Transdermal Hormone Replacement Therapy Research Articles

The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

Treatments and Management of Menopausal Symptoms: Current Status and Future Challenges

In the United States (US), menopause occurs at an average age of 52. Menopausal symptoms tend to be maximal during the few years before and the year after menopause (during perimenopause), except for symptomatic vulvovaginal atrophy, which may worsen over time. Up to 20% of bone density loss occurs during the first 5 years after menopause, followed by an age-related bone loss rate similar to that in men. Menopause should be considered confirmed if an age-appropriate woman who is not pregnant has not had a menstrual period for 12 months. Regarding treatment, for vaginal dryness or dyspareunia due to menopause, vaginal stimulation and vaginal lubricants and moisturizers are recommended, and if these are ineffective, low-dose vaginal estrogen, in the form of creams, tablets, suppositories, or rings should be considered; other options include oral ospemifene or intravaginal dehydroepiandrosterone (DEHA) suppositories. Before prescribing hormone replacement therapy (HRT) and periodically while therapy continues, women should be informed of risks (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], stroke, breast cancer, gallbladder disease, and urinary incontinence); potential harms are greatest for women who start HRT after 60 years of age or who are 10-20 years past menopause onset. If women choose HRT to relieve hot flushes, estrogen plus, a progestin or conjugated estrogen/bazedoxifene could be prescribed for women who still have the uterus. Treatment with HRT should be tailored to maximize benefits and minimize harms, and periodically benefits and harms should be reassessed; low-dose transdermal HRT may lead to a lower risk of DVT and stroke. Selective serotonin reuptakereuptake inhibitors (SSRIs), selective serotonin-nor-epinephrine reuptake inhibitors (SNRIs), and gabapentin could be considered as less effective alternatives to HRT for relieving hot flushes; paroxetine 7.5 milligrams (mg) is the only non-hormonal drug approved in the US for the relief of hot flushes. Effective non-drug options include cognitive behavioral therapy and hypnosis.

Association between hormone replacement therapy and sex hormones in postmenopausal women: a systematic review and meta-analysis.

The aim of the study was to systematically review and meta-analyze the available data on changes in the hormonal profile of postmenopausal women treated with hormone replacement therapy (HRT). Full-text articles published up to April 30, 2021, were searched through PUBMED, EMBASE, the Cochrane library and Web of Science (WOS) databases and were screened strictly according to inclusion criteria. Randomized clinical trials and case control studies were enrolled. Studies not reporting steroid serum levels or not providing a control group were excluded from the analysis. Studies enrolling women with genetic defects or severe chronic systemic diseases were excluded. Data are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Random effect models were used for the meta-analysis. HRT administration increases estradiol (E2) and reduces follicle stimulating hormone (FSH) serum levels compared with pre-treatment. Their changes are evident when oral and transdermal HRT are administered, while vaginal HRT not. No significant effect on E2 and FSH was found between 6 and 12 months, as well as between 12 and 24 months. No significant effect on E2 and FSH was shown between different regimes. No difference was observed between different HRT regarding their effect on lipid profiles, breast pain and vaginal bleeding, but oral estrogen combined synthetic progestin caused a reduction in sex hormone-binding globulin (SHGB). The review suggested oral and transdermal HRT could lead to a rise in E2 serum levels and a decrease in FSH. The types and doses of HRT did not seem to modify the E2 and FSH level. Also, oral estrogen combined synthetic progestin could cause a reduction in SHGB. This might be crucial when choosing the best possible treatment for each patient individually taking into consideration if potential benefits outweigh the risks.

Endocrine disorders in chronic kidney disease

The increasing prevalence of chronic kidney disease gives rise to many diagnostic challenges in the daily care of this group of patients. This paper presents the most clinically significant endocrine disorders accompanying chronic kidney disease, their aetiology, diagnosis, clinical picture and treatment. Endocrine disorders may occur in patients with chronic kidney disease with greater or equal frequency as in the general population. The most important endocrine disorders include: low triiodothyronine syndrome, subclinical and overt hypothyroidism, hypercortisolaemia, hyperprolactinaemia, increased levels of growth hormone, hyperinsulinaemia, insulin resistance and hypogonadism. Hyperthyroidism and autoimmune thyroid disease occur with the same frequency in patients with chronic kidney disease as in the general population. Chronic kidney disease also affects commonly used hormone determinations. The choice of the therapeutic method in patients with chronic kidney disease is not without importance for endocrine disorders. Among patients undergoing dialysis therapy, a temporary increase in free thyroid hormones, a decrease in the severity of hypercortisolaemia and a decrease in hormone levels were observed. Dialysis therapy does not normalise prolactin levels, unlike kidney transplantation, where an improvement in glomerular filtration rate results in the normalisation of serum prolactin. The therapeutic management of some of the presented endocrine disorders is not based on a causal effect, but mainly on controlling their complications (e.g. secondary to hypercortisolaemia – hypertension, diabetes, osteopenia or abdominal obesity). In the remaining cases, hormone replacement therapy was associated with a beneficial effect for the patient: testosterone replacement in obese men with hypogonadism led to a decrease in body mass index, and cyclical transdermal hormone replacement therapy in women with oestrogen deficiency secondary to renal failure inhibited bone demineralisation and thus prevented early osteoporosis.

Use of Hormonal Therapy Increases the Risk of Venous Thrombosis in COVID-19 Patients; Results of 1071 Patient Cohort

Introduction Coagulopathy is a well-recognized complication of COVID-19, with an incidence of thrombotic events as high as 31% in patients who are critically ill from COVID-19 infection. Estrogen-containing hormonal therapies are also well known to increase the risk of thrombosis. There have been no studies evaluating if estrogen-containing hormonal therapies potentiate thrombotic risk during COVID-19 infection, and there is no consensus on the clinical role of holding hormonal therapy during infection. We performed a large retrospective cohort study to evaluate the thrombotic risk of estrogen therapy during COVID-19 infection in both pre-menopausal and post-menopausal patients. Methods To assess the association between hormonal therapies and thrombosis in COVID-19 patients, we collected data on all female Oregon Health & Science University patients aged 18-80 years who tested positive for COVID-19 between 12/2020 and 2/2022 and were on hormonal therapies. We included a comprehensive range of hormonal therapies to ensure an accurate representation of both pre-menopausal and post-menopausal patients. The experimental group consisted of patients on combined hormonal contraceptives and hormone replacement therapy via the oral and transdermal routes, which have all been associated with increased thrombotic risk. The control group consisted of patients with a progesterone intrauterine device or on topical estrogen, neither of which is associated with an increased thrombosis risk. Pregnant individuals and patients on therapeutic anticoagulation before testing positive for COVID-19 were excluded. We collected data on demographics, vaccination status, thrombotic risk factors, venous thrombotic events, and outcomes (Table 1). The continuous variables were not normally distributed, and p-values were calculated using the Mann-Whitney test. The p-values for the categorical variables were calculated using Fisher's exact test. We then performed cox proportional hazards regression analysis to assess the thrombotic risks between control and experimental groups, while controlling for potential confounding variables. Venous thrombotic events were defined as pulmonary embolism (PE), deep vein thrombosis (DVT), cerebral vein sinus thrombosis (CVST), or hepatic vein thrombosis that occurred within 6 months of testing positive for COVID-19. Results In total, 1071 individuals met inclusion criteria. The experimental group included 546 patients, 407 on combined hormonal contraceptives (CHC) and 139 on oral or transdermal hormone replacement therapy (HRT). The control group included 525 patients, 410 with a progesterone intrauterine device and 115 using topical estrogen creams. The control and experimental groups were similar in all demographics and thrombotic risk factors, except for age (P<0.001) and body mass index (BMI) (p<0.001). There were no differences between groups in the rate of hospitalization for COVID-19, ICU stay for COVID-19, or death. There were 2 venous thrombotic events with an event rate of 1.3% in the control group and 9 events with a rate of 2.3% in the experimental group (p= 0.065). All of these events occurred within 2 months of COVID-19 positive test results. Increasing age (p<0.001) was significantly associated with a higher venous thrombosis risk. A cox proportional hazards regression analysis was utilized to evaluate the hazards ratio (HR) of venous thrombosis between groups, controlling for age and BMI. Patients in the experimental group had a HR of 5.76 (CI 1.24-26.77, p=0.026) for venous thrombotic events. In this model, the HR was 1.06 for age (CI 1.02-1.11, p=0.003) and 1.05 for BMI (CI 1.01-1.10, p=0.018). Conclusion Overall, this data suggests that estrogen-containing oral and transdermal hormonal therapies increase the risk of thrombosis in COVID-19 positive patients, although absolute risks were small. Thrombotic risk was also associated with increasing age and higher BMI. Based on these findings, providers may consider temporarily discontinuing hormonal therapies in patients with COVID-19 who are at high risk for thrombosis, especially older patients, those with a higher BMI, and those on higher doses of oral estrogen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Body composition, but not insulin resistance, influences postprandial lipemia in patients with Turner's syndrome.

The aim of the present study was to examine the influence of body composition and insulin resistance on the magnitude of postprandial lipemia in patients with Turner's syndrome receiving oral versus transdermal estrogen replacement. Twenty-five patients with Turner's syndrome receiving oral or transdermal estrogen replacement were evaluated for body mass index, waist-to-hip and waist-to-height ratios, fasting glycemia, insulin, body composition (dual-energy X-ray absorptiometry), and postprandial lipid metabolism. For statistical analysis, we used parametric tests to compare numeric variables between the two subgroups. We observed no difference in postprandial triglyceride levels between patients receiving oral versus transdermal hormone replacement therapy. The postprandial triglycerides increment correlated positively with the percentage of total fat mass (p=0.02) and android fat mass (p=0.02) in the transdermal group. In the oral estrogen group, a positive correlation was observed between the increment in postprandial triglycerides and waist-to-hip (p=0.15) and waist-to-height (p=0.009) ratios. No association was observed between the estrogen replacement route and insulin resistance evaluated by the homeostatic model assessment-insulin resistance (HOMA-IR) index (p=0.19 and p=0.65 for the oral and transdermal groups, respectively). We concluded that body composition and anthropometric characteristics possibly affect the extent of postprandial lipemia independently from the route of estrogen replacement.

Transdermal hormone replacement therapy with nanostructured medicines.

Due to hormonal changes during the menopause, women experience a variety of perimenopause and postmenopause symptoms. This review examines the various aspects of nanostructured hormone therapy and its application in the treatments of menopausal symptoms. Excerpta Medica DataBase, Medical Literature Analysis and Retrieval System Online, Web of Science, and Google Scholar were searched basing on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Seven eligible studies out of 51 related papers, which satisfied the initial search criteria, were extracted and carefully reviewed to clarify the role of nanomedicine in maintaining postmenopausal women's health. Review of the seven eligible studies confirmed nanostructured hormone therapy as a safe and effective method for the alleviation of menopausal symptoms. According to the existing studies, nanostructured hormone therapy decreased the mean daily frequency and severity of menopausal symptoms. The use of transdermal nanoformulations in hormone therapy can relieve climacteric symptoms and prevent other postmenopausal symptoms.

Evaluation of the in vitro Human Skin Percutaneous Absorption of Progesterone in Versabase® Using the Franz Skin Finite Dose Model

Women may benefit from hormone replacement therapy to alleviate undesirable menopausal symptoms such as hot flashes, disruption of sleep and fatigue. Transdermal hormone replacement therapy consists in the delivery of hormones through the skin and into the blood stream, avoiding gastrointestinal drug absorption difficulties and the first pass effect. Transdermal compounded medications may be customized to meet the individual needs of women by changing the hormones used, the respective concentrations and the medicine’s formulation. Two compounded medications were prepared for progesterone 50 mg/g, as follows: Progesterone in VersaBase® Cream and progesterone in VersaBase® Cream Gel. The purpose of this study is to determine the in vitro human skin percutaneous absorption of progesterone for both test formulations. The Franz Skin Finite Dose Model was the methodology used to evaluate the total absorption, the rate of absorption and the skin content of progesterone applied to the outer surface of ex vivo skin. This model has proven to be a valuable tool for the study of percutaneous absorption of topically applied drugs and to accurately predict in vivo permeation kinetics. The skin samples were obtained within 24 h to 48 h of death from three adult Caucasian donors and a total of 17 Franz diffusion chambers were prepared for testing. Results are presented as the mean ± standard error per parameter, for each test formulation. The rate of percutaneous absorption, presented as mean flux, was similar for the two test formulations and characterized by 2 peaks at approximately 6 hours and 28 hours after dose application, followed by a decline in flux over time. The total absorption and the skin content of progesterone were also similar: 21.6% and 21.8% of the applied doses for the test formulations 1 and 2, respectively. Although in vitro, these results suggest that progesterone in VersaBase® is likely to be delivered through the skin and into the general circulation for systemic effects. Practitioners may then consider transdermal progesterone as a viable route of drug administration for menopausal women.

Comparison of efficacy and local tolerability of estradiol metered-dose transdermal spray to estradiol patch in a network meta-analysis

Objectives: Transdermal hormone replacement therapy is preferred for menopausal vasomotor symptoms. Our purpose was to compare the efficacy and local tolerability of a patch and a metered-dose transdermal spray that have never been directly compared.Method: The relative change in the number of hot flushes between baseline and week 12 was selected as an efficacy indicator and the frequency of local skin reactions as a tolerability indicator. A network meta-analysis was performed to compare efficacy. Application site tolerability was compared descriptively.Results: Overall 46 studies were identified. In the efficacy analysis, eight active treatment arms and a placebo arm were determined based on the estradiol daily dose (from 14 μg to 50 μg). All but one had a significantly higher effect on relative change in the number of hot flushes than did the placebo. We found no evidence for different efficacy of the patch and the metered-dose transdermal spray. The latter performed better in terms of local skin reactions.Conclusion: The patch and the metered-dose transdermal spray seem to have the same efficacy on vasomotor symptoms in estradiol hormone replacement. The local tolerability of the metered-dose transdermal spray is favorable.

Effects of transdermal and oral hormone replacement therapies on monocyte chemoattractant protein-1 levels: a randomized clinical trial

ObjectivesTo assess the effects of oral and transdermal hormone replacement therapies (HRT) on levels of important cardiovascular disease (CVD) markers, MCP-1 and homocyteine, in the early postmenopausal period. Study designSeventy-six healthy, early postmenopausal women were enrolled in the study. Patients were randomly assigned to receive oral or transdermal HRT for 6 months. The first group received continuous combined oral HRT containing 1mg 17β-estradiol and 0.5mg norethisterone acetate (n=39), and the second group received sequential transdermal HRT releasing 50μg/day estradiol alone given twice a week on days 1–14 and 50μg/day estradiol plus 0.25mg/day norethisterone acetate given twice a week on days 15–28 (n=37). Circulating levels of MCP-1 and homocysteine, along with other CVD markers, were assessed before and after treatment in all patients. ResultsThere were no significant differences between the baseline characteristics of the two groups. Baseline serum MCP-1 levels were similar between the oral and transdermal HRT groups (150.1±12.8 vs. 145.2±11.6pg/ml; P=.219). The mean MCP-1 levels did not change after 6 months of HRT in both oral (150.1±12.8 vs. 153.6±12.5pg/ml; P=.192) and transdermal HRT groups (145.2±11.6 vs. 146.1±15.1pg/ml; P=.419). Moreover, there was no significant difference between the groups in MCP-1 serum levels after 6 months of HRT. Similarly, no difference was found in serum homocyteine levels following 6 months of HRT. ConclusionsBoth oral continuous and sequential transdermal HRTs do not have significant effects on serum MCP-1 and homocyteine levels in women during the early postmenopausal period.

Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study

OBJECTIVE:To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms.METHODS:A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512.RESULTS:An improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol.CONCLUSION:The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women.

EFFECTS OF A NEW TESTOSTERONE TRANSDERMAL DELIVERY SYSTEM, BIOLIPID B2®-TESTOSTERONE IN HEALTHY MIDDLE AGED MEN: A CONFOCAL RAMAN SPECTROSCOPY STUDY

The Transdermal Delivery System (BIOLIPID B2®) is a nanoemulsion that can be a pplied directly to the skin by a metered pump to deliver hormones into the systemic circulation. The ai ms of this study were to assess the efficacy of BIOLIPID B2 ® to deliver testosterone systemically and evaluate the short - term effects on Thyroid - Stimulating Hormone (TSH), C - reactive protein (CRP) serum levels and blood pressure in middle aged men with tes tosterone deficiency . An open label randomized prospective study enrolled 14 Brazilian middle aged men with testosterone deficiency . The volunteers received in the forearm 50mg of transdermal BIOLIPID B2® - testosterone nanostructured formulation daily for 3 months. Confocal Raman Spectroscopy (CRS) was used to determine depth and concentration of testosterone on skin layers. Clinical parameters and serum concentrations were compared between the base line and 3 months after treatment. Serum concentrations of t estosterone, CPR and TSH changed significantly (p 0.05) and no changes were observed in the blood pressure . N o adverse events were attribu ted to this transdermal hormone replacement therapy protocol. The BIOLIPID B2 ® nanoemulsion formulation is safe and effective in reestabli shing testosterone and Thyroid - Stimulating Hormone (T SH) serum levels. This transdermal protocol may serve as a strate gy for hormone replacement therapy in middle aged men.

Should hormone replacement therapy be used in postmenopausal women for voiding dysfunction?

Should hormone replacement therapy be used in postmenopausal women for voiding dysfunction?

Abstract P039: Physiologic Transdermal Sex Steroid Hormone Replacement Therapy and Effects on Cardiovascular Biomarkers, Quality of Life, and Age- related Decline in Peri/Postmenopausal Women

Background: Menopause annually affects 25 million women worldwide, and WHO estimates 1.2 billion women will be postmenopausal by 2030. Symptoms of vasomotor changes resulting in hot flashes and night sweats, dysphonic mood, and sleep disturbances affect quality of life in this aging population. Age- related conditions including cardiovascular disease, depression, osteoporosis, osteoarthritis, dementia, and frailty, are linked to menopause. Conventional oral HRT results in increased adverse effects and health outcomes as revealed in the WHI, yet animal studies and some epidemiologic data support benefits of HRT. Hypothesis: Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a favorable risk/benefit profile yet comparative effectiveness studies of this treatment model long term are lacking. Methods: Participants were recruited from the community at large. 300 women gave signed consent, and 75 met strict inclusion/exclusion criteria. Each subject was age and ethnicity matched to a control in the family medicine or women’s clinics. Treatment model subjects(n=75) received physiologic sex steroid transdermal therapy including: estrogen, progesterone and androgens, titrated to physiologic reference ranges. Treatment subjects were prohibited from use of lipid lowering or anti-inflammatory drugs. Control subjects (n=75) received usual care including conventional HRT and lipid lowering drugs. Subjects were evaluated at baseline and follow-up at 3 years for comparative effectiveness on biomarkers related to cardiovascular disease, health outcomes, and quality of life measures. Mixed modeling analysis tested for main effects and group by time interactions including relevant covariates. Results: Of the 9 measures, 4 revealed statistically significant interactions between group membership and time. Fasting Glucose, Co-morbidities, Medication use, and Pain displayed patterns of means indicating that the Treatment Model group either improved while the status quo group remained constant, or the Treatment Model group remained constant while the status quo worsened. Triglycerides improved in both groups. No significant group interactions occurred for BMI and blood pressure. Treatment model subjects did not have any adverse events or adverse changes in inflammatory, hemostatic or endometrial measurements, and improvements occurred for: Visual Analog Bodily Pain, Greene Climacteric Scale, Hamilton Anxiety/ Depression Scales. Conclusion: Transdermal physiological sex steroid hormone therapy was not associated with any adverse events or effects over 3 years, and lead to improved health outcomes and favorable changes on some biomarkers of cardiovascular disease, health outcomes, and quality of life indicators as compared to usual care in aging women.

Quantification of the adverse effect of ethinylestradiol containing oral contraceptive pills when used in conjunction with growth hormone replacement in routine practice

Oestrogen antagonizes the action of growth hormone (GH). For women with combined GH and oestrogen deficiency, transdermal oestradiol is more favourable in this regard compared to oral oestradiol. Oral contraceptive pills containing ethinylestradiol (EE) are commonly used in young women with GHD and there is little information on the impact of this form of oestrogen. A case note review of women with growth hormone deficiency (GHD) attending a tertiary endocrine clinic comparing the dose of GH and serum insulin-like growth factor 1 concentrations and the type of exogenous oestrogen. All women with GHD between the ages of 18 and 47 attending University College London Hospitals (UCLH) were included and grouped according to type of oestrogen replacement. Weight, GH dose and serum IGF-I concentrations were recorded at 121 visits in 88 women. The daily dose of GH was significantly higher and the GH responsivity was significantly lower in the EE group compared to those taking no oestrogen and transdermal oestrogen. The additional cost of GH for women using EE compared to transdermal oestradiol was £6016 per patient per year. Effectiveness of GH improved in all women changing from EE to another form of oestrogen. Use of oral contraceptive pills containing EE should be avoided in women receiving treatment with GH. Alternative options include oral or transdermal hormone replacement therapy (HRT) preparations for those that require oestrogen replacement or a progesterone-based regimen for contraceptive purposes.

Benefits and risks during HRT: main safety issue breast cancer.

To assess the benefits and risks during hormone replacement therapy (HRT) in postmenopausal women, the only placebo-controlled study testing clinical endpoints with high statistical power has been the Women's Health Initiative (WHI). Although this trial, conducted mainly in older high-risk women, might not reflect the practical conditions for the normal use of HRT, the WHI for the first time provides the main risks in relative as well as in absolute numbers, which are venous thromboembolism and breast cancer, and in older women also myocardial infarction and stroke. Proven benefits such as treatment of climacteric symptoms, reduction of osteoporotic fractures and decrease of colon cancer risk seem to be only important for younger women, because only with early start of HRT cardiovascular risks can be reduced. Reduction of cardiovascular risks can be achieved using transdermal HRT, which, however, was not tested in a placebo-controlled study design similar to that in the WHI. This review focuses on the results of the WHI, comparing different age groups, and in general especially on the main fear of women, risk of breast cancer, which has been defined as a special project between two universities, a close collaboration of a German and Chinese research group.

Risk of venous thromboembolic disease in postmenopausal women taking oral or transdermal hormone replacement therapy

The influence of hormone replacement therapy (HRT) on hemostasis processes depends on the type of hormone, the combination of doses, the time of taking HRT, and the route of administration (oral, transdermal, implanted). The aim of the current study was to assess some parameters of coagulation, especially tissue factor pathway inhibitor (TFPI) and tissue factor (TF) in postmenopausal women using oral or transdermal HRT. The study was conducted on 76 healthy women, including 46 women aged 44-58 years who were taking oral (26) or transdermal (20) HRT, and 30 women aged 44-54 years who did not take HRT as the control group. Plasma concentrations of TF, TFPI, thrombin-antithrombin complex (TAT), and D-dimer were performed by enzyme-linked immunosorbent assay (ELISA). Moreover, the concentration of fibrinogen and activity of protein C were measured by chromogenic and chronometric methods. We observed a significantly higher concentration of TF and a significantly lower concentration of TFPI in women taking oral and transdermal HRT in comparison with the control group. We also found a significantly lower concentration of fibrinogen in women taking oral HRT vs. the control group. Moreover, no statistically significant changes in concentrations of TAT and D-dimer, or activity of protein C were noted. In this study, the occurrence of an increased TF concentration simultaneously with a decreased concentration of TFPI in women taking HRT indicates hypercoagulability. No significant modification of TAT or D-dimer occurred, and thus there may not be increased risk of thrombosis.

The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy.

The metabolism of estrogen contained within hormone replacement therapy (HRT) is influenced by the route of administration, and this may affect the risk of venous thromboembolism. Thrombin generation, a global coagulation assay, is a marker of hypercoagulability and is of potential use in determining the thrombotic risk associated with particular HRT administration routes. To determine whether any effect of oral and transdermal HRT on thrombin generation is related to the plasma estrogen profile. We investigated the effects of oral, transdermal and no HRT (controls) in 52, 39 and 52 postmenopausal women, respectively, on thrombin generation, standard markers of thrombophilia, estradiol level and estrone level. All parameters of thrombin generation were altered in women using oral HRT as compared with controls (P<0.001 for all comparisons). No such differences were found in women using transdermal HRT. Estrone levels correlated with peak thrombin generation (R=0.451, P<0.001) in women using oral HRT, but there was no correlation in women using the transdermal route. Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first-pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.

Clinical guidelines for testing for heritable thrombophilia

Trevor Baglin, Elaine Gray, Mike Greaves, Beverley J. Hunt, David Keeling, Sam Machin, Ian Mackie, Mike Makris, Tim Nokes, David Perry, R. C. Tait, Isobel Walker and Henry Watson Addenbrooke’s Hospital, Cambridge, NIBSC, South Mimms, University of Aberdeen, Aberdeen, Guy’s and St Thomas’, London, Churchill Hospital, Oxford, University College Hospital, London, Royal Hallamshire Hospital, Sheffield, Derriford Hospital, Plymouth, Glasgow Royal Infirmary, Glasgow and Aberdeen Royal Infirmary, UK

Hormone replacement therapy and the risk of venous thromboembolism: a population-based study.

Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. Among the United Kingdom's General Practice Research Database, we identified the cohort of all women aged 50-79 between 1 January 1987 and 1 March 2008. Using a nested case-control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89-1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77-1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77-1.10), relative to non-use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37-1.63) and oral estrogen-progestogen (RR 1.54; 95% CI, 1.44-1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.