to -0.35; P < 0.05). On factor analysis, procoagulant factors VII and X, proteins C and S, and plasminogen activator inhibitor-1 were components of the cluster of variables that explained the greatest proportion of the variance in the data (39.2%). Other variables included in this cluster were those typical of the metabolic syndrome and also serum gamma-glutamyl transferase activity. These results suggest that factors VII and X and proteins C and S are features of the intercorrelated disturbances of the metabolic syndrome. Associations with adiposity and liver enzyme activity suggest the involvement of hepatic fat deposition.

Erythrocyte-derived measures of membrane lipid composition in healthy men: associations with arachidonic acid at low to moderate but not high insulin sensitivity.

The lipid composition of erythrocyte membranes was explored as a surrogate for that of skeletal muscle in investigations into the influence of membrane fatty acid composition on insulin sensitivity. In a preliminary study (study 1), erythrocyte and monocyte/platelet membrane fatty acid percentages were compared with those of muscle membrane in 10 otherwise healthy men undergoing orthopedic surgery. In a further study (study 2), relationships between erythrocyte membrane fatty acid concentrations and insulin sensitivity, S(I), measured using the intravenous glucose tolerance test (IVGTT), were evaluated in 30 asymptomatic men. In study 1, significant positive correlations were found between muscle and erythrocyte membrane fatty acid percentages for 16:0 saturated fatty acid (r = 0.92, P <.001), and for the 18:2n-6, 20:4n-6, 20:5n-3, and 22:5n-3 polyunsaturated fatty acids (PUFAs) (r = 0.67 to 0.83, P <.05 to.01). There were fewer and weaker associations between muscle and monocyte/platelet membrane fatty acid compositions. In study 2, highly insulin-sensitive individuals (n = 8) had significantly lower erythrocyte membrane fatty acid concentrations than those with low/normal S(I). Among those with low/normal S(I) (n = 22), S(I) correlated positively with erythrocyte membrane arachidonic acid concentration (r = 0.57, P <.01) and with total PUFAs (r = 0.46, P <.05). Indices of delta 6 and delta 5 desaturase activities were significantly higher and lower, respectively, in high compared with low/normal S(I) individuals. For a range of fatty acids, erythrocyte membrane fatty acid composition shows close associations with that of muscle membranes. Measurements in erythrocyte membranes support a role for membrane arachidonic acid content in the modulation of insulin sensitivity, specifically at low/normal insulin sensitivities.

Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women.

OBJECTIVE: Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes. DESIGN: Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol-17 beta with 5 or 10 mg/day dydrogesterone for days 17-28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol-17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9). MEASUREMENTS: Patients underwent measurement of glucose, insulin and C-peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured. RESULTS: In both groups there were significant reductions in fasting glucose, insulin and C-peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P < 0.01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0.05) and hepatic (18% to 31%, P < 0.05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment. CONCLUSIONS: Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause-associated changes in insulin secretion and elimination.