Pulmonary embolism in menopausal hormone therapy: a population-based register study.

OBJECTIVE: Oral but not transdermal menopausal hormone therapy (MHT) increases the risk of venous thromboembolism. There is no evidence regarding the risk of the serious complication pulmonary embolism (PE). The aim was to investigate the risk of PE in women using MHT depending on administration route, type of progestin and treatment duration. METHOD: The population-based case-control study covered 1,771,253 women aged 40-69 years, during 2006-2015. Diagnoses of PE (n = 13,974) and drug dispensations were received from national validated registers. RESULTS: Current MHT users had a higher risk of PE than non-users (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.05-1.26). First ever users had the highest risk (OR 2.07, 95% CI 1.23-3.50). Transdermal administration was not associated with increased risk of PE. The OR was slightly but non-significantly higher with estrogen combined with medroxyprogesterone acetate than with norethisterone acetate. DISCUSSION: The risk of PE was significantly increased in users of oral but not transdermal MHT, with the highest risk in first ever users of oral estrogen combined with medroxyprogesterone acetate. The risk was considerably lower in women with recurrent treatment, probably because of the healthy user effect. CONCLUSION: PE was most common close to initiation of oral treatment. Transdermal MHT did not increase the risk of PE.

Effects of resistance training on quality of life in postmenopausal women with vasomotor symptoms.

OBJECTIVE: Most women experience vasomotor symptoms (VMS) around menopause that may affect quality of life negatively. Effective pharmacological treatment exists but is not recommended for all women, and there is a demand for alternatives to reduce symptoms and improve quality of life. The objective of this study was to investigate the effect of a resistance training intervention on health-related quality of life (HRQoL) in postmenopausal women with VMS. METHODS: This open randomized controlled trial included 65 postmenopausal women >45 years old with daily VMS. The participants were randomized to 15 weeks of resistance training three times per week or an untreated control group. The Women's Health Questionnaire (WHQ) and Short Form Health Survey (SF-36) were used to assess HRQoL at baseline and after 15 weeks. RESULTS: The resistance training group improved compared to the control group in the WHQ domains of VMS (p = 0.002), sleep problems (p = 0.003) and menstrual symptoms (p = 0.01) from baseline to post intervention. No significant between-group differences were found in SF-36 summary scores, or in any of the domains. CONCLUSION: In postmenopausal women with moderate to severe VMS, resistance training three times per week for 15 weeks improved menopause-specific HRQoL.

Hormone therapy might be underutilized in women with early menopause.

STUDY QUESTION: Are Swedish women age 40-44 years with assumed early menopause 'undertreated' by hormone therapy (HT)? SUMMARY ANSWER: Many women with probable early menopause discontinue their HT after a short period of time. Thus, they fail to complete the recommended replacement up to age 51-52 years, the average age of menopause. WHAT IS KNOWN ALREADY: Spontaneous early menopause occurs in ∼5% of women age 40-45 years. Regardless of the cause, women who experience hormonal menopause due to bilateral oophorectomy before the median age of spontaneous menopause are at increased risk of cardiovascular disease, neurological disease, osteoporosis, psychiatric illness and even death. STUDY DESIGN, SIZE, DURATION: The study is descriptive, and epidemiological and was based on the use of national registers of dispensed drug prescriptions (HT) linking registers from the National Board of Health and Welfare and Statistics Sweden from 1 July 2005 until 31 December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population consisted of 310 404 women, 40-44 years old on 31 December 2005 who were followed from 1 July 2005 until 31 December 2011. MAIN RESULTS AND THE ROLE OF CHANCE: Only 0.9% of women 40-44 years old started HT during the study period. A majority of these women used HT <1 year. LIMITATIONS, REASONS FOR CAUTION: We do not know the indications that led to the prescription of HT but assume that early onset of menopause was the main reason. Because of the study design-making a retrospective study of registers-we can only speculate on the reasons for most of the women in this group discontinuing HT. Another limitation of this study is that we have a rather short observation time. However, we have up to now only been able to collect and combine the data since July 2005. WIDER IMPLICATIONS OF THE FINDINGS: As the occurrence of spontaneous early menopause in women age 40-45 is reported to be ∼5%, the fact that <1% of Swedish women age 40-44 are prescribed HT, and can be shown also to have had the medication dispensed at a pharmacy suggests an unexpectedly low treatment rate. Some women with early menopause may have used combined contraceptives as supplementation therapy, but in Sweden HT is the recommended treatment for early menopause so any such women are not following this recommendation. Women who experience early menopause are at increased risk for overall morbidity and mortality, and can expect to benefit from HT until they have reached at least the median age of spontaneous menopause. It is therefore important to individualize the information given these women and to convey new knowledge in this area to gynaecologists and physicians in general as well as the recommendation that women in this group continue HT at least until the average age for spontaneous menopause is reached. STUDY FUNDING/COMPETING INTERESTS: No competing interests exist.

Hot flushes, hormone therapy and alternative treatments: 30 years of experience from Sweden.

OBJECTIVES: The use of hormone therapy (HT) for hot flushes has changed dramatically over the past five decades. In this cross-sectional questionnaire study, the aim was to describe the use of HT and alternative treatments and to study the frequency of hot flushes. A further aim was to compare data from the present questionnaire with data from previous studies made in the same geographic area. METHOD: A questionnaire was sent to a random sample of 2000 women aged 47-56 years living in Östergötland County, Sweden. The results were compared with findings from previous studies regarding use of HT, alternative treatment and hot flushes, and the number of HT prescriptions dispensed during the corresponding time using data derived from the Swedish Prescribed Drug Registry. RESULTS: The response rate was 66%. Six percent used HT, in line with prevalence data from the Swedish Prescribed Drug Registry. Alternative treatments were used by 10%. About 70% of postmenopausal women reported flushes and almost one-third of those with flushes stated that they would be positive to HT if therapy could be shown to be harmless, a view more often stated by women with severe complaints of hot flushes (67%). CONCLUSION: The use of HT and alternative treatments is low and many women suffer from flushes that could be treated. Women considered their knowledge of the climacteric period and treatment options as insufficient. Individualized information should be given and women with significant climacteric complaints, without contraindications, should be given the opportunity to try HT.

Hot flushes still occur in a population of 85-year-old Swedish women.

OBJECTIVES: Hot flushes and night sweats often cause discomfort and may negatively affect sleep and quality of life. Studies have shown that menopausal symptoms, like hot flushes, may persist for up to 20 years after the menopausal transition, but there are no published studies regarding the occurrence of hot flushes among women older than 80 years. The aim of this study is to determine the prevalence of hot flushes in 85-year-old women. METHODS: All 85-year old women living in Linköping municipality in 2007 (n = 415) received a postal questionnaire. The majority, 74% (n = 307), answered the questionnaire and 47% (n = 194) agreed to visit the Department of Geriatric Medicine; during this visit questions regarding hot flushes and use of hormone therapy were asked. RESULTS: About 16% (n = 29) of the women experienced hot flushes during the day and/or during the night and 6.5% (n = 12) of the women were currently using hormone therapy. Almost 10% (n = 17) of all responding women were very to moderately distressed by their hot flushes. CONCLUSION: Our results confirm and extend previous knowledge based on studies of younger postmenopausal women in showing that menopausal symptoms still occur in elderly women. We found that, while the prevalence of menopausal symptoms decreases with age, these symptoms are still experienced by some 85-year-old women.

Salivary cortisol and serum prolactin in relation to stress rating scales in a group of rescue workers.

BACKGROUND: Rescue service personnel are often exposed to traumatic events as part of their occupation, and higher prevalence rates of psychiatric illness have been found among this group. METHODS: In 65 rescue workers, salivary cortisol at 8 AM and 10 PM and serum prolactin at 8 AM were related to the psychiatric self-rating scale General Health Questionnaire (GHQ-28) measuring psychiatric health, and the Impact of Events Scale (IES) and Post Traumatic Symptom Scale (PTSS) measuring posttraumatic symptoms. RESULTS: Seventeen percent of the study population scored above the GHQ-28 cut-off limit but none scored beyond the cut-off limit in the IES and PTSS questionnaires. Salivary cortisol concentration at 10 PM correlated with statistical significance to anxiety (p < .005) and depressive symptoms (p < .01) measured with GHQ-28, as well as to posttraumatic symptoms, with avoidance behavior measured with IES (p < .01) and PTSS (p < .005). Two of the rescue workers were followed over time with the same sampling procedure after a major rescue commission. CONCLUSIONS: The correlation between evening salivary cortisol and anxiety, depressiveness, and posttraumatic avoidance symptoms indicates that these parameters can be used in screening and follow-up after traumatic stress events.

Salivary cortisol--an alternative to serum cortisol determinations in dynamic function tests.

Salivary cortisol was measured as an alternative to serum cortisol as a marker for adrenocortical function following insulin tolerance test, corticotropin-releasing-hormone stimulation and adreno-corticotrophic hormone stimulation. During insulin tolerance test and corticotropin-releasing-hormone stimulation adreno-corticotrophic hormone was also measured. The tests were performed on healthy control subjects as well as on patients under investigation for various disturbances in the hypothalamic-pituitary-adrenocortical axis (insulin tolerance test: 3 controls on two occasions and 14 patients; corticotropin-releasing-hormone stimulation: 4 controls and 18 patients; adreno-corticotrophic hormone stimulation: 6 controls and 10 patients). Five patients underwent both insulin tolerance test and corticotropin-releasing-hormone stimulation. Using criteria for adequate cortisol response in serum, the patients were classified as good or poor responders. In 42 of the 45 tests performed the same conclusion as to cortisol status was drawn when based on serum and salivary cortisol responses. In healthy subjects and good responders the mean cortisol relative increase was greater in saliva than in serum in all three tests (p < 0.05). Characteristic of the results for the insulin tolerance test was a significant initial mean decrease (p < 0.05), not found in serum, and the highest observed salivary cortisol value was delayed for at least 30 minutes compared to that in serum. Plasma adreno-corticotrophic hormone correlated significantly with the cortisol concentrations determined 15 minutes later in serum (r = 0.54-0.64) and in saliva (r = 0.76-0.85). The more pronounced cortisol response in saliva than in serum and its closer correlation with adreno-corticotrophic hormone offer advantages over serum cortisol, suggesting salivary cortisol measurement may be used as an alternative parameter in dynamic endocrine test.

Cortisol in saliva--reference ranges and relation to cortisol in serum.

The aim of this study was to establish morning and evening reference ranges for cortisol in saliva. Another objective was to compare the concentrations of the mainly free cortisol in saliva to those of total cortisol in serum as determined with a commercial radioimmunoassay. The concentrations were determined in matched samples of saliva and serum collected at 8 am and 10 pm from 197 healthy volunteers. The saliva samples were stable for at least 7 days at room temperature and for 9 months at -20 degrees C. Reference ranges, the central 95%, were estimated to 3.5-27.0 nmol/l at 8 am and < 6.0 nmol/l at 10 pm. The intra-assay coefficient of variation (CV) was below 5% and total CV below 10%. The relation between the cortisol concentrations in serum and saliva was non-linear with r = 0.86 for serum concentrations < 450 nmol/l and r = 0.44 for serum concentrations > or = 450 nmol/l. In conclusion, the satisfactory precision of the analysis and the simple non-invasive sampling procedure suggest that saliva may be used for cortisol measurements in situations where blood sampling is difficult to perform.

Tolerability of remoxipride in the long term treatment of schizophrenia. An overview.

506 patients with schizophrenia, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria, were included in a long term treatment programme with remoxipride, a selective dopamine (D2)-receptor antagonist. This overview includes pooled data from all patients who have been treated long term with remoxipride in clinical trials, focusing on patients treated for more than 6 months (n = 283). Remoxipride was administered in daily doses of 75 to 600mg. The assessment tools were Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Simpson and Angus scale, Abnormal Involuntary Movements Scale (AIMS) for abnormal involuntary movements, adverse events/symptoms using a 26-item checklist, clinical chemistry, and haematology and cardiovascular investigations. The majority of patients had a long duration of illness (median 11 years). 67% of patients (340/506) withdrew from treatment before 12 months and 44% (223/506) stopped treatment before 6 months. The median BPRS total score decreased during the first 3 months from 23 to 12, and this level of improvement was maintained throughout the 12-month period. Treatment-emergent adverse events reported by more than 5% of the patients were insomnia, tiredness, drowsiness and tremor in the group treated for 6 to 12 months. No symptoms, including checklist extrapyramidal symptoms (EPS), were reported by more than 5% of patients treated for 12 months. Low frequencies of EPS according to the Simpson and Angus scale were seen in patients treated for more than 6 months (n = 147). A small but statistically significant reduction of the mean total AIMS score from baseline to last rating was observed. There were infrequent changes in heart rate, resting diastolic blood pressure and electrocardiogram (ECG). Clinical chemistry and haematology data showed no evidence of clinically significant changes over time during the 12 months of treatment. Among 506 patients, 7 suicides and 7 suicide attempts occurred during the study period. Other serious adverse events were abnormal liver function test (2 cases), gastrointestinal, urinary retention, status epilepticus (psychotic polydipsia), granulocytopenia (1 each) and myocardial infarction (5 cases). Remoxipride is of potential value as a drug which is both effective and well tolerated in the long term management of patients with schizophrenia.

Hyperhomocyst(e)inaemia: an independent risk factor for intermittent claudication.

The aim of this study was to test the question of hyperhomocyst(e)inaemia as a risk factor for intermittent claudication (IC) independent of other important risk factors for peripheral atherosclerotic disease, such as smoking, hypertension, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, low levels of high-density-lipoprotein (HLD) cholesterol and age. The study population was recruited from an epidemiological study in Linköping County, Sweden, where all middle-aged men (n = 15,253, 45-69 years of age) were screened for IC. Seventy-eight subjects with verified IC and 98 healthy sex- and age-matched controls were randomly selected. Plasma levels of homocyst(e)ine (including the sum of free and bound forms of homocysteine and their disulphide oxidation products, homocystine, and homocysteine-cysteine mixed disulphide) were significantly higher (16.74 +/- 5.45 mumol l-1, mean value +/- SD, P = 0.0002) in IC subjects than in controls (13.80 +/- 3.21 mumol l-1), with 23% of the claudicants above the 95th percentile for controls. Stepwise logistic regression analysis revealed that the difference in plasma homocyst(e)ine was independent of the other above-mentioned risk factors. Moreover, the elevation of plasma homocyst(e)ine in claudicants was mainly confined to subjects with serum folate levels of less than or equal to 11.0 nmol l-1. The results suggest that folic acid supplementation should be tried in IC subjects with hyperhomocyst(e)inaemia.

Experiences of long-term treatment with remoxipride: efficacy and tolerability.

An international clinical trial programme was undertaken to evaluate the clinical safety and tolerability of remoxipride during a 12 month long-term study and to evaluate safety, tolerability and efficacy of remoxipride for up to 6 months in a double-blind comparison with haloperidol. A total of 145 patients were treated with remoxipride for at least 12 months. In the double-blind evaluation 106 patients on remoxipride and 50 on haloperidol were included. The doses of remoxipride ranged between 90-600 mg daily and of haloperidol between 5-45 mg daily. The therapeutic efficacy of remoxipride obtained in short-term studies was maintained during long-term treatment in most patients and was similar to that of haloperidol. Remoxipride had a clear cut advantage concerning extrapyramidal symptoms and anticholinergic drugs were needed less frequently with remoxipride than with haloperidol. The tolerability and safety showed no clinically significant differences compared to the data from short-term studies. This indicates that remoxipride can be used safely and with maintained efficacy for long-term treatment.

Case two. Development of a strategic plan and the planning process at a medical center.

In 1983, the medical center had no strategic planning process and no individual or department with an identified responsibility for planning to meet the needs of the organization and its service community. There were limited resources to apply to this endeavor and a prevailing attitude among current leadership that any planning done should be focused solely on facilities development. While the process pursued in this case is similar to that in Case One, unlike Case One, conditions within the organization are less than ideal for the implementation of any process, formal or informal, for the formulation of strategy. Read alone, the case is instructive. Considered in combination with Case One, it provides grist for a good discussion of the differences between organizations which have the capacity to be strategically managed and those which have learning to do.

Kinetics of triiodothyronine uptake by erythrocytes in hyperthyroidism, hypothyroidism, and thyroid hormone resistance.

We studied the initial uptake of L-T3 in erythrocytes isolated from normal subjects and patients with abnormal thyroid function. The uptake was saturable, with a mean maximum velocity (Vmax) of 3.60 pmol/min.10(8) cells and a Km of 248 nmol/L in normal subjects. Women had a somewhat lower Km but a similar Vmax compared to those in men. The Vmax was increased in patients with hyperthyroidism and decreased in those with hypothyroidism. Successful treatment lowered the initially high Vmax in hyperthyroid patients and raised the low Vmax in hypothyroid patients. One subject with the rare syndrome of thyroid hormone resistance had a Vmax in the upper normal range. The mean Km values of the hyperthyroid and hypothyroid groups and of the subject with thyroid hormone resistance were similar to that of the normal subjects. The results indicate that the initial saturable uptake of T3 by the human erythrocyte is increased in hyperthyroidism and decreased in hypothyroidism.

Active transport of L-tri-iodothyronine through the red cell plasma membrane--true or false?

The membrane transport of L-tri-iodothyronine has been studied in human erythrocyte ghosts. Initial uptake showed saturability with a Km of 33.8 nmol/l, suggesting carrier-mediated transport. Ouabain partly inhibited this uptake. ATP, on the other hand, caused a significant increase in the Vmax indicating an active transport of L-tri-iodothyronine across the erythrocyte plasma membrane. Ghosts from patients with hyperthyroidism, hypothyroidism or thyroid hormone resistance did not differ significantly from controls in their uptake of the hormone.

Mitogenic activity of glia maturation factor. Interaction with insulin and insulin-like growth factor-II.

The mitogenic activity of glia maturation factor (GMF) was tested on sparse-cultured cells. GMF stimulates the growth rate of normal astroblasts and fibroblasts grown in the presence of fetal calf serum (FCS), and raises the saturation density of the cells over what is imposed by the corresponding serum concentrations. GMF has no mitogenic effect in the complete absence of serum. The mitogenicity of GMF is also demonstrable in defined media where certain serum components are present. In particular, GMF in combination with the defined medium N2 partially mimics the proliferative effect of serum alone. Insulin, an ingredient of N2, can substitute for the complete N2 formula. Insulin-like growth factor-II (IGF-II), in turn, can substitute for insulin. The interaction of GMF with insulin or IGF-II can be demonstrated in a sequential manner, suggesting that GMF is a competence factor. Since insulin is required at a concentration well above the physiologic serum level, and must be used at a dose 1000 times higher than IGF-II, we suspected that insulin acts on IGF-II receptors. This was substantiated by the demonstration of IGF-II receptors and the absence of detectable insulin receptors on the astroblasts. The combined effect of IGF-II and GMF mimics the combined effect of 10% FCS and GMF, in both growth rate and saturation density.

Alaproclate, a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia.

Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanisms in vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studies in vitro: 5-HT, histamine-H1, alpha 1, -alpha 2-adrenergic and dopamine D2 receptors. Alaproclate had also a weak affinity for 3H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulation in vivo. Contrary to clomipramine alaproclate failed to block NA uptake in vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptake in vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.

The pharmacology of zimelidine: a 5-HT selective reuptake inhibitor.

Zimelidine (ZIM) and its main active metabolite norzimelidine (NZIM) have been shown to preferentially inhibit 5-hydroxytryptamine (5-HT) neuronal uptake both in vitro and in vivo while having much less effect on noradrenaline (NA) uptake. ZIM in vivo blocked the 5-HT uptake mechanism in the cerebral cortex, hippocampus, striatum, hypothalamus and spinal cord, thus indicating effects on both the ascending and descending 5-HT pathways. ZIM is devoid of a 5-HT releasing action, MAO-inhibitory properties and effects on dopamine (DA) uptake. ZIM failed to reduce NA turnover even in high doses, but markedly reduced 5-HT turnover in very low doses in the rat. ZIM also enhanced 5-HT mediated behaviours in mice in doses related to the inhibition of 5-HT uptake. In contrast to amitriptyline (AMI) and mianserin (MIAN), ZIM only in extremely high doses displayed a 5-HT receptor blocking action in vitro and failed to block 5-HT mediated behaviour. ZIM was practically devoid of action on histamine H1 and H2 receptors, and had also a neglible action on noradrenergic alpha 1- and alpha 2-receptors, and on beta-receptors. Unlike the tricyclic antidepressants (TAD's) ZIM had a negligible action on muscarinic receptors and failed to affect cholinergic induced activity. Long-term treatment with ZIM did not result in any attenuation of the 5-HT uptake blocking potency or the reduction of 5-HT turnover. This long-term treatment slightly reduced the number of beta-receptors in the brain. However, repeated ZIM-treatment induced a new 5-HT receptor binding site characterized by a low affinity and with a high number of binding sites and decreased the number of high affinity 5-HT receptor binding sites. Unlike the TAD's zimelidine failed to block the action of reserpine. Metabolic and behavioural interactions studies in mice showed that ZIM was devoid of any significant interactions with ethanol, barbiturates and benzodiazepines. It is concluded that ZIM markedly differs from both the TAD's and new antidepressants such as mianserin and nomifensine. ZIM seems preferentially to effect the presynaptic 5-HT reuptake mechanism while having a negligible action on noradrenergic, 5-HT, acetylcholine and histamine receptors in the brain.