Effects In Postmenopausal Women Research Articles

Fatty acids and lignans in unground whole flaxseed and sesame seed are bioavailable but have minimal antioxidant and lipid-lowering effects in postmenopausal women

Fatty acids and lignans in ground flaxseed and sesame seed are absorbed, metabolized, and exert some health benefits in vivo. However, it is unclear if they are absorbed, metabolized, and exert health benefits when consumed as unground whole seed; therefore, it was investigated in this study. In a randomized crossover study, 16 postmenopausal women supplemented their diets with food bars containing either 25 g unground flaxseed, sesame seed, or their combination (12.5 g each) (flaxseed+sesame seed bar, FSB) for 4 wk each, separated by 4 wk washout periods. Total serum n-3 fatty acids increased with flaxseed (p<0.05) and FSB (p=0.064) while serum n-6 fatty acids increased with sesame seed (p<0.05). Urinary lignans increased similarly with all treatments (p<0.05). Plasma lipids and several antioxidant markers were unaffected by all treatments, except serum gamma-tocopherol (GT), which increased with both sesame seed (p<0.0001) and FSB (p<0.01). In conclusion, fatty acids and lignans from unground seed in food bars are absorbed and metabolized; however, except for serum GT, the 25 g unground seed is inadequate to induce changes in plasma lipids and several biomarkers of oxidative stress.

Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women

BackgroundEvidences have showed that the incidence of arterial hypertension is greater in postmenopausal women as compared to premenopausal. Physical inactivity has been implicated as a major contributor to weight gain and abdominal obesity in postmenopausal women and the incidence of cardiovascular disease increases dramatically after menopause. Additionally, more women than men die each year of coronary heart disease and are twice as likely as men to die within the first year after a heart attack. A healthy lifestyle has been strongly associated with the regular physical activity and evidences have shown that physically active subjects have more longevity with reduction of morbidity and mortality. Nitric oxide (NO) produced by endothelial cells has been implicated in this beneficial effect with improvement of vascular relaxing and reduction in blood pressure in both laboratory animals and human. Although the effect of exercise training in the human cardiovascular system has been largely studied, the majority of these studies were predominantly conducted in men or young volunteers. Therefore, the aim of this work was to investigate the effects of 6 months of dynamic exercise training (ET) on blood pressure and plasma nitrate/nitrite concentration (NOx-) in hypertensive postmenopausal women.MethodsEleven volunteers were submitted to the ET consisting in 3 days a week, each session of 60 minutes during 6 months at moderate intensity (50% of heart rate reserve). Anthropometric parameters, blood pressure, NOx- concentration were measured at initial time and after ET.ResultsA significant reduction in both systolic and diastolic blood pressure values was seen after ET which was accompanied by markedly increase of NOx- levels (basal: 10 ± 0.9; ET: 16 ± 2 μM). Total cholesterol was significantly reduced (basal: 220 ± 38 and ET: 178 ± 22 mg/dl), whereas triglycerides levels were not modified after ET (basal: 141 ± 89 and ET: 147 ± 8 mg/dl).ConclusionOur study shows that changing in lifestyle promotes reduction of arterial pressure which was accompanied by increase in nitrite/nitrate concentration. Therefore, 6-months of exercise training are an important approach in management arterial hypertension and play a protective effect in postmenopausal women.

The effects of metformin on endogenous androgens and SHBG in women: a systematic review and meta‐analysis

Elevated circulating androgens are risk factors for several chronic, metabolic and reproductive disorders. Metformin is an insulin-sensitizing agent that may lower androgen levels. To evaluate the effects of metformin on endogenous androgens and SHBG levels in women, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing metformin with placebo or no treatment. We used OVID to search MEDLINE, EMBASE and CENTRAL until March 2007. Two reviewers independently extracted data on methodological quality, participants, interventions and outcomes of interest. Our a priori primary outcome was post-treatment measurements. In a secondary analysis, we evaluated the difference between the pre- and post-treatment levels. We computed the weighted mean difference (WMD) as a measure of effect for each outcome using the DerSimonian-Laird random effects method. We used the I2 statistic to assess heterogeneity and explored its causes in subgroup analyses of features related to participants' characteristics and study design. Based on a regression model, we conducted sensitivity analyses by investigating the use of placebo as a predictor of effect size. Twenty RCTs fulfilled the inclusion criteria. Pooled WMDs in post-treatment levels between the metformin and control group were -0.31 nmol/l (95% CI -0.65 to 0.03) for total testosterone (TT), 0.10 pmol/l (95% CI -0.89 to 1.10) for free testosterone (FT), 0.14 micromol/l (95% CI -0.34 to 0.62) for dehydroepiandrosteronesulfate (DHEAS), -0.60 nmol/l (95% CI -1.67 to 0.46) for androstenedione (AND) and 5.88 nmol/l (95% CI 2.01-9.75) for SHBG. Pooled WMDs of the pre- to post-treatment differences (i.e. with adjustment for baseline hormone levels) were -0.38 (95% CI -0.51 to -0.25) for TT, -2.71 (95% CI -10.35 to 4.93) for FT, -0.50 (95% CI -0.83 to -0.16) for DHEAS, -1.39 (95% CI -2.30 to -0.49) for AND and 6.63 (95% CI 2.32-10.94) for SHBG. In subgroup analyses, features related to the administered treatment (i.e. metformin as a single agent or as part of combined regimens) partly explained the heterogeneity. Sensitivity analyses of studies using placebo showed similar results to those not using placebo. Our systematic review and meta-analysis provides evidence of metformin-induced changes in circulating androgens and SHBG levels in women but the quality of evidence is not high. However, there are no data from RCTs regarding these effects in postmenopausal women or healthy premenopausal women. High-quality RCTs are required to evaluate whether metformin has effects on surrogate markers and patient-important outcomes in these patient groups.

Vertebral fracture risk and alendronate effects in postmenopausal women assessed by CT-based nonlinear finite element analysis

Vertebral fracture risk and alendronate effects in postmenopausal women assessed by CT-based nonlinear finite element analysis

Continuing Medical Education: The Use of Estrogen Therapy in Women's Sexual Functioning (CME)

Estrogen is relevant to women's well-being including sexual functioning. Aim. The goal of this Continuing Medical Education article was to provide a comprehensive review of the effect of exogenous estrogen use on women's sexual function. Main Outcome Measures. We present a literature review. The medical literature was accurately searched (1990-2008) with regard to estrogen therapy in menopausal women by using several terms related to and including the terms "estrogen" and "sexual function." A review of the studies most useful to guide menopausal practice. Estrogen decline is one of the key factors contributing to sexual functioning during menopausal transition and beyond. Systemic estrogen treatments are associated with significant benefits in some domains of menopausal sexual function, especially when estradiol is delivered transdermally, whereas local estrogens are effective in preventing urogenital aging. Even tibolone, a selective tissue estrogenic activity regulator, displays positive effects in postmenopausal women with sexual complaints. However, a tailored approach to the individual woman is always needed.

Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women

Recent interventional studies indicate that post-menopausal hormone replacement therapy is associated with an increased risk of cardiovascular mortality and breast cancer. Isoflavones, a class of plant estrogens, have structural similarities to estradiol. Hence, isoflavones may exert beneficial estrogenic health effects in postmenopausal women with fewer adverse effects. To evaluate the effect of high-dose isoflavones on self-reported quality of life (QOL), cognition, lipoproteins and androgen status in post-menopausal women. Double-blind, randomized, placebo-controlled, 12-week trial of 93 healthy, ambulatory, post-menopausal women (mean age 56 yr). The study was conducted at a tertiary care center in the United States. Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). Both soy and the placebo were provided in the form of a powder to be mixed with beverages. QOL was judged by the Menopause-specific Quality of Life (MENQOL) questionnaire while cognitive function was assessed with standard instruments. Total, free, and bioavailable testosterone, gonadotropins, SHBG, and fasting lipids were measured. Eighty-four women (90%) completed the study (active=38, placebo=46). There was a significant improvement in all 4 QOL subscales (vasomotor, psychosexual, physical, and sexual) among the women taking isoflavones, while no changes were seen in the placebo group. No significant changes in cognition, serum androgens or plasma lipids were seen within any of the groups. However, at the end of the study, a group-by-time interaction was observed such that total testosterone and HDL levels were significantly lower in the isoflavones compared to placebo groups. High-dose isoflavones is associated with improved QOL among women who have become menopausal recently. Hence, the timing of isoflavone supplementation with regards to the onset of menopause appears to be important. The use of isoflavones, as an alternative to estrogen therapy, may be potentially useful and seemingly safe in this group of women who are looking for relief from menopausal symptoms.

Effects of hormone therapy on soluble cell adhesion molecules in postmenopausal women with coronary artery disease

Although observational studies showed an apparent lower ischemic coronary disease risk in postmenopausal women receiving hormone therapy (HT), randomized clinical trials in postmenopausal women showed an increase in ischemic cardiovascular events. Soluble cell adhesion molecules have been associated with cardiovascular risk factors and events. HT reduces circulating levels of soluble cell adhesion molecules in healthy postmenopausal women, but its effects in postmenopausal women with coronary artery disease are less clear. We assessed the effect of HT on soluble cell adhesion molecules in the Estrogen Replacement and Atherosclerosis trial. The Estrogen Replacement and Atherosclerosis trial was a double-blind, placebo-controlled study that randomized 309 postmenopausal women (mean age, 65.8 y) to daily unopposed estrogen (conjugated estrogens 0.625 mg), estrogen plus 2.5 mg of medroxyprogesterone acetate, or placebo, with a mean follow-up period of 3.2 years. Soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were measured in serum obtained from participants at baseline and after 12 months of follow-up. Of the 265 women with complete data, 87 women were assigned to unopposed estrogen, 88 women to estrogen plus medroxyprogesterone acetate, and 90 women to placebo. Compared with placebo, 12 months of HT (n = 175) was associated with reductions in soluble intercellular adhesion molecule-1 (25.6 +/- 4.7 vs 10.6 +/- 6.4 ng/mL, P = 0.06), soluble vascular cell adhesion molecule-1 (80.2+/- 10.6 vs 28.8 +/- 14.7 ng/mL, P = 0.005), and E-selectin (8.8 +/- 0.9 vs -1.1 +/- 1.2 ng/mL, P < 0.001). Twelve months of HT in postmenopausal women with established coronary artery disease was associated with reductions in serum markers of endothelial cell activation/injury such as soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin.

Effects in Postmenopausal Women of Estradiol and Medroxyprogesterone Alone and Combined on Resistance Artery Function and Endothelial Morphology and Movement

Endothelial dysfunction in resistance arteries after menopause is important for the development of high blood pressure and cardiovascular disease. Our objectives were to study the effects of different hormone replacement therapies on the function and morphology of isolated resistance arteries, and to look for their mechanistic basis. This was a randomized, placebo-controlled double-blind study in a University hospital, along with laboratory based studies. We isolated resistance arteries in sc biopsies from 55 postmenopausal women before and after 3-month therapy with estradiol (E2), medroxyprogesterone acetate (MPA), E2 plus MPA, or placebo. In addition, we studied isolated human endothelial cells. Artery flow-mediated dilatation was augmented after treatment with E2 or E2 plus MPA, whereas MPA or placebo had no effect. Pressure-induced myogenic tone was reduced by E2 plus MPA, whereas it was unchanged in the other groups. Scanning microscopy showed that E2 improved endothelial cell morphology and decreased signs of endothelial apoptosis, but the addition of MPA impaired these events. E2, MPA, or the combination all increased the expression and phosphorylation of the actin-binding protein, moesin and of the focal adhesion complex controller, focal adhesion kinase, and induced the rearrangement of cytoskeletal actin and vinculin fibers. All treatments promoted endothelial cell horizontal migration, with E2 inducing the strongest effect. This study suggests that hormone replacement therapy with estrogens or in combination with MPA may benefit the function of resistance arteries and may preserve the morphological integrity of endothelial cells by regulatory actions on the cytoskeleton.

USE OF VASCULAR DOPPLER ULTRASOUND TO DETECT ACUTE ESTRADIOL VASCULAR EFFECT IN POSTMENOPAUSAL WOMEN

To report on a simple practical test for assessing acute estradiol vascular effects on healthy and unhealthy postmenopausal women. Estradiol acts in the endothelium to promote vasodilatation through genomic and non-genomic mechanisms, but its vascular action may be impaired in diabetes mellitus, hypertension, smoking and obesity. Nineteen postmenopausal women (nine healthy and 10 with two or more of the above factors) of similar age and time since menopause were examined with vascular Doppler ultrasound. Resistance indexes and systolic and diastolic flow velocities were determined for the brachial and internal carotid arteries at baseline and 20 minutes after administration of a nasal estradiol formulation, available on the market, which reaches 1,200-1,500 pg/ml in the serum in 10-30 minutes. Estradiol blood levels were measured at 30 minutes. The carotid resistance index increased 14.2% (vasoconstriction) in the unhealthy group after estradiol, from a mean +/- S.E. of 0.56 +/- 0.016 at baseline to 0.64 +/- 0.05 (p=0.033), and remained unchanged in healthy women. Brachial diastolic flow velocity increased 19.7% (vasodilatation) in healthy women, from 16.2 +/- 1.93 to 19.4 +/- 0.64 cm/s (p=0.046), and did not change in the unhealthy subjects. Estradiol levels were similar in both groups. Healthy postmenopausal women showed brachial vasodilatation while unhealthy postmenopausal women displayed vasoconstriction at the carotid artery. Vascular responses to estradiol were divergent between the groups. The acute estradiol test, coupled with Doppler ultrasound, seemed to be able to differentiate women with normal and abnormal endothelial function in a simple, non-invasive manner.

Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator

Traditionally, it was accepted that long-term hormone replacement therapy (HRT) has a cardiovascular beneficial effect in postmenopausal women with and without coronary artery disease (CAD). However, randomized trials in postmenopausal women have not shown any benefit in either primary or secondary prevention of cardiovascular events. Therefore, these findings have raised the question of whether traditional HRT (i.e., estrogen and progesterone) has a cardioprotective effect in women at risk for or with established CAD. Concerns about the use of conventional HRT have led to a search for alternatives. Tibolone is a synthetic compound with estrogenic, androgenic, and progestogenic properties that relieves climacteric symptoms and prevents postmenopausal bone loss. Tibolone possesses a tissue-selective mechanism of action that differs from that of estrogen and/or progestogen. Unlike these compounds, tibolone's metabolites play a central role in its mode of action. Tibolone is widely used for HRT. However, its clinical impact on cardiovascular disease is still under study. The current review focuses on the effects of tibolone on the cardiovascular system and discusses clinical investigations with this compound in postmenopausal women.

Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

Effect of isolated isoflavone supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women

Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. Postmenopausal women (n=56) were treated with either isoflavone or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after isoflavone and placebo treatment, respectively. Thus, isoflavone supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, isoflavone treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. In postmenopausal women, isolated isoflavone treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects.

Drospirenone with 17β-estradiol in the postmenopausal woman with hypertension

Hypertension is one of the most important risk factors for the development of cardiovascular disease. The prevalence of hypertension increases with age and also after the menopause; therefore, blood pressure monitoring and effective control of elevated blood pressure are very important in postmenopausal women. The knowledge that aldosterone is a dual cardiovascular and endocrine hormone has blurred the once distinct boundary between gynecology and cardiovascular medicine. Aldosterone plays a major role in salt and water homeostasis, but also binds to mineralocorticoid receptors in the cardiovascular system, leading to structural and functional changes and consequent organ damage. Highly selective aldosterone blockade via the mineralocorticoid receptor has long-term antihypertensive effects. Drospirenone is a novel progestogen with aldosterone receptor antagonism (PARA), and therefore has antihypertensive effects through reduced salt and water retention. A new hormone therapy that combines 17β-estradiol with drospirenone has been shown in several clinical studies to have a blood pressure-lowering effect in postmenopausal women with elevated blood pressure, in addition to effectively relieving symptoms of the menopause. These findings suggest a potential additional benefit on the cardiovascular system for the drospirenone/17β-estradiol combination in the treatment of women with menopausal symptoms and elevated blood pressure.

A New Hormone Therapy With Drospirenone and NO Production in Postmenopausal Women

To the Editor: We read with great interest the article by White et al1 dealing with the combination therapy of drospirenone (DRSP), a novel progestin with antialdosterone activity, and 17-β-estradiol (E2) in postmenopausal women. The results of their study demonstrated that DRSP and E2 might have a significant antihypertensive effect in postmenopausal women with stage 1 to 2 hypertension. The authors also indicated that treatment of DRSP and E2 was not associated with a significant increase in serum potassium. The authors proposed that …

Long-term effects of tibolone on circulating levels of vascular cell adhesion molecules and E-selectin in postmenopausal women

Adherence of lymphocytes and monocytes to cell adhesion molecules (vascular cell adhesion molecules [VCAMs]) expressed by activated endothelial cells is the first step in the development of atherosclerotic disease. It is known that administration of tibolone for 8 weeks reduces serum levels of VCAMs in postmenopausal women. We evaluated the effects of the administration of tibolone in postmenopausal women for 1 year. Randomized, placebo-controlled, crossover trial. Healthy volunteers in an academic environment. Thirty-six healthy women in postmenopause since 1-4 years. Group A received 2.5 mg/d of tibolone and group B received placebo for 12 months; treatment was subsequently crossed over for 1 month. Serum concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and E-selectin were evaluated at baseline and at 6, 12, and 13 months. Baseline concentration of VCAM-1, ICAM-1, and E-selectin were similar in both groups. At months 6 and 12, mean concentrations of VCAM-1, ICAM-1, and E-selectin decreased significantly in group A but not in group B. At month 13, levels returned to baseline in group A, whereas they decreased significantly in group B. Tibolone causes a rapid and sustained decrease in circulating levels of VCAMs; the effect is lost soon after stopping the treatment. Tibolone induces favorable changes in endothelial function and may exert a direct cardiovascular protective effect in postmenopausal women.

Estrogen and hypertension

Menopause is accompanied by a dramatic rise in the prevalence of hypertension in women, suggesting a protective role of endogenous estradiol on blood pressure (BP). Both animal experimental and human clinical investigations suggest that estrogen engages several mechanisms that protect against hypertension, such as activation of the vasodilator pathway mediated by nitric oxide and prostacyclin and inhibition of the vasoconstrictor pathway mediated by the sympathetic nervous system and angiotensin. However, emerging evidence from recent clinical trials indicates a small increase, rather than decrease, in systolic BP with oral estrogen administration in postmenopausal women, without any detectable effect on diastolic BP. Mechanisms underlying this selective rise in systolic BP in postmenopausal women and oral contraceptive-induced hypertension in premenopausal women remain unknown, but the rise may be related to supraphysiologic concentration of estrogen in the liver. To date, transdermal delivery of estrogen, which avoids the first-pass hepatic metabolism of estradiol, appears to have a small BP-lowering effect in postmenopausal women and may be a safer alternative in hypertensive women.

Modeling and Simulation of Sexual Activity Daily Diary Data of Patients with Female Sexual Arousal Disorder Treated with Sildenafil Citrate (Viagra®)

To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies. Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD. The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women. A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.

Pharmacokinetics and systemic endocrine effects of the phyto‐oestrogen 8‐prenylnaringenin after single oral doses to postmenopausal women

Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first C(max) and AUC(0-48 h) showed dose linearity with ratios of 1 : 4.5 : 13.6 (C(max)) and 1 : 5.2 : 17.1 (AUC). The750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women.

LBOVI-A-3Identification of skin biomarkers following testosterone administration in postmenopausal women

BACKGROUND/AIMS To pilot a pharmacodynamic (PD) model of short-term androgen administration that may be used to predict long-term effects of androgen administration in postmenopausal women. The study was specifically designed to identify biomarkers that evaluate early skin response to exogenous androgens. The clinical consequences of androgen administration include hirsutism and acne. Skin biopsies were performed to document morphological changes in the pilosebaceous unit (PSU) and gene expression changes (Taqman and microarray). Functional skin response was gauged by measuring sebum excretion rates (SER). METHODS A double-blind, randomized, placebo-controlled, parallel-group study was conducted in 36 healthy postmenopausal female subjects to identify early biomarkers of androgen administration. Subjects were randomized to receive either 2.5 mg of transdermal testosterone gel (TTG; AndroGel®), 300 μg of TTGtransdermal testosterone gel, or placebo gel, daily for 6 weeks in a 1:1:1 ratio. Skin biopsies were performed to document morphological changes in the pilosebaceous unit (PSU) and gene expression changes (Taqman and microarray). Five-mm skin punch biopsies were obtained from the back of subjects at baseline, after 6 weeks of treatment, and 4 weeks post treatment. Biopsies were analyzed for histological changes characterized by total sebaceous gland volume and sebocyte cell size. Skin biopsies were also analyzed for molecular skin changes using skin Taqman/microarray assays. Measurements of sebum excretion rates (SER) were obtained at baseline and after 6 weeks of treatment. RESULTS Six weeks of treatment with the 2.5-mg TTGdose of AndroGel® increased sebaceous gland volume on average by 42% (p=0.0410) and sebum excretion rateSER by 52% (p=0.0021) relative to placebo. Microarray and Taqman analyses on skin samples also demonstrated changes in the 2.5-mg TTG AndroGel® group. Histological and molecular findings were noted to be reversible 4 weeks after discontinuing therapy. Analysis of Total Sebaceous Gland Volume (106 μm3) at Week 6 (See Tables 1 and 2) Mean (SD) % Change from Baseline Treatment N Baseline Week 6 Mean (SD) LS Mean 95% CI Placebo 13 19.58 (32.51) 24.00 (32.27) 4.42 (33.53) 4.42 (−21.79, 30.63) 300 ug TTG 13 37.20 (39.16) 45.59 (47.20) 8.40 (51.97) 8.40 (−17.81, 34.61) 2.5 mg TTG 10 31.93 (36.34) 77.91 (71.76) 45.98 (53.01) 45.98 (16.10, 75.87) Analysis Results for SER at Week 6 Geometric Mean (CV) % Change from Baseline Treatment N Baseline Week 6 Geometric Mean (CV) Geometric LS Mean† 95% CI‡ Placebo 13 0.67 (0.52) 0.67 (0.51) −0.14 (0.29) −0.14 (18.22, −15.65) 300 ug TTG 12 0.81 (0.55) 0.89 (0.56) 10.80 (0.38) 10.80 (32.08, 7.05) 2.5 mg TTG 10 0.82 (0.43) 1.24 (0.42) 52.09 (0.22) 52.09 (84.37, 25.46) CONCLUSIONS TTG treatment is associated with marked increases in sebaceous gland volume and SER, consistent with side effects including hirsutism and acne. Biomarkers sufficiently robust to support using to test for androgen-mediated skin effects in postmenopausal women were identified. Clinical Pharmacology & Therapeutics (2005) 79, P84–P84; doi: 10.1016/j.clpt.2005.12.299

Short-term effect of transdermal estrogen on autonomic nervous modulation in postmenopausal women

To evaluate the effect of short-term transdermal estradiol-l7b on cardiac autonomic nervous modulation in postmenopausal women. Prospective study. A tertiary medical center. Twenty-one postmenopausal women. Transdermal estradiol or placebo therapy for 3 weeks in randomized, double-blinded, crossover fashion. Heart rate variability measures in both time and frequency domains, serum biochemistry, and climacteric symptoms were compared among baseline, placebo and transdermal estrogen therapies. Plasma concentration of estradiol rose significantly from 11.0 +/- 5.2 pg/ml to 48.2 +/- 34.0 pg/ml after transdermal estrogen. The standard deviation of RR-interval increased significantly from 30.3 +/- 9.9 ms (placebo) to 31.3 +/- 7.4 ms (transdermal estrogen), and the coefficient of variation of RR-interval increased significantly as compared with the baseline session. The total power was marginally increased as compared among baseline, placebo, and transdermal estrogen sessions. The irritability symptom decreased significantly after transdermal estrogen therapy, as compared with baseline and placebo treatment. Transdermal estradiol for 3 weeks could significantly increase the global heart rate variability and reduce the irritability symptom in the postmenopausal women. Short-term transdermal estrogen for 3 weeks could improve cardiac autonomic nervous modulation and climacteric symptoms, and might have some cardioprotective effect in postmenopausal women.