Oral HRT Research Articles

European active surveillance study of women taking HRT (EURAS-HRT): study protocol [NCT00214903

BackgroundThe post marketing safety surveillance program for a drug containing a new chemical entity should assess both, the safety outcomes that relate specifically to the targeted population, as well as those that could potentially be related to special pharmacological characteristics of the drug. Active safety surveillance using valid epidemiological study designs has been proven to be a pertinent and reliable method to approach this endeavor.Methods/designThe primary objective of the study is to compare incidence rates of serious adverse events in users of all types of newly prescribed oral HRT products. This active surveillance study will assess pertinent cardiovascular outcomes - in particular venous and arterial thromboembolism - and other serious adverse events (SAEs) in new HRT users over a period of several years. One product under surveillance is Angeliq®, which contains the novel progestagen drospirenone (DRSP) combined with estradiol. In addition, all other oral combined HRT products with a novel progestagen or estrogen that will be newly marketed during the study period will be studied. These new HRT products will be compared with established HRT products. The combined cohort will include at least 30,000 women recruited in several European countries. At least 90,000 years of observation are expected from the field work which started in early 2002 and will end around 2008. The participating women will complete a baseline survey using a self-administered questionnaire to describe the baseline risk. After 6 months, 12 months, and then on an annual basis, they will fill out a questionnaire in which they record complaints and events during the use of the prescribed HRTs. All adverse outcomes occurring during the observational period will be evaluated.DiscussionA complete lifetime medical history, individually validated SAEs over time, and a low loss to follow-up rate are essential for a robust safety assessment. Therefore, the lifetime history of diseases and relevant medications will be documented. Reported SAEs will be validated and analyzed. A four level, multi-faceted follow-up process was established to ensure low loss to follow-up rates (e.g., 3–5% after three years of follow up). Multivariate methods will be used to adjust for confounding.

Long-term, oral HRT does not lead to increased platelet activation in women with coronary artery disease

Long-term, oral HRT does not lead to increased platelet activation in women with coronary artery disease

Long-term, oral HRT does not lead to increased platelet activation in women with coronary artery disease

Long-term, oral HRT does not lead to increased platelet activation in women with coronary artery disease

The thoughts of physicians regarding the need to start hormone replacement therapy in breast cancer survivors

Objectives To investigate how physicians felt about HRT use in breast cancer survivors a half year after the WHI trial. Methods In December 2002, a questionnaire was conducted in Flanders (Belgium). The survey contained a presentation of a 35-year-old breast cancer survivor who presented with climacteric symptoms after treatment with tamoxifen. Results With a response rate of 33.65%, a majority of the physicians did not prescribe classical oral HRT (5.40%) in this patient. Physicians prefer to prescribe tibolone (30.68%) or other alternative treatment (50.00%). The main reason was the fear for increased recurrence of breast cancer. Furthermore the WHI oestrogen plus progestin trial and its attention in the media, a half year prior to the survey, influenced one-third of the physician's prescribing attitude. Conclusions Two-thirds of the physicians did not change prescribing attitude after the WHI oestrogen plus progestin trial. HRT is a well proven effective treatment in breast cancer survivors with severe climacteric complaints, but a majority of physicians is not convinced of its safety in breast cancer survivors. Therefore, a majority of physicians do not find the need to prescribe HRT in breast cancer survivors.

Oral HRT appears to be associated with an increase in ovarian cancer risk in women who have not undergone hysterectomy,

Oral HRT appears to be associated with an increase in ovarian cancer risk in women who have not undergone hysterectomy,

Mood Scores in Relation to Hormone Replacement Therapies during Menopause: A Prospective Randomized Trial

There is lack of studies in literature about the long-term effects of hormone replacement therapies and cholesterol levels on mood scores in menopause. In the present study we have investigated whether serum lipid levels affect mood scores in menopause and evaluated the long-term effects of the combined hormone replacement regimens (HRT) on depressive symptoms in postmenopausal women. In this prospective-randomized, placebo-controlled, double-blind study, 286 women in menopause were divided into four groups according to therapeutic regimens they received; 1) Conjugated equine estrogen (CEE) of 0.625 mg plus medroxyprogesterone acetate (MPA) of 2.5 mg (n = 79), 2) CEE (0.625 mg) plus MPA of 5 mg (n = 77), 3) tibolone of 2.5 mg (a selective tissue estrogenic activity regulator) (n = 76), and 4) Calcium (Ca) of 1,000 mg (n = 54). Beck Depression Inventory (BDI), and serum levels of lipoprotein lipids were assessed before and after 12-months of treatment with oral continuous HRT and Ca supplementation. BDI scores in the study groups were not correlated with lipid profiles. We compared two subgroups of patients with initial BDI scores 0-14 (normal mood scores) in order to asses for the possible relation between the lipid profile and mood. Following treatment, first subgroup had increased scores to 15-30 (mildly depressed women, n = 27) and the second subgroup preserved BDI scores of 0-14 (normal mood scores, n = 23). Serum levels of total cholesterol, high-density lipoprotein, low-density lipoprotein and body mass index were found to be similar between these two groups. BDI scores decreased significantly in all HRT groups after 12 months of treatment, compared to Ca group (p < 0.05). We did not observe any correlation between BDI scores and lipid profiles before and following continuous HRT or Ca supplementation. Continuous combined hormone replacement regimens, CEE + MPA and tibolone, have superior long-term effects on mood scores in menopause and should be considered during the decision process for use of HRT due to menopausal symptoms.

Does hormone therapy increase allergic reactions and upper gastrointestinal problems?: Results from a population-based study of Swedish woman. The women’s health in the Lund area (WHILA) study

Objectives: To delineate the use of various drugs particularly pertaining to allergy and upper gastrointestinal problems in relation to hormone status in middle aged women. Methods: An analysis from a population-based study on women born between 1935 and 1945 and lived in the Lund area southern Sweden. Of 10766 women, 6917 provided complete data sets; in turn 5673 were assessed for the use of medication in this study. Among the cohort, 9% of women were premenopausal (PM), 54% were postmenopausal without hormone replacement therapy (PM0) and 37% were current hormone replacement therapy users (PMT). Results: There were 7 (1.3%) women in PM, 11 (0.4%) in PM0 and 21 (1.0%) in PMT group who used loratadine regularly. There was a significant difference between the PM and PM0 groups and also between the PM0 and PMT groups in the use of loratadine ( P<0.05). Among 21 loratadine users in PMT group 4 (19%) used transdermal patches and 17 (81%) used oral HRT. The result for omeprazole use was as follows: 4 (0.8%) of PM group, 39 (1.3%) of PM0 group and 42 (2.0%) of PMT group. The use of omeprazole was significantly higher in the PMT group than in the PM ( P=0.05) and PM0 group ( P<0.05). There was no relation between the use of omeprazole and smoking or alcohol consumption. Conclusions: Use of hormone replacement therapy seems to be related to a higher frequency of omeprazole and loratadine use, which implies that hormone replacement therapy, may be associated with more upper gastrointestinal symptoms as well as allergy.

3P-0892 Changes in hs-CRP and TC/HDL with transdermal vs. oral HRT and atorvastatin aiming at primary prevention of cardiovascular diseases

3P-0892 Changes in hs-CRP and TC/HDL with transdermal vs. oral HRT and atorvastatin aiming at primary prevention of cardiovascular diseases

Oral HRT increases C-reactive protein levels

Oral HRT increases C-reactive protein levels

Oral HRT increases C-reactive protein levels

Oral HRT increases C-reactive protein levels

Autonomic and cardiovascular function in postmenopausal women: The effects of estrogen versus combination therapy

Objective: This study examined the effects of oral estrogen (ERT) alone versus oral estrogen/medroxyprogesterone acetate (HRT) therapy on cardiovascular function, as controlled by the autonomic nervous system. Study Design: Forty-three postmenopausal women received ERT, HRT, or a placebo for 3 months in a double-blind, randomized, placebo-controlled study. Cardiovascular hemodynamics and heart rate variability were assessed at rest and during stress. Results: After 3 months of therapy, oral HRT significantly increased high-frequency power (P =.0002) and decreased total peripheral resistance (P =.04). The changes were evident at rest and during stress. Conclusion: Our findings suggest that combination therapy produces a more favorable alteration of autonomic cardiovascular function than estrogen alone (ie, combination therapy increases vagal activity). (Am J Obstet Gynecol 2002;186:954-61.)

Hormone replacement therapy and the prevention of cardiovascular disease.

Cardiovascular disease (CVD) is the primary killer of both men and women in Western societies. The implementation of preventive strategies has led to a fall in the rate of CVD, but there is still much to be achieved. Proven interventional strategies are largely under-utilized, and the search continues for further promising interventions. HRT appears to reduce CVD in post-menopausal women, based on observational data supported by plethora of evidence for the beneficial cardiovascular effects of estrogen. However, a recent controlled trial in post-menopausal women with established CVD has shown that a specific combined oral HRT regimen did not reduce, and may even contribute to, an early increase in cardiovascular events, suggesting that HRT is inappropriate in secondary prevention. HRT may be useful in the primary prevention of CVD, yet observational data that suggested cardiovascular benefit with HRT also suggests that 80% of CVD in women could be eliminated by lifestyle modification, without the attendant risks of HRT including thrombosis and (potentially) breast cancer. At present, it is arguable that the evidence is inadequate to recommend HRT solely for the purpose of CVD prevention, and that the challenge for the health professional should be appropriate utilization of established preventative therapies, with further research into the potential role of HRT and estrogen-receptor modulators.

Transdermal Estradiol in Menopausal Women Depresses Interleukin-6 without Affecting Other Markers of Immune Response

Objective: The aim of this study was to analyze the effect of transdermal estradiol replacement therapy (HRT) on immune function in menopausal women. Study Design: A prospective comparative study was carried out in 30 women, aged 48–55 years, who were divided into two groups; 20 of them received transdermal estradiol 50 µg/day during 3 months and 10 who refused to receive HRT served as controls. Serum interleukins were quantified by specific immunoenzymatic assays; in addition, hormones of somatotropin axis and prolactin (PRL) were quantified by IRMA and RIA. Results: Baseline elevated interleukin (IL)-6 levels decreased significantly (p < 0.001) after transdermal HRT as compared with the nontreated group. Contrarily, IL-2 and IL-10 levels as well as mitogenic induced T-cell proliferation were unchanged under HRT. Insulin-like growth factor-I, growth hormone and PRL levels were unaltered by transdermal HRT. Conclusion: Decrement of IL-6 in parallel with absent effect on some indices of immune activity suggests a beneficial action of transdermal HRT. These findings contrast with those demonstrating an increment of immune response in women taking oral HRT. Thus, the route of administra tion determines the effect of HRT on immune function.

Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel

Objectives: The oral combined formulation of levonorgestrel with estradiol valerate (LNG+EV) has demonstrated to be effective on some postmenopausal symptoms. The availability of a transdermal HRT in sequential formulation with 17-β-estradiol plus levonorgestrel (TSE2+TSLNG) induced us to do this control-study with the aim to evaluate the efficacy and safety of both oral and transdermal treatments. Methods: At baseline, the psychological symptoms with the psychometric scale SCL-90, the bone resorption with the measurement of the urinary levels of pyridinoline and dexoxypirydinoline, and the insulin and lipid metabolism were assessed in 30 postmenopausal women (PMW) and in 18 premenopausal women. Then, the PMW women were randomly divided in three groups: group A ( N=10) assumed EV+LNG, group B ( N=10) did not assume any treatment, group C ( N=10) was treated with TSE2+TSLNG. The length of the study was 12 months. The aforementioned assessments were repeated at different time-intervals up to the end of the study. Results: The total score of SCL-90, the bone resorption, the levels of LDL-cholesterol, total-cholesterol and the parameters of insulin metabolism were higher in PMW than in premenopausal women. During the study, the SCL-90, the bone resorption, total-cholesterol, and LDL-cholesterol levels significantly decreased only in the groups A and C. By contrast, in the group B bone resorption significantly increased at the 12th month. During the treatments, insulin metabolism did not change in the groups A and B. In the group C the secretion of C-peptide and the C-peptide:insulin ratio after OGTT were significantly higher at the 12th month than before treatment. In all groups the endometrium thickness did not change during the study. Conclusion: A 12-month of either oral or transdermal HRT containing levonorgestrel seems to exert beneficial effects on the main postmenopausal symptoms without negative interferences on the endometrium.

The impact of testosterone imbalance on depression and women's health

Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression in a parabolic curve: at about 0.4–0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the “baby blues”. It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that “environmental factors” during the time of growing up might be responsible for emotional “up and downs”. T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a “four-level-hormone classification scheme” was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E–low T levels are correlated with osteoporosis, depression, and obesity; (2) high E–low T with obesity, decreased libido; (3) high T–low E levels with aggression, depression, increased libido, and substance abuse; (4) high E–high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.

Oral HRT Does Not Affect UTI Frequency

Urinary tract infections (UTIs) are frequent in women of all ages, but results of controlled trials have suggested that vaginal estrogen treatment

Will the Route of Administration Influence the Potential Cardiovascular Benefits of Postmenopausal HRT?

A widely held, though as yet unproven, belief is that HRT will reduce the incidence of myocardial infarction and stroke in postmenopausal women, in contrast to the slight increase in risk of venous thrombotic events. As oral HRT induces an unphysiological peak in the concentrations of oestrogen in the liver, hepatic protein synthesis is over-stimulated, leading to increased plasma levels of many of the proteins involved in vascular disease, such as apolipoproteins, coagulation factors and components of the renin-angiotensin system. Non-oral HRT minimises hepatic first-pass and so avoids these effects. This has led to a belief that the excess risk of venous thrombo-embolism seen in users of oral HRT will be negated. Non-oral HRT may also have less impact on aspects of the renin-angiotensin system; it may also reduce insulin responses to glucose and improve insulin sensitivity. However, plasma levels of PAI-1, are lowered by oral but not transdermal oestradiol. It is even more difficult to predict whether non-oral HRT will be better or worse in terms of the effect on lipoprotein risk markers for CHD. Non-oral oestrogens are less able to reduce plasma levels of LDL and Lp(a), but may protect these lipoproteins from oxidation. The increased HDL levels typical of oral therapy are not seen, but neither are the elevated triglycerides. Experimental studies, especially those using animal models of atherosclerosis, indicate that non-oral therapies will reduce the risk of arterial disease. It would seem unlikely that there will be any substantial differences between the effects of oral and non-oral HRT on CHD risk.

Transdermal and oral HRT

Transdermal and oral HRT

Inherited prothrombotic risk factors and cerebral venous thrombosis.

Fifteen patients with cerebral venous thrombosis were ascertained retrospectively. Their case notes were reviewed, and stored or new blood was assayed for factor V Leiden (FVL) mutation, prothrombin gene mutation 20201A, and 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T mutation. A clinical risk factor was identified in 13 patients--the oral contraceptive pill (5), puerperium (1), HRT (1), mastoiditis (1), dehydration (1), lumbar puncture and myelography (1), carcinoma (1), lupus anticoagulant (2). In addition, two patients had the FVL mutation and five (one of whom also had the FVL mutation) were homozygous for the MTHFR mutation. The latter showed a higher than expected frequency compared to 300 healthy controls from South Wales (OR 3.15.95% Cl 1.01-9.83). No patient had the prothrombin 20201A mutation. Two patients died and three had a monocular visual deficit following anticoagulation (13) or thrombolytic (2) treatment, but there was no association between the presence of a primary prothrombotic risk factor and outcome. These results confirm the importance of investigating patients for both clinical predisposing factors and primary prothrombotic states.

Prolapse of pedunculated submucous myoma after insertion of a levonorgestrel intrauterine system: two cautionary tales

A 48-year-old woman para 2 presented with a history of heavy menstruation while taking oral HRT (Prempak-C 0.625 mg: Wyeth UK) for perimenopausal symptoms. Clinical examination revealed myomatous enlargement of her uterus. This was confirmed by an ultrasound scan with uterine diameter measurements of 14.3 X 6.1 X 5.7 cm. Her recent cervical smear had been reported as normal and her haemoglobin level was 12g/dl. An endometrial biopsy was performed and reported as normal with no signs of inflammation hyperplasia or malignancy. In an attempt to avoid surgical intervention a levonorgestrel intrauterine system (LNG-IUS) (Mirena: Pharmacia UK) was inserted uneventfully under local anaesthesia. Although she did well initially she presented 5 months later with a 2-week history of lower abdominal pain and heavy vaginal bleeding while using transdermal oestrogen replacement (Estraderm TTS 50 patch: Ciba UK). Vaginal examination revealed a large necrotic myoma extruding through the cervix and lying in the upper vagina. An ultrasound scan confirmed this finding and the prolapsed myoma was measured at 7.4 X 7.1 cm. The remainder of the uterus was visualised above the myomatous mass measured 5.0 X 5.3 cm and the IUS was seen within it. (excerpt)