Search

SummaryObjective The aim of this study was to examine the effects of testosterone on verbal learning and memory in postmenopausal women. Design Randomized, placebo-controlled trial in which participants were randomized (1:1) to transdermal testosterone gel 300 mcg/day, or identical placebo, for 26 weeks. Patients Ninety-two postmenopausal women aged 55–65 years, on no systemic sex hormone therapy. Measurements The primary outcome was the score for the International Shopping List Task (ISLT) of CogState. Secondary outcomes included other CogState domains, the Psychological General Well-Being Index (PGWB) and safety variables. Results Eighty-nine women, median age 60 years, were included in the primary analysis. Testosterone treatment resulted in statistically significantly better performance for the ISLT (improved verbal learning and memory) compared with placebo, adjusted for age and baseline score (mean difference 1·57; 95%CI 0·13, 3·01) P = 0·03). There were no significant differences for other CogState domains or the PGWB scores. At 26 weeks, the median total testosterone was 1·7 nm (interquartile range (IQR) 1·1, 2·4) in the testosterone group and 0·4 nm (IQR 0·3, 0·5) in the placebo group. Conclusions The small but statistically significant effect of testosterone treatment on verbal learning and memory in postmenopausal women provides the basis for further clinical trials.

OBJECTIVE: Women's cardiovascular risk factors, including inflammatory markers such as C-reactive protein (CRP) which is emerging as a major association with cardiovascular disease (CVD) risk, can be influenced by the oral contraceptive (OC) pill in premenopausal and hormone replacement (HR) in postmenopausal women and by central adiposity which is associated with a heightened inflammatory state. The interaction between central obesity and different hormone use in both pre and postmenopausal women has not previously been reported in a study spanning the whole age range associated with hormone use. DESIGN: Observational, cross-sectional study. PATIENTS: Only healthy women were included in this study. MEASUREMENTS: A total of 21,310 women aged 30-64 employed by Marks and Spencer participated. They completed a health questionnaire and were screened for CVD risk factors including blood pressure, weight, height, waist and hip circumference, lipids and lipoproteins, CRP and fibrinogen. RESULTS: Compared with non-users, women who took the OC or HR had significantly higher CRP levels. This was more marked than effects on other CVD risk factors. It was further compounded by the independent effect of increased waist circumference. The CRP increase was greatest (more than twice that of nonhormone users) in premenopausal women with the highest quartile of waist circumference who took the combined contraceptive pill. CONCLUSIONS: Women who received first the combined OC and then HR may be exposed over much of their life to high CRP levels aggravated by central obesity. The health consequences of this require further investigation.

Summary Aims To assess factors associated with excess rates of fractures in women with Turner's syndrome (TS). Outcome measures History of bone fracture and treatment with oestrogen, growth hormone (GH), oxandrolone and thyroxine, anthropometry, blood measurements of calcium, vitamin D (25-hydroxycholecalciferol), parathyroid hormone and karyotype, pure tone audiometry and spinal bone mineral density (BMD). Results One hundred and seventy-seven consecutive women with TS, aged 19–60 years, were interviewed with respect to bone fracture history. BMD and hearing information were recorded from the medical notes. Karyotype was available in 94% of patients (55% monosomy 45X, 45% other X chromosome defects and mosaicism). Subjects had a mean (SD) height of 1·47 (0·07) m and BMI 25·8 (5·2) kg/m2. The prevalence of fractures was 32% and hearing impairment 84% (18% conductive and 67% sensorineual, of whom 32% and 16%, respectively, used hearing aids). BMD T score was

BACKGROUND Increasingly strong links are being recognized between diabetes, insulin resistance and liver fat accumulation [e.g. nonalcoholic fatty liver disease (NAFLD)]. Recent data indicating that hormone replacement therapy (HRT) may lessen diabetes risk is intriguing but explanatory mechanisms are unclear. OBJECTIVE Post hoc investigation of the possibility that HRT may favourably influence liver enzyme levels commonly elevated in patients with diabetes. We examined liver function test data from a 6-month trial of a low-dose continuous combined HRT (1 mg 17beta oestradiol and 0.5 mg norethisterone acetate). DESIGN Double-blind, randomized placebo-controlled. PATIENTS Fifty women with type 2 diabetes. MEASUREMENTS Liver enzyme levels (AST, ALT, gamma-glutamylytransferase [GGT], and alkaline phosphatase [ALP]). RESULTS Forty-five women completed the study with 19/22 in the active group demonstrating compliance as measured by sex hormone changes. Relative to placebo recipients (n = 23), women randomized and compliant to HRT demonstrated significant reductions in ALT [-14 (-23 to -6) U/l, P = 0.002], AST [-9.2 (-14 to -5) U/l, P < 0.001] and ALP [-60.8 (-80 to -42) U/l, P < 0.001]. Circulating concentrations in GGT were also significantly reduced (P = 0.035). All changes were significant using an intention-to-treat analysis. CONCLUSION HRT containing low-dose oestradiol and norethisterone reduces serum concentrations of liver function enzymes, potentially due to a lowering of liver fat accumulation. Better understanding of mechanisms by which this HRT improves liver function tests could help the design of new therapies to treat individuals with NAFLD.

Summary Objective Women with Turner syndrome have increased heart rate and high blood pressure (BP), and have been described as having high tolerance for emotional stress. We hypothesized that women with Turner syndrome have reduced catecholaminergic and physiological response to sympathetic stimulation, and that changes in BP and heart rate are related to their catecholamine response to sympathetic stimulation. Design and patients Ten young women with Turner syndrome, age 17–34 years were the subjects of this study. Their response to sympathetic stimulation was compared to a group of 10 age-matched healthy women. Measurements After a period of 30 min resting, subjects and controls were subjected to an escalating series of sympathetic stimulation: orthostatic, cold pressor and exercise, and their plasma catecholamines and haemodynamic response were monitored and compared to resting levels. Results Resting heart rate was higher in Turner syndrome patients at 83 ± 9 beats per min (bpm, mean ± SD), as compared to controls (74 ± 10 bpm, P

Summary Objective The aim of this study was to determine whether salivary cortisol measured by a simple enzyme immunoassay (EIA) could be used as a surrogate for serum total cortisol in response to rapid changes and across a wide range of concentrations. Design Comparisons of matched salivary and serum samples in response to dynamic hypothalamic‐pituitary‐adrenal (HPA) axis testing. Subjects Healthy women ( n = 10; three taking oral oestrogens) and men ( n = 2), aged 23‐ 65 years, were recruited from the community. Measurements Paired saliva and serum samples were obtained during three protocols: 10 min of exercise at 90% of maximal heart rate ( n = 8), intravenous administration of corticotrophin-releasing hormone (CRH; n = 4), and dexamethasone suppression ( n = 7). Cortisol was measured in saliva using a commercial high-sensitivity EIA and total cortisol was measured in serum with a commercial radioimmunoassay (RIA). Results The time course of the salivary cortisol response to both the exercise and CRH tests paralleled that of total serum cortisol. Salivary cortisol demonstrated a significantly greater relative increase in response to the exercise and CRH stimuli (697 ± 826% vs. 209 ± 150%, P = 0·04 saliva vs. serum). A disproportionately larger increase in free cortisol, compared with total, would be expected when the binding capacity of cortisol-binding globulin (CBG) is exceeded. In response to dexamethasone suppression, relative decreases in cortisol were not significantly different between the two media ( − 47 ± 56% vs. − 84 ± 8%, P = 0·13 saliva vs. serum). Although a significant linear correlation was found for all paired salivary and serum total cortisol samples ( n = 183 pairs, r = 0·60, P < 0·001), an exponential model provided a better fit ( r = 0·81, P < 0·001). The linear correlations were strengthened when data from subjects on oral oestrogens ( n = 52 pairs, r = 0·75, P < 0·001) were separated from those not taking oestrogens ( n = 131 pairs, r = 0·67, P < 0·001). Conclusions Salivary cortisol measured with a simple EIA can be used in place of serum total cortisol in physiological research protocols. Evidence that salivary measures represent the biologically active, free fraction of cortisol includes: (1) the greater relative increase in salivary cortisol in response to tests that raise the absolute cortisol concentration above the saturation point of CBG; (2) the strong exponential relationship between cortisol assessed in the two media; and (3) the improved linear correlations when subjects known to have increased CBG were analysed separately. Thus, an advantage of measuring salivary cortisol rather than total serum cortisol is that it eliminates the need to account for within-subject changes or between-subject differences in CBG.

OBJECTIVE: Oestrogen replacement reduces the increased rate of bone remodelling after the menopause. Osteoprotegerin (OPG) is a negative regulator of osteoclast-mediated bone resorption. In vitro studies have shown that oestrogen stimulates OPG production. However, the role of OPG in physiological bone remodelling and its regulation by oestrogen in vivo remain controversial. In this study, we analysed the association between changes in serum OPG levels and bone turnover status before and after hormone therapy (HT) in healthy postmenopausal women. PATIENTS AND MEASUREMENTS: Ninety-nine healthy postmenopausal women of Korean ethnicity, aged 42-64 years (52.3 +/- 4.9 years, mean +/- SD) were enrolled in our study. Serum OPG levels were assessed by a highly sensitive sandwich-type enzyme immunoassay. Serum concentrations of osteocalcin (OC) and carboxyterminal telopeptides (CTx) were determined by electrochemiluminescence immunoassays. Bone mineral density (BMD) at the lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Baseline levels of OPG correlated neither a the bone formation marker, serum OC, nor with a bone resorption marker, serum CTx. No significant association of baseline OPG was found with baseline BMD measured at the lumbar spine and femoral neck. Serum OPG levels measured after 3 months and 1 year of HT decreased significantly compared to baseline (P < 0.001 in both). The changes in circulating OPG at 3 months of HT correlated with the changes in both serum OC (r = 0.226, P = 0.029) and serum CTx (r = 0.214, P = 0.038) at 3 months after HT. However, there was no significant association between the changes in circulating OPG after 3 months of HT and BMD values of the lumbar spine or femoral neck after 1 year of HT. CONCLUSIONS: Our results suggest that baseline OPG levels do not reflect bone turnover status and that serial measurements of serum OPG after HT are not a useful predictor of the long-term effects of oestrogen on bone density. The decrease in serum concentrations of OPG after HT may occur to compensate for the action of oestrogen in suppressing bone resorption.

Summary objective Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. design and measurements Thirty-four women were treated with conjugated equine oestrogens (CEE) 0·625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 µg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. results The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P

OBJECTIVE AND SUBJECTS Current data suggest a permissive role for the somatotrophic axis in the reproductive process, mainly by affecting the onset of puberty and the maintenance of regular menstrual cyclicity. To assess a possible interface between GH and reproductive axes in determining the uterus size, we retrospectively evaluated 58 pelvic ultrasound scans in adult women with either isolated growth hormone deficiency (GHD; n = 12), hypogonadotrophic hypogonadism (HH; n = 24) or hypopituitarism (HP; n = 22) of prepubertal onset. Pelvic ultrasound was performed before oestrogen replacement in patients with HH or HP, and after completion of GH treatment in the majority of patients with HP. Eight women with HH and seven with HP had a second pelvic ultrasound examination after being established on oestrogen replacement therapy. A group of 19 young healthy women with no previous history of pregnancy or miscarriage were included for comparison of ultrasound data. RESULTS Uterine measurements, length and uterine cross-sectional area (UXA) were significantly less in the three study groups compared to healthy controls [median UXA: GHD 18.0 cm(2) (range 9.9-28.6 cm(2)), HH 7.0 cm(2) (range 1.3-18.5 cm(2)), HP 11.8 cm(2) (range 1.6-21.8 cm(2)) and controls 23.0 cm(2) (range 16.1-31.7 cm(2)); P < 0.001]. The median age of oestrogen replacement was significantly later in HH [19 years (range 16-26 years)] compared to HP [16.5 years (range 13-20 years)]P = 0.03, while the median age of menarche of GHD patients was 14.5 years (range 11-16 years), which was not statistically different from controls [13.0 years (range 12.5-14.5 years)]. Repeat uterine measurements on oestrogen in the subgroup of 15 patients did not reach the normal values [pretreatment UXA: 4.2 cm(2) (range 1.6-16.1 cm(2)), post-treatment UXA: 12.6 cm(2) (range 4-23 cm(2))]. Ovarian volume was smaller in the two groups of women with gonadotrophin deficiency (HH and HP), while a polycystic ovarian morphology was notably more prevalent in the two groups who had received GH treatment being found in 75 and 58% of women with GHD and HP, respectively, compared with 12.5% in women with HH (P < 0.004). CONCLUSIONS Our findings suggest that GHD might have an independent effect in determining uterus size and therefore the consequences of GHD plus oestrogen deficiency on uterus growth might be additive. The fact that uterine measurements between HH and HP patients did not differed significantly in this study may be explained by the fact that oestrogen replacement has been substituted earlier in the latter group. Furthermore, it appears that standard oestrogen replacement therapy did not result in normal uterine growth. A polycystic ovarian morphology may be a consequence of GH treatment.

objective Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex-specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood. design Prospective, intervention study. subjects In 37 young (age range 16¿36 years), nonobese [body mass index (BMI)

To compare the effects on body composition and body weight of tibolone vs two different sequential oral or transdermal oestrogen-progestogen hormone replacement therapies versus no therapy.One hundred postmenopausal women were assigned to a control group (n = 26), or randomized to 1) tibolone (TIB) 2.5 mg/day (n = 28), 2) oral oestradiol 2 mg/day (PO) plus sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 26), or 3) transdermal oestradiol patch (TTS) releasing 50 micrograms/day plus oral sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 20). Body composition was measured at the base-line and every 6 months for 2 years by DXA (Hologic QDR 1000 W).Total body fat mass increased (P0.05) in controls (+3.6 +/- 1.5%) and in TTS treated (+4.7 +/- 2.2%), but not in PO (-1.2 +/- 2.4%) and TIB (-1.6 +/- 2.2%) treated subjects. This increase in total fat mass in controls and TTS treated women was mostly due to an increase in fat mass of the trunk (P0.05), but not legs. As a result, a redistribution of body fat to the trunk occurred in controls, TTS and TIB, but not in PO treated women (P0.05). Total lean body mass decreased (P0.02) in controls (-1.7 +/- 0.7%) and PO (-1.4 +/- 0.6%) but not in TTS (+0.3 +/- 0.8%) and TIB (+0.4 +/- 0.5%) treated subjects.The menopause is associated with an increase in total body fat and a decline in lean body mass. Oral oestradiol/dydrogesterone and tibolone prevent total body fat changes, whereas transdermal oestradiol/oral dydrogesterone and tibolone prevent the lean mass changes. Furthermore, oral oestradiol/dydrogesterone prevents the shift to a central, android fat distribution.

OBJECTIVE Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post-menopausal women. As older age is associated with progressive arterial endothelial damage, a key event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause. DESIGN Using high resolution external vascular ultrasound, brachial artery diameter was measured at rest and in response to reactive hyperaemia, with increased flow causing endothelium-dependent dilatation (flow-mediated dilatation). PATIENTS We investigated 135 healthy women; 40 were pre-menopausal (mean +/- SD age/26 +/- 6 years, group 1), 40 were post-menopausal and had never taken HRT (aged 58 +/- 3 years; group 2) and 55 were age-matched post-menopausal women who had taken HRT for > or = 2 years, from within 2 years of the menopause (aged 57 +/- 4 years; group 3). In group 3, 40 women were on combined oestrogen and progesterone and 15 on oestrogen-only HRT. RESULTS In group 2, flow-mediated dilatation was significantly reduced compared with group 1 (4.4 +/- 3.4 vs 9.6 +/- 3.6%, P < 0.001), consistent with a decline in arterial endothelial function after the menopause. In group 3, however, flow-mediated dilatation was significantly better than group 2 (6.2 +/- 3.3 vs 4.4 +/- 3.4%, P = 0.01), suggesting a protective effect of HRT. Flow-mediated dilatation was similar in women taking oestrogen alone and in those on combined HRT (5.5 +/- 2.8 vs 6.5 +/- 3.4%, P = 0.40). CONCLUSIONS Long-term HRT is associated with improved arterial endothelial function in healthy post-menopausal women. This benefit was observed in both the combined hormone replacement and unopposed oestrogen therapy groups. This may explain some of the apparent cardioprotective effect of HRT after the menopause.

OBJECTIVE It has previously been shown that 17β-oestradiol (E2) implants counteract the formation of more acidic isoforms of the gonadotrophins in post-menopausal women. A much lesser effect was observed on the charge of the gonadotrophin isoforms in women with chronic oral daily therapy with 2 mg E2 combined with a progestogen, 1 mg norethisterone acetate (NETA), in spite of similar serum levels of E2 and SHBG. The presence of the progestogen in the latter study may explain the difference observed. The present study investigated the effect of the progestogen NETA on the charge and concentration of serum FSH and LH in E2 implant treated women. DESIGN A group of 8 post-menopausal women, mean age 65 years (range 50–80 years) treated with 20 mg E2 implants every 6 months, participated in the study. The women were given a daily oral medication of 5 mg NETA for a 4-week period starting at 4 weeks after the insertion of an E2 implant (mean serum E2 420 pmol/l). This treatment with NETA was repeated in 6 of the women starting at 18 weeks after the insertion of the E2 implant (mean serum E2 317 pmol/l). Blood samples were obtained at the start of the NETA therapy, after 2 and 4 weeks of treatment and at 4 weeks after the last NETA treatment. The effects of NETA therapy on the charge of the serum gonadotrophin isoforms was determined by electrophoresis in 0.1% agarose suspension and FSH, LH, E2, and SHBG were determined with fluoroimmunoassays. RESULTS The NETA treatment decreased the serum FSH and LH levels after 2 weeks to 24 and 23% of the levels before NETA and after 4 weeks to 14.6 and 8.8%, which were 1.3 and 2.2% of the mean levels for non-treated post-menopausal women. Both FSH and LH isoforms became more acidic during the first 2 weeks of treatment. During the following 2 weeks of NETA treatment the isoforms of both FSH and LH became more basic again. Ten weeks later both the concentration and the charge of the gonadotrophins were similar to those before the NETA treatment. The changes in concentration and charge of the gonadotrophins during the second treatment period were similar to those during the first. All the changes were statistically significant (P

OBJECTIVES We wished to appraise the effectiveness of hormone replacement therapy (HRT) in early ( 67 years) post-menopausal women referred to a metabolic outpatient clinic for assessment of their bone status. Because older women often experience side-effects with conventional HRT, a low dose preparation (Estraderm 25) was also compared with conventional HRT (Estraderm 50). DESIGN AND SETTING Since all patients were symptomatic, the investigation was open and not placebo controlled. Patients were offered HRT and told about the two dosages. If they wished to use HRT, allocation of dosage was made randomly unless there were reasons to use a specific dose. PATIENTS One hundred and ninety-six women were studied over 1 or 2 years with 80 reaching 3 years of treatment. Patients were divided into those under 67 years and those over 67 years at the start of treatment. Each group was further divided into those taking Estraderm 25 and those taking Estraderm 50 with norethisterone if appropriate. MEASUREMENTS Bone mineral density (BMD) was measured (DXA, Hologic) at the lumbar spine and femoral neck at 0 year (196 patients), at 1 year (169 patients), at 2 years (139 patients) and at 3 years (80 patients). Patients losing bone were expressed as those whose 3 year BMD was lower than initial or as those whose BMD at 3 years had fallen by more than twice the coefficient of variation for that site (non-responders). RESULTS In lumbar spine, BMD increased maximally in the first year in all groups and the gain was maintained after 3 years. The change was similar whether patients were divided by age or dosage. For those on Estraderm 25, mean change after 3 years was 8.1 ± 6.8% and on Estraderm 50, 9.0 ± 8.3% (combined 8.7 ± 7.8%). Only 3.9% of patients were non-responders at the lumbar spine after 3 years. At femoral neck, changes were significant at 3 years only in the Estraderm 25 >67 years and Estraderm 50

Summary OBJECTIVE GnRH analogues are being used Increasingly for a number of oestrogen dependent conditions In women. The resultant profound hypo-oestrogenism is a disadvantage, however, but the preservation of pituitary sensitivity to negative feedback by oestradiol is not well defined. We have determined the effect on gonadotrophins and Inhibin of GnRH analogue plus low-dose continuous combined hormone replacement therapy In comparison with GnRH analogue therapy alone. DESIGN Randomized controlled trial. PATIENTS Fifty premenopausal women with endometriosis randomized to treatment with goserelin alone (Group 1) or goserelin plus 17βoestradiol and medroxyprogesterone acetate (Group 2). MEASUREMENTS FSH, LH, oestradiol, oestrone, Inhibin before and during treatment. RESULTS Oestradiol and oestrone were suppressed in both groups, but Group 2 had significantly higher oestradiol during the hormone replacement therapy period. LH was suppressed in both groups. In Group 1, FSH levels recovered during treatment but, in contrast, in Group 2, FSH levels remained suppressed throughout treatment. Inhibin was significantly lower in Group 2, but not In Group 1, during treatment compared to pretreatment. CONCLUSIONS Pituitary secretion of FSH appears to remain responsive to feedback control by oestradiol during GnRH analogue therapy and Is Incompletely suppressed, unlike LH which remains completely suppressed. The possible mechanisms for this are discussed.

Summary OBJECTIVE Chronic treatment with 17βoestradlol (E2Implants has been found to counteract the formation of more acidic isoforms of the gonadotrophins in post-menopausal women. Oral medication with an oestrogen in combination with a progestagen is a common hormone replacement therapy (HRT) in post-menopausal women. The present study investigated the effect of such a therapy on the concentration and charge of the gonadotrophin isoforms in serum. DESIGN Serum samples were obtained from 20 post-menopausal women, mean age 60 years (range 50–72 years), treated with continuous dally oral medication of 2 mg E2 combined with 1 mg norethisterone acetate (NETA). FSH, LH and E2 in the serum was measured with fluoroimmunoassays. The median charge and charge heterogeneity of the FSH and LH isoforms were determined for each serum by electrophoresis in 0·1% agarose suspension. Sera from 20 post-menopausal women without a history of HRT served as controls. The results were compared with those from previous studies on post-menopausal women treated with E2 Implants and on women with normal menstrual cycles. RESULTS The E2 level in the oral-E2+ NETA treated women was 198-610 pmol/l, within the range expected during the mid-luteal phase of the normal menstrual cycle and similar to that of the group of women with an E2 Implant. The mean LH level was similar to that of the luteal phase of the cycle and significantly lower than that of the controls (P < 0·001), the E2 Implant group (P < 0·001) and at the follicular phase of the cycle (P < 0·01). The mean FSH level was slmllar to that of the folllcular phase and the E2 implant group but lower than that of the controls (P < 0·001) and higher than at the luteal phase of the cycle (P < 0·01). The mean values for median charge of both FSH and LH were less acidic than those of the controls (P < 0·001) but more acidic than those for the E2 Implant group (P < 0·01; P < 0·001) and for different phases of the menstrual cycle (P < 0·05; P < 0·001). The mean degree of charge heterogeneity of FSH was larger (P < 0·01), while that of LH was smaller (P < 0·01), than for the controls. The mean concentrations of SHBG in the oral E2+ NETA group, the E2 implant group and the controls were similar. CONCLUSION Chronic oral therapy with 2mg 17β oestradiol combined with 1 mg norethisterone in post-menopausal women efficiently decreased the serum gonadotrophin levels but only partly counteracted the formation of the more acidic isoforms of FSH and LH after menopause. The differences in the charge for both FSH and LH between the E2 Implant and the oral E2+ NETA treated groups may be due to the differences in route of administration of E1 or to the effect of norethisterone or both.

Both cigarette smoking and use of exogenous hormones are associated with changes in regional distribution of body fat, but their combined effects are less investigated. We examined the interrelation between smoking, exogenous hormones and fat distribution in premenopausal and postmenopausal women.We used data from 20, 962 women without known cardiovascular disease (CVD) who were employees of a major department store in Britain. They completed a health questionnaire and attended a clinical examination that included waist and hip circumference measurements. The cross-sectional analyses were conducted using linear regression models.Cigarette smoking, particularly smoking ≥20 cigarettes/day, was associated with larger waist circumference and higher waist/hip ratio (WHR) in pre- and postmenopausal women after adjusting for potential confounding factors (all P 0·001). Premenopausal women using combined oral contraceptive (COC) and postmenopausal women using oestrogen-only hormone replacement therapy (HRT) had lower WHR than non-hormone users in both smokers and nonsmokers. However, smokers had higher WHR than nonsmokers in both groups of hormone users and nonusers. There was no significant interaction between smoking and hormone use in premenopausal and postmenopausal women (P 0·05).Although exogenous hormones use was related to a more favourable fat distribution in women, smoking was associated with greater abdominal fat accumulation.

Summary OBJECTIVES We investigated the effect of the menopause when followed longitudinally for a decade to evaluate whether women with an increased bone loss continue to have elevated urinary excretion of pyridinium cross-links later in menopause. Furthermore, we investigated the effect of oestrogen/progesterone therapy on the urinary excretion of pyridinium cross-links. PARTICIPANTS In the cross-sectional study: 18 healthy premenopausal, 142 healthy post-menopausal women and 41 osteopenic post-menopausal women. In the longitudinal study: 45 healthy post-menopausal women followed up for 7-10 years after the menopause; these women were further divided into two equal groups, according to their loss of forearm bone mineral content over 2 years. In the oestradiol/progesterone double-blind, placebo-controlled 2-year trial: early post-menopausal women were given either hormone replacement therapy (n = 38) or placebo (n= 16). MEASUREMENTS The urinary excretion of pyridinoline/ creatinine (Pyr/Cr) and urinary deoxypyridinoline/creatinine (D-Pyr/Cr), two new markers of bone resorption. RESULTS Pyr/Cr and D-Pyr/Cr increased significantly after the menopause (Pyr/Cr, 77%; D-Pyr/Cr, 98%, P < 0.001). Hormone replacement therapy reversed this increase towards premenopausal levels. Both pyridinium cross-links remained fairly constant during the first decade of the menopause, when measured in the longitudinal study. When the women were divided according to loss in forearm BMC., those with a loss greater than 3-5%/2 years had significantly higher levels of pyridinium cross-links (P

Summary OBJECTIVE Epidemiological studies suggest that postmenopausal oestrogen replacement reduces the incidence of cardiovascular disease. The purpose of this study was to establish the effects of oestrogen replacement therapy on subfractions of plasma low density lipoprotein in bilaterally oophorectomized women. DESIGN In a placebo controlled, double-blind study, patients were randomized on a two to one basis to receive either oestradiol valerate (2 mg/day) or placebo respectively for a period of 16 weeks. PATIENTS Seventeen women aged 28–51 years who had all had hysterectomy and bilateral oophorectomy at least 2 months before recruitment were assigned to either the active (n= 12) or placebo (n= 5) group. MEASUREMENTS Plasma lipids, lipoproteins, apolipoproteins and LDL subfractions were determined immediately before and after the treatment period. LDL subfractions were isolated directly from plasma by density gradient ultracentrifugation within 24 hours. Non-parametric statistical analysis was carried out within each group using Wilcoxon's signed rank test for matched pairs. RESULTS After 16 weeks of treatment, HDL cholesterol, apo A-1 and HDL-2 were increased in the group receiving oestrogen (HDL cholesterol +12%, P < 0.01; apo A-I + 14%, P < 0.01; HDL-2 + 24%P < 0.01). While there were no significant changes in serum cholesterol, LDL cholesterol or triglycerides, the proportion and concentration of the least dense LDL-I subtraction was decreased significantly (-27%, P < 0.05). The LDL subtraction of intermediate density (LDL-II) was decreased in eight subjects, while small, dense LDL-III was unaffected. Overall, these changes resulted in an apparent shift in the distribution of LDL subfractions towards small, dense LDL-III, although there was no net increase in the latter. CONCLUSION In view of a similar and characteristic response of LDL subfractions to hypolipidaemic drugs that enhance the clearance of LDL via the LDL receptor, the present findings suggest that oestrogen promotes the preferential removal of LDL-I and II by activating LDL receptors. As this effect is normally associated with a reduction in the circulating level of LDL, it should not be regarded as an unfavourable response to oestrogen replacement therapy.

The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF).In an open-label randomized controlled crossover trial, 34 women with POF were randomized to 4-week cycles of pSSR (transdermal oestradiol, 100 μg daily for week 1, 150 μg for weeks 2-4; vaginal progesterone, 200 mg twice daily for weeks 3-4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 μg and 1·5 mg norethisterone daily for weeks 1-3, week 4 'pill-free') for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12-month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N-terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre-/postwashout and after 3, 6 and 12 months of each treatment.Eighteen women, mean 27 (range 19-39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z-score was -0·89 (95% CI -1·27 to -0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI -0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z-score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = -0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P0·001) but decreased in the sHRT arm (P0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P0·001).We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.

Within endocrinology, the long-term management of Turner syndrome (TS) in adults is fast becoming a specialist subject in its own right. The complications of TS can affect every system in the body, and the main reason why it falls to endocrinologists to coordinate health care is that many features are clearly within the endocrine remit: hypothyroidism, diabetes, hypertension, osteoporosis, hypogonadism. Endocrinologists as general physicians can often cover surveillance of problems in other areas such as congenital heart disease, inflammatory bowel disease and deafness, calling upon specialist input only if the need arises. In this way, a simple 'one stop shop' can offer a well-woman service for women with TS in a cost-effective manner. Such a service requires a multidisciplinary approach.

Summary Objectives Raised liver enzymes are a common feature of Turner's syndrome (TS), but the cause remains unclear. We studied the hepatic function in a large cohort of women with TS and tested the effect of increasing doses of hormone replacement therapy (HRT) on liver function tests (LFTs). Design and patients LFTs were assessed in three studies. A cross-sectional review of liver function of 125 women (median age: 31 years), a longitudinal study of 30 women (mean follow-up period: 8 years) and a dose–response study of 14 women with TS and 11 controls with hypogonadism, who received oral 17-β-oestradiol (E2) 1, 2 and 4 mg daily in a cyclical formulation for 12 weeks each. Measurements Clinical features, oestrogen use and metabolic parameters were compared to liver enzymes (γ-glutamyl transferase (GGT), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), albumin and bilirubin. LFTs were also measured during each treatment interval of the dose–response study. Hepatic autoimmunity was sought in the cross-sectional study. Results When compared to the control population, as opposed to reference ranges, 91% of women with TS demonstrated liver enzyme elevation, with a yearly incidence of 2·1%. LFTs correlated positively with cholesterol (P

Summary Objective Several studies suggest that oral menopausal hormone therapy (MHT) is associated with an increased risk of gallbladder disease. It has been hypothesized that nonoral MHT may reduce the risk of cholelithiasis. The objective of the present study was to analyse the association between (1) use of life-time MHT (ever use) and gallbladder disease and (2) nonoral use of MHT and gallbladder disease. Design Cross-sectional study using population-based data from the Study of Health in Pomerania (SHIP). Population The study population included 994 postmenopausal women, aged 40–79 years. The subgroup of current oral and nonoral MHT users comprised 139 women. Methods and measurements Sociodemographic, medical and reproductive characteristics were based on computer-assisted personal interviews, and selected laboratory parameters were analysed. Gallbladder disease was defined by either a prior history of cholecystectomy or the presence of current sonographically diagnosed gallstones. Data analyses consisted of descriptive, bivariable and multivariable procedures. We performed Poisson regression with Huber/White standard errors to investigate the association between ever use, current nonoral use of MHT and gallbladder disease. Results We found no significant association between ever use of MHT and gallbladder disease and sonographically diagnosed gallstones in fully adjusted analyses. Women who used MHT had a significantly higher risk for cholecystectomy compared to nonusers. There was no association between nonoral use of MHT and gallbladder disease. Conclusions Our analyses do not lend support to the hypothesis that use of MHT is associated with gallbladder disease.

OBJECTIVE: Young hypogonadal women appear to have an increased risk of cardiovascular disease. We studied the influence of increasing doses of hormone replacement therapy (HRT) on markers of metabolism and vascular physiology. DESIGN: Nine-month sequential dose-ranging study. PATIENTS: A total of 25 young hypogonadal women (Turner Syndrome, n = 14; 46,XX gonadal dysgenesis, n = 9), hypogonadotrophic hypogonadism (n = 2), mean age 31.9 years (range 18.5-42.2). All subjects sequentially received oral 17beta-oestradiol 1,2 and 4 mg daily in a cyclical formulation for 12 weeks each. MEASUREMENTS: Metabolic markers and vascular physiology measurements to assess intima media thickness (IMT); arterial stiffness: pulse wave velocity (PWV) and augmentation index (AIx); endothelial function: flow-mediated dilatation (FMD). Results Increasing doses of oestrogen resulted in a reduction in IMT (0.63 +/- 0.06 vs. 0.58 +/- 0.06 vs. 0.56 +/- 0.06 mm at 1 mg, 2 mg and 4 mg 17beta-oestradiol, respectively, P = 0.001). RESULTS: were similar in women with Turner Syndrome and normal karyotype. High-density lipoprotein (HDL) cholesterol concentrations increased (1.9 +/- 0.4 vs. 2.0 +/- 0.5 vs. 2.2 +/- 0.4 mmol/l, P = 0.001) and plasma glucose (4.8 +/- 0.4 vs. 4.7 +/- 0.3 vs. 4.6 +/- 0.6 mmol/l, P = 0.038) decreased slightly with the increasing dose of HRT. There was no correlation between the changes in IMT and HDL. Increasing HRT dose had no significant impact on blood pressure, weight, other lipid parameters, insulin, C-reactive protein, interleukin-6 and fibrinogen concentrations or FMD, PWV and AIx. CONCLUSIONS: Increasing doses of HRT result in a reduction in carotid IMT in young hypogonadal women, along with increased serum HDL and decreased plasma glucose. This study raises the possibility that exogenous oestrogen may be cardioprotective in young women, but this observation needs to be balanced against a prothrombotic effect which is predominant in postmenopausal women.

Low-dose hormone replacement therapy (HRT) has attracted interest for the treatment of postmenopausal symptoms in diabetes because of concerns about increased risk of coronary heart disease (CHD) and stroke with conventional HRT containing conjugated equine oestrogens (CEEs) and medroxyprogesterone acetate (MPA).We assessed the effects on glucose homeostasis and cardiovascular risk factors of continuous oral 17beta oestradiol (1 mg) and norethisterone (0.5 mg) in postmenopausal women with type 2 diabetes.Double-blind, randomized placebo-controlled trial.Hyperinsulinaemic isoglycaemic clamp and cardiovascular risk factors were assessed before and after 3 months of treatment.Twenty-eight women completed the study. HRT decreased fasting glucose compared with placebo [-9.4% with HRT vs.+2.3% for placebo, 95% confidence interval (CI) -23.2 to -0.3] and total cholesterol (-13.7 vs.+1.0%, 95% CI -22.4 to -3.1%) No significant effect was seen on metabolic clearance rate of glucose, glycated haemoglobin (HbA1c), triglycerides, high density lipoprotein (HDL)-cholesterol or C-reactive protein (CRP).In women with type 2 diabetes, low-dose HRT decreased fasting glucose and total cholesterol without detectable adverse effects on glucose clearance, triglycerides and CRP as reported with conventional HRT.

Summary Objective Data concerning the relationship between sex steroid hormones and the cellular antioxidative enzyme system are controversial. We investigated the effects of oestradiol deficiency after menopause and the influence of transdermal oestradiol therapy (ET) and hormonal (oestradiol plus medroxyprogesterone) replacement therapy (HT) on erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). GSH and selenium (Se) concentrations were also estimated. Serum lipid peroxide (LPO) levels were measured as an indicator of free-radical production and lipid peroxidation. Patients The study group consisted of 80 postmenopausal women, divided into two subgroups: 26 women with surgically induced menopause (ET1) and 54 women with physiological menopause (HT1). Forty premenopausal healthy volunteers were controls (C group). Results LPO was higher in postmenopausal women and decreased after both ET and HT. GSH-Px and GSH were lower in the postmenopausal groups but increased significantly after both types of therapy. Se concentrations did not differ significantly among the groups. CAT activities were similar in all groups and decreased after ET and HT. SOD activities in postmenopausal women were similar to those in the C group and did not change significantly after treatment. Conclusions The administration of natural oestrogens to postmenopausal women diminishes oxidative stress and increases antioxidative cell potency.

objectives To assess effects of GH replacement therapy on cardiac structure and function, exercise capacity as well as serum lipids in elderly patients with GH deficiency (GHD). patients and methods Thirty-one patients (six females, 25 males), aged 60-79 years (mean 68 years) with GHD on stable cortisone and thyroxine substitution were studied. All men with gonadotropin deficiency had testosterone and one woman had oestrogen replacement. They were randomized in a double-blind manner to GH or placebo treatment for 6 months, followed by another 12 months GH (Humatrope, Eli Lilly & Co, Uppsala, Sweden). GH dose was 0·017 mg/kg/week for 1 month and then 0·033 mg/kg/week divided into daily subcutaneous injections at bedtime. Echocardiography, exercise capacity tests and serum lipid measurements were performed at 0, 6, 12 and 18 months. results During the 6-month placebo-controlled period there were no significant changes in the placebo group, but in the GH-treated group there was a significant increase in IGF-I to normal levels for age, with median IGF-I from 6·9 to 18·5 nmol/l, increase in resting heart rate and maximal working capacity. During the open GH study, IGF-I increased from 8·7 to 19·2 nmol/l at 6 months and 18·8 nmol/l at 12 months (P conclusions GH substitution to elderly patients with GHD caused only a transient increase in heart rate. At the end of the 12 months there were no significant changes on cardiac noninvasive structural and functional parameters. Maximal working capacity transiently improved. Thus, the therapy was safe without negative effects on cardiac structural and functional noninvasive parameters. Lipid profiles improved with reduction of serum LDL cholesterol accompanied by significant improvement of LDL/HDL ratio and serum HDL cholesterol after 12 months treatment.

Summary 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