Continuous Combined Hormone Therapy Research Articles

Risk of venous thromboembolism during the use of oral estrogen-progestogen hormone therapies in light of most recent research findings.

Two important studies evaluating the safety profile of oral estrogen-progestogen hormonal therapies conducted in standard clinical practice with respect to the venous system were recently published.A large prospective controlled cohort study (PRO-E2) based on the non-inferiority design has shown that the relative risk of developing venous thrombosis (VTE) in women using combined oral hormonal contraceptives (COHC) containing 17β-estradiol (1.5 mg) and nomegestrol acetate (2.5 mg) (E2/NOMAC) was not statistically different from that in users of COHC containing ethinylestradiol and levonorgestrel (EE/LNG).The aim of the recently presented study was to compare the risk of VTE in patients treated with a product for oral continuous combined menopausal hormone therapy containing 1 mg of 17ß-estradiol and 100 mg of micronized progesterone (1 mgE2/100 mgP4) with patients taking conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). The study was based on an analysis of records retrieved from a US health insurance database, and was therefore concerned the real-life clinical practice. The hazard ratio of VTE when comparing 1 mgE2/100 mgP4 with CEE/MPA was 0.70 (95% CI: 0.53–0.92). The difference was found to be statistically significant (p < 0.05).The rewieved studies provide further evidence that the use of hormones bioidentical with endogenous steroids in oral contraception and menopausal hormone therapy creates an opportunity to combine high efficacy with a favorable safety profile.

Influence of Menopausal Hormone Therapy on Body Composition and Metabolic Parameters.

The loss of estrogen with menopause is associated with an increase in central fat. The objective of this study was to evaluate the effects of menopause hormone therapy (HT) on body composition and metabolic parameters in postmenopausal women. A prospective study was conducted among postmenopausal women from the Climacteric clinic, Universidade Federal de São Paulo. Thirty-two participants, median age 51 years, were included. Sixteen women were eligible to receive a low-dose continuous combined HT, containing 1 mg of E2 plus 0.125 mg of trimegestone for 6 months. The other 16 women remained in the control group. In the HT group, significant decreases from baseline were evident for the total cholesterol (TC) (p < 0.05) and LDL levels (p < 0.05). The HDL significantly decreased (p < 0.05). However, the TC/HDL ratio also decreased (p = 0.05). The parameters of body composition, after 6 months of HT, were maintained. In the control group, body mass index levels increased from baseline, however, with nonstatistically significant differences (p = 0.06). Analyzing the body composition showed a significant increase in the trunk body fat (p = 0.04), trunk region fat (p = 0.04), and total region fat (p = 0.03) after 6 months. In conclusion, the present study provides evidence that HT can stunt the increase in total body fat and prevent the shift from a more central fat distribution observed in early postmenopausal period.

Long-term hormone therapy for perimenopausal and postmenopausal women.

Long-term hormone therapy for perimenopausal and postmenopausal women.

Menopausal hormone therapy use in 17 European countries during the last decade

IntroductionThe first ‘Women's Health Initiative’ (WHI) randomised controlled trial assessed use of continuous combined menopausal hormone therapy (cc-MHT). It was prematurely stopped because of an increased invasive breast cancer (BC), coronary heart disease (CHD), stroke and pulmonary embolism risk. Consequently, scientific societies recommended use of MHT at the lowest effective dose for the shortest duration. As a result, a sharp decline in MHT use occurred worldwide. AimTo report in a uniform way the change in MHT use in European countries. To evaluate whether the variability of the MHT changes were related to some medical indicators. Materials and methodsIMS Health provided MHT sales data for the years 2002 till 2010 for 17 countries. We tested several hypotheses to explain the heterogeneity of MHT use changes. Results and discussionIn 2002, the estimated MHT rate in women 45–69 years old varied considerably between countries ranging from less than 5% to more than 25%. In all countries a profound decrease occurred between 2002 and 2010, ranging from 50% to 77%. By the end of 2010, the MHT uptake was lower than 10% in all countries except in Finland. MHT use change was not correlated to MHT use and prevailing BC incidence at baseline, nor to the number of gynaecologists per 100,000 women or to the level of information about MHT. ConclusionThe global MHT use experienced a sharp decrease in all the analysed countries, although some variability exists. The decrease was unrelated to the assessed parameters.

Efficacy and safety of DT56a compared to hormone therapy in Greek post-menopausal women.

Hormone therapy (HT) is the treatment of choice for the alleviation of menopausal symptoms; concerns, however, about its concomitant long-term health risks have limited its use. DT56a is a unique enzymatic isolate of soybeans. The purpose of our study was to evaluate the efficacy and safety of DT56a, compared to HT, in symptomatic post-menopausal women. Eighty-nine post-menopausal women were studied prospectively. Women with climacteric symptoms were randomly assigned to receive eitherDT56a (no.=27) or oral low dose continuous combined HT (no.=26). Symptomatic women not wishing to receive any treatment served as controls (no.=36). Menopausal symptoms as assessed through the Kupperman index, serum lipids and lipoproteins, calcium, as well as bone mineral density (BMD), endometrial thickness, and mammography were assessed at baseline and at 12 months. Patients receiving HT and DT56a showed a significant and independent decrease in menopausal symptoms (mean difference in Kupperman score, DT56a group: -3.98, HT group -5.601, no treatment group +1.76, p-value <0.001). Lumbar spine BMD T-score was significantly lower in women receiving no treatment, as opposed to the two treatment arms which showed no significant change (No treatment, baseline: -0.60, final: -0.85, p=0.001; HT, baseline: -84, final -0.99, p=0.79; DT56a, baseline -0.51, final: -0.76, p=0.75). No differences in femoral bone density, ET or mammography classification were detected in any of the treatment arms. Likewise, serum lipids or lipoproteins did not differ between the three groups. DT56a decreased menopausal symptoms significantly and in the same degree as HT.

Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles

This study investigated the impact of chronic exposure to continuous (CoP4) versus cyclic progesterone (CyP4) alone or in combination with 17β-estradiol (E2) on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX) led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1), redox homeostasis (peroxiredoxin 5; Prdx5), insulin signaling (insulin-like growth factor I; Igf1), and cholesterol trafficking (liver X receptor α subtype; Nr1h3), differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX) and E2+CyP4 (up-regulation relative to OVX). In contrast, genes involved in amyloid metabolism (β-secretase; Bace1) differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1). In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT) can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.

Unscheduled bleeding in continuous combined hormone therapy users

Continuous combined hormone therapy (HT) is effective for menopausal vasomotor symptoms and vaginal dryness but commonly leads to unscheduled vaginal bleeding and spotting. Unscheduled bleeding is disliked by women and may lead to invasive investigations to exclude underlying pelvic pathology. In most cases investigations do not reveal any underlying cause for the bleeding.

Digitized assessment of mammographic breast density – Effects of continuous combined hormone therapy, tibolone and black cohosh compared to placebo

ObjectivesTo determine the effects of continuous combined hormone therapy, tibolone, black cohosh, and placebo on digitized mammographic breast density in postmenopausal women. Study designA prospective, double-blind, placebo-controlled study of 154 postmenopausal women randomized to estradiol 2mg/norethisterone acetate 1mg (E2/NETA), tibolone 2.5mg or placebo and a prospective, open, uncontrolled drug safety study, of which 65 postmenopausal women were treated with black cohosh. Mammograms, at baseline and after six months of treatment, were previously classified according to visual quantification scales. Main outcome measuresReanalysis of assessable mammograms by digitized quantification of breast density. ResultsTreatment groups were comparable at baseline. During treatment, both E2/NETA and tibolone significantly increased breast density (mean increase 14.3%, p<0.001 and 2.3%, p<0.001, respectively), while black cohosh and placebo did not. Twenty-four out of the 43 women on E2/NETA had an increase in density exceeding 10% and 6 women had an increase of 30% or more. In the tibolone group, only one woman had an increase in density of more than 10%. The difference in increase in breast density between E2/NETA on the one hand and tibolone, black cohosh and placebo on the other was highly significant (p<0.0001). ConclusionsDigitized mammographic breast density is a highly sensitive method confirming significant increase in density by standard E2/NETA treatment and to a lesser extent by tibolone, whereas black cohosh does not influence mammographic breast density during six months treatment. Digitized assessment also yields data on individual variation and small increases left undetectable by visual classification.

Sex Hormones in Postmenopausal Women Receiving Low‐Dose Hormone Therapy: The Effect of BMI

The aim of our study was to evaluate the effect of BMI on the change in circulating sex hormone in postmenopausal women during 6 months of oral continuous combined low-dose hormone therapy (HT). Fifty postmenopausal women were allocated to receive daily one tablet containing combination of 17β-estradiol (1 mg)/norethindrone acetate (0.5 mg) for 6 months. Serum levels of follicle-stimulating hormone (FSH), estradiol, total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), free estrogen index (FEI), Δ4-androstendione (Δ4A), and dehydroepiandrosterone sulfate were assessed at baseline and at the end of 6 months. Mean absolute values and percent changes from baseline were compared between lean and overweight women. Mean FSH decreased and mean 17β-estradiol increased significantly in both groups (FSH lean: 82.3 ± 26.7 decreased to 45.0 ± 17.0 mIU/ml, P = 0.0001; FSH overweight: 85.5 ± 22.1 decreased to 52.3 ± 23.8 mIU/ml, P = 0.003; P between groups = 0.661; E2 lean: 23.24 ± 12.55 increased to 53.62 ± 28.29 pg/ml, P = 0.006; E2 overweight: 24.17 ± 10.88 increased to 68.36 ± 53.99 pg/ml, P = 0.0001; P between groups = 0.619). Lean individuals had statistically significant higher increments of FAI and specifically FEI compared to overweight (FEI lean; 0.14 ± 0.09 increased to 0.29 ± 0.14, P = 0.009; overweight 0.23 ± 0.18 increased to 0.52 ± 0.40, P = 0.126; P between groups = 0.034). Although BMI does not affect total 17β-estradiol changes, free sex steroid concentrations increase more steeply in lean compared to overweight women receiving oral low-dose HT.

Endometrial bleeding in postmenopausal women

The aim of this study was to present a review of the potential mechanisms involved in the occurrence of endometrial bleeding in postmenopausal women using hormone therapy. Selected literature on the incidence of bleeding in postmenopausal women using estrogen progestogen therapy was reviewed. The incidence of spotting and bleeding in women using continuous-combined hormone therapy was presented. Relevant articles related to the role of angiogenic factors and vasculogenesis in the endometrium, endometrial leukocytes, and endometrial metalloproteinases were used for the review. The cause or etiology of endometrial bleeding with hormone therapy is unknown. Several options are known to alter angiogenesis or be involved in tissue remodeling during normal menstruation. Vascular endothelial growth factor and thrombospondin-1 are proangiogenic and antiangiogenic factors that could cause dysfunction in vasculogenesis that could result in blood vessel fragility and bleeding. The role of pericytes in maintaining vessel morphology and integrity is discussed. Endometrial leukocytes and metalloproteinases are involved in normal menstruation, but their role in postmenopausal bleeding is not clear suggesting involvement of mechanisms in the bleeding. There is limited information on clinical investigation into the etiology of postmenopausal bleeding associated with hormone therapy. The major cause of hormone therapy-related bleeding is unknown. Alterations in angiogenic factors that could result in vascular dysfunction and vessel breakdown provide a working hypothesis as to the potential cause of vessel breakdown.

Comparative effects of continuous combined hormone therapy and tibolone on body composition in postmenopausal women

ObjectiveTo compare the effects of tibolone with those of continuous combined hormone replacement therapy (HT) on body composition in postmenopausal women.MethodsOne hundred and fifty postmenopausal women were enrolled in a randomized, controlled trial to compare the effects of tibolone with continuous combined HT on body composition. Patients were randomly allocated into three groups and followed for 9 months. Of the subjects included, 50 women received 2.5 mg tibolone plus one Cal+D tablet (500 mg calcium and 200 IU vitamin D) daily, 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (CEE/MPA) plus one Cal+D tablet daily, and the rest (50 women) received only one Cal+D tablet and served as a control group. Body composition was evaluated with measurements of body mass index (BMI), weight, waist-to-hip ratio (WHR), fat mass and fat-free mass (FFM) before and after the intervention. Measurements of body fat mass percentage, fat mass, body fat-free mass percentage and fat-free mass (FFM) were assessed by measurement of skin-fold thickness.Results Tibolone significantly increased weight, BMI and FFM and decreased WHR after the treatment in comparison with baseline (p < 0.05). However, only weight and BMI increased significantly in the CEE/MPA group after the treatment (p < 0.05). There were significant increases in weight, BMI and fat mass in the control group after 9 months. In the comparison of the parameters after the treatment between the three groups, tibolone significantly increased FFM compared with the control and CEE/MPA groups (p < 0.01).Conclusions The effect of tibolone on body composition is favorable and therefore tibolone may be regarded as an alternative to continuous combined hormone therapy in postmenopausal women.

Hormone therapy in Brazilian postmenopausal women with chronic hepatitis C: a pilot study

Objective To evaluate liver function and hemostatic parameters in postmenopausal women who have chronic infection with the hepatitis C virus and climacteric symptoms and are undergoing hormone therapy (HT) (standard dose of transdermal continuous combined hormone therapy).Design Fifty out of 336 postmenopausal patients with chronic infection with the hepatitis C virus were selected. The non-inclusion criteria were other chronic or systemic liver diseases, severe vascular diseases, autoimmune diseases or malignant tumors. The patients were randomized into two groups: the HT group with 25 patients to be given transdermal hormone therapy (50 μg estradiol plus 170 μg norethisterone/day) and the control group with the other 25 patients (no medication). Hepatic tests (alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, total alkaline phosphatase, albumin, serum bilirubin) and hemostatic parameters (prothrombin time, factor V, fibrinogen) were evaluated at baseline and at 1, 4, 7 and 9 months of treatment.Results No significant changes in parameters were found in the comparison between the treated group and the controls, except for a decrease in total alkaline phosphatase (p = 0.002), presumably due to changes in bone remodelling.Conclusions There were no changes in liver function after a 9-month treatment with transdermal estradiol plus norethisterone in symptomatic postmenopausal patients with hepatitis C.

Optimal tolerability of ultra-low-dose continuous combined 17β-estradiol and norethisterone acetate: laboratory and safety results

Objective To evaluate the influence of two ultra-low doses of oral continuous combined hormone therapy and placebo on metabolic parameters, and to assess safety endpoints and overall tolerability in healthy postmenopausal women.Design In a subpopulation of the Clinical study on Hormone dose Optimisation In Climacteric symptoms Evaluation (CHOICE) trial, lipids and parameters of glucose metabolism and hemostasis were analyzed in Nordic women (n = 158) at baseline and after 12 and 24 weeks of treatment with 0.5 mg 17β-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA or placebo. Adverse events occurring from the first trial-related activity, whether related or not related to the study medication, were recorded for the entire population (n = 575) of the trial. The seriousness, relationship to treatment and the reason for withdrawal were reported.Results Both ultra-low-dose combinations were neutral to changes in lipid and lipoprotein, hemostasis parameters and carbohydrate metabolism during the trial. The incidence of serious adverse events was only 1% in respective treatment groups. Adverse events were the reason for withdrawal in only 2% and 6% of women in the 0.5 mg E2 + 0.25 mg and 0.1 mg NETA groups, and in 8% in the placebo group. No weight gain or change in blood pressure was reported during the trial in any of the study groups.Conclusion The treatments had neutral effects on metabolic parameters in the study population. Excellent tolerability of both ultra-low doses resulted in high completion rates.

Hormone Therapy and Risk of Myocardial Infarction: A National Register Study

There was a discrepancy between data in the Women's Health Initiative (WHI) showing increased risk of coronary artery disease and stroke associated with continuous combined hormone therapy (HT), and prior observational studies suggesting that HT would have a primary preventive effect on cardiovascular disease. A previous study suggested that WHI data and observational results would be more in agreement if time since initiation of HT was controlled. Some investigators believed that the WHI data may not be applicable for healthy younger peri-menopausal women. This population-based observational study evaluated the influence of age, various regimens, routes of administration, duration of use, progestagen types, and estrogen dose on the risk of myocardial infarction (MI) associated with HT. National registry information on 698,098 healthy Danish women, aged 51-69, were followed from 1995 to 2001. Exposure to HT was recorded on a daily basis from a central prescription registry. Relative risk (RR) estimates were analyzed by Poisson regression analysis. A total of 4957 MI events were identified within the 6 year study period. Compared to women who never used HT, current use of hormones did not increase the overall risk of MI (RR, 1.03; 95% confidence interval [CI], 0.95-1.11). Among women in the youngest age group (51-54 years), however, there was an increased risk of MI (adjusted RR, 1.24; 95% CI, 1.02-1.51). The adjusted RR was 0.92 with a 95% CI of 0.80-1.06 in the older age groups. Increased risk of MI was also associated among women in the youngest age group with longer duration of HT (>4 years); this association was not found in the older age groups. The highest risk of MI among all age groups was found with the continuous combined regimen (adjusted RR, 1.35; 95% CI, 1.18-1.53). No significant risk was associated with cyclic combined therapy, unopposed estrogen, or tibolone. The risk associated with the dermal route for unopposed estrogen was significantly lower than for oral delivery (P ≤.04). No overall indication of increased risk of MI was found with increasing doses of estrogen or progestagen type. These data did not show any overall association between HT and risk of MI among older women who currently used HT; increased risk was found in younger women. Longer duration of HT also increased the risk among younger women, but not older women.

One Case of Malignant Mixed Müllerian Tumor Developed in a Postmenopausal Woman under Hormone Therapy

Hormone therapy for peri- and postmenopausal women is widely used for relieving vasomotor symptoms or preventing osteoporosis. Even though exogenous hormone is the most common cause of vaginal bleeding in postmenopausal women under hormone therapy, in clinical practice, physicians must never exclude the possibility of endometrial disorders, such as endometrial hyperplasia or cancer. Taking thorough medical history and performing physical and pelvic examinations are essential for the evaluation of abnormal uterine bleeding in menopausal hormone therapy. Transvaginal ultrasonography, endometrial aspiration biopsy, dilatation and curettage, and hysteroscopy are the options which physicians may use. This case is about a woman with continuous combined hormone therapy for 5 years who had experienced rather sudden onset of vaginal spotting lasting for several months and was fi nally diagnosed as having malignant mixed Mullerian tumor. Our purpose is to inquire into the proper approaching steps for vaginal bleeding in menopausal hormone therapy.

Prospective study evaluating olfactometric and rhinomanometric outcomes in postmenopausal women on 1 mg 17β-estradiol and 2 mg drospirenone HT

To evaluate the effects of drospirenone on the olfactory sensitivity in postmenopausal women treated with hormone therapy (HT). Forty-seven naturally postmenopausal women participated in the prospective study. The women underwent continuous combined HT containing 1 mg 17beta-estradiol and 2 mg drospirenone (DRSP). Airflow resistance values and olfactometric thresholds were measured by using rhinomanomety and olfactometry, respectively, performed at baseline and in the third and sixth cycle of HT. Rhinomanometric values were better during 17beta-estradiol/DRSP HT with respect to those observed at baseline (P < 0.001). Olfactometric threshold data indicated a higher sensitivity during both the third (P < 0.05), and sixth cycles of 17beta-estradiol/DRSP HT (P < 0.001) than at baseline. Our study confirmed that the nasal airflow resistance and olfactory thresholds to odors may depend on steroid hormones. We believe that estrogens could influence neuronal plasticity and the neuronal conduction time in the olfactory system. The antimineralocorticoid activity of DRSP may produce a decrease in nasal edema, inducing a better interaction between odorous substances with receptors.

Characteristics of nasal epithelial cells in naturally postmenopausal women receiving hormone therapy with 1 mg 17β-estradiol and 2 mg drospirenone

To investigate the effects of drospirenone on nasal respiratory epithelium in postmenopausal women who are treated with hormone therapy (HT). Thirty-five naturally postmenopausal women participated in the prospective study. Women received continuous-combined HT containing 1 mg 17beta-estradiol and 2 mg drospirenone. Cytological changes of nasal middle and inferior turbinate respiratory epithelium were evaluated by using the maturation index, performed at baseline and on the sixth cycle of HT. Hematoxylin-eosin staining for the maturation index of the epithelial nasal cells of women reached better trophic aspects during 17beta-estradiol/drospirenone intake with respect to those observed at baseline (P < 0.001). The smears during HT emphasized the superficial and the intermediate types of cells, with a ratio index greater than 2. The parabasal cell content was less than 20%, and the karyopyknotic index showed degenerative changes in superficial and intermediate cells. Our study confirmed that the nasal respiratory epithelium is an ovarian steroid target. Drospirenone acts on nasal cells similarly to other progestogens.

The Risk of Uterine and Ovarian Cancer for Different Formulations of Hormone Therapy (HT)

Little has been published about the impact of different HT formulations or ways of administration on gynecological cancer risk. Two population-based case-control studies in collaboration with regional cancer registries and tumor centers in Germany were performed. Some 777 cases of ovarian cancer (OvC) and 1026 cases of uterine corpus cancer (UC) were compared with 3211 and 3668 matched controls for OvC and UC, respectively. The adjusted odds ratios for risk of cancer were 0.7 (0.6 -0.9) and 0.8 (0.7 -0.99) for OvC and UC for ever vs never use of HT. No clinically relevant trends for OvC and UC risk were observed with increasing duration of HT or with time since first/last use for ever or current use, in all and in postmenopausal women. Oral, transdermal, and other ways of HT administration were not associated with increased OvC or UC risk: nonsignificant adjusted ORs ranged between 0.6 and 1.3. Sequential and continuous-combined HT formulations showed reduced risk of OvC and UC, predominantly non-significant. This was similar for different types of estrogens and progestins. Combinations of CEE and MPA showed no other OvC/UC risk than combinations without CEE an MPA. In this study, HT use was not associated with an increased risk of OvC or UC and did not vary markedly among different HT formulations (estrogens, progestins, oral, and transdermal administration). However, small numbers and other limitations suggest cautious interpretation.

Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial.

BackgroundThe aim of the study was to determine the effect of postmenopausal hormone therapy on women's symptom reporting and quality of life in a randomized trial.Methods1823 women participated in the Estonian Postmenopausal Hormone Therapy (EPHT) Trial between 1999 and 2004. Women were randomized to open-label continuous combined hormone therapy or no treatment, or to blind hormone therapy or placebo. The average follow-up period was 3.6 years. Prevalence of symptoms and quality of life according to EQ-5D were assessed by annually mailed questionnaires.ResultsIn the hormone therapy arms, less women reported hot flushes (OR 0.20; 95% CI: 0.14–0.28), sweating (OR 0.56; 95% CI: 0.44–0.72), and sleeping problems (OR 0.66; 95% CI: 0.52–0.84), but more women reported episodes of vaginal bleeding (OR 19.65; 95% CI: 12.15–31.79). There was no difference between the trial arms in the prevalence of other symptoms over time. Quality of life did not depend on hormone therapy use.ConclusionPostmenopausal hormone therapy decreased vasomotor symptoms and sleeping problems, but increased episodes of vaginal bleeding, and had no effect on quality of life.Trial registration numberISRCTN35338757

Hemostatic markers in healthy postmenopausal women during intranasal and oral hormone therapy

To study changes in the hemostatic balance during intranasal compared with oral administration of 17beta-estradiol (E2) and norethisterone (NET) or NET acetate in postmenopausal women. A wide range of markers of coagulation and fibrinolysis associated with coronary artery disease was tested. In a two-center, randomized, double-blind, comparative trial, 90 healthy postmenopausal women (aged 56.6 +/- 4.7 y) received daily continuous combined hormone therapy, either E2/NET 175 microg/275 mug intranasally as a spray (n = 47) or E2/NET acetate 1 mg/0.5 mg orally as a capsule (n = 43) for 1 year. Hemostatic markers were measured in blood samples taken at baseline and after 12, 24, and 52 weeks of treatment. After 52 weeks of treatment, changes in the intranasal group in markers of coagulation-fibrinogen (-1.3%), factor VII activity (-14.0%), and prothrombin fragment 1 + 2 (+5.8%)-were significantly less (P < 0.05) than the changes in the oral group for these parameters (-6.5%, -20.3%, and +19.0%, respectively). Changes in activated factor VII did not differ between the groups. Neither group showed significant changes in thrombin-antithrombin complex. In the intranasal group, decreases in markers of fibrinolysis-tissue-type plasminogen activator (-10.4%) and plasminogen activator inhibitor-1 antigen (-13.8%)-were significantly less (P < 0.05) than the decreases in the oral group (-17.8% and -38.0%, respectively). A decrease in plasminogen activator inhibitor-1 activity and increases in D-dimer and plasmin-alpha2-antiplasmin complex did not differ between the groups. No differences were found between the groups in homocysteine, which overall was unaltered in both groups. During intranasal E2/NET therapy, changes in the coagulatory and fibrinolytic markers were to some extent less than those observed during oral therapy.