Effects of oral and transdermal low-dose estrogen therapy on echocardiographic parameters of cardiac function

OBJECTIVE: To investigate the effects of transdermal 17 beta-estradiol (E(2)) compared with oral unopposed as well as opposed E(2) on echocardiographic parameters of left ventricular (LV) systolic and diastolic function. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multi-center study. SETTING: Gynecologic and cardiologic outpatient departments. PATIENT(S): One hundred fifty-two healthy hysterectomized postmenopausal women. INTERVENTION(S): Participants received daily placebo (n = 49) or transdermal E(2) (50 microg; tE(2) group, n = 33), or oral E(2) (1 mg; oE(2) group, n = 37), or oral E(2) (1 mg) combined with gestodene (25 microg; oE(2)+G group, n = 33) for thirteen 28-day treatment cycles. MAIN OUTCOME MEASURE(S): M-mode, quantitative two-dimensional, and Doppler echocardiographic measurements were performed at baseline and after 1 year. RESULT(S): Compared with placebo, tE(2) and oE(2) showed no statistically significant changes in LV function. oE(2)+G resulted in a statistically significant favorable increase in peak flow velocity, flow velocity integral, and mean acceleration. Furthermore, a favorable decrease was observed in interventricular septum thickness and ejection time. CONCLUSION(S): After 1 year of unopposed E(2), LV function remained unchanged. The oE(2)+G treatment showed a potential beneficial influence on LV systolic function.     

Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial

OBJECTIVE: To investigate safety and efficacy and identify the lowest effective dose of a new transdermal estradiol (E2) gel for relief of menopausal symptoms in a population of postmenopausal women. METHODS: This study was a randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Postmenopausal women with at least 60 hot flushes per week applied 0.87 g/d (n=136), 1.7 g/d (n=142), or 2.6 g/d (n=69) E2 gel or placebo gel (n=137) topically for 12 weeks. The changes from baseline in hot flush frequency and severity at 4 and 12 weeks and changes from baseline in vaginal atrophy symptoms at 12 weeks were examined. RESULTS: With increasing E2 doses, mean trough serum E2 increased from 17 to 29 pg/mL. By weeks 3-5, E2 gel reduced moderate-to-severe hot flush rate by at least seven hot flushes per day (P<.001) and reduced the severity score (P<.01). The numbers needed to treat for benefit for an 80% and 100% decrease in hot flush number were 3.2 and 6.3 for the 0.87-g/d group and 1.3 and 2.3 for the 2.6-g/d group. At week 12, vaginal pH was more acidic and vaginal maturation index more mature compared with placebo (P<.001). The lowest dose improved most bothersome vulvovaginal atrophy symptoms (P<.05). Estradiol gel was well tolerated at the site of application and produced no unexpected adverse effects. The 0.87 g/d dose produced fewest adverse events. CONCLUSION: The 0.87 g/d dose of this new transdermal E2 gel, which delivers an estimated 0.0125 mg E2 daily, delivered the lowest effective dose for treatment of vasomotor symptoms and vulvovaginal atrophy in a population of postmenopausal women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00391417. LEVEL OF EVIDENCE: I.     

Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial

OBJECTIVE: Because small increments in levels of endogenous plasma estradiol are associated with higher postmenopausal bone mineral density, we investigated the safety and effectiveness in preventing bone loss of unopposed, very-low-dose transdermal estradiol for postmenopausal women. METHODS: This was a randomized, placebo-controlled, double-blind trial with 2-year follow-up at 9 United States clinical centers. The study population comprised 417 postmenopausal women, aged 60-80 years, with intact uterus and bone mineral density z scores of -2.0 or higher, who were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). All participants received calcium and vitamin D supplementation. Lumbar spine and total hip bone mineral density change was measured by dual-energy X-ray absorptiometry; endometrial hyperplasia incidence was assessed by endometrial biopsy. RESULTS: Median plasma estradiol level in the estradiol group increased from 4.8 pg/mL at baseline to 8.5 pg/mL at 1 year (P <.001 versus baseline) and to 8.6 pg/mL at 2 years (P <.001 versus baseline) and was unchanged in the placebo group. Lumbar spine bone mineral density increased 2.6% in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%, P <.001). Mean total hip bone mineral density increased 0.4% in the estradiol group and decreased 0.8% in the placebo group (between-group difference 1.2%, P <.001). Osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group than the placebo group (P <.001 each). Endometrial hyperplasia developed in 1 woman in the estradiol group but in none of the placebo group (difference in 2-year rates 0.5%, 95% confidence interval 0-7.3%). CONCLUSION: Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.     

A randomized placebo-controlled study of the effect of transdermal vs. oral estradiol with or without gestodene on homocysteine levels

OBJECTIVE:To assess the effect of transdermal vs. oral administration of E2 on plasma homocysteine levels and to evaluate the impact of adding a progestogen to these regimens. DESIGN: Prospective, double-blind, double-dummy, placebo-controlled study. SETTING: Outpatient clinics in two university hospitals and two teaching hospitals in The Netherlands. PATIENT(S): One hundred fifty-two healthy hysterectomized postmenopausal women. INTERVENTION(S): Thirteen 28-day treatment cycles with placebo (n = 49); transdermal 17beta-E2, 50 microg (n = 33), oral E2, 1 mg (n = 37), or oral E2, 1 mg, plus gestodene, 25 microg (n = 33), followed by four cycles of placebo in each group. MAIN OUTCOME MEASURE(S): Fasting plasma total homocysteine concentrations at baseline and cycle 4, 13, and 17. RESULT(S): Mean (+/-SD) homocysteine concentrations in the oral E2 group decreased from baseline to cycle 4 (9.0 +/- 2.5 micromol/L vs. 8.2 +/- 2.0 micromol/L; mean change, -7.6%). Homocystine values in the oral E2 plus gestodene group did not change substantially from baseline to cycle 4 (8.9 +/- 1.6 micromol/L vs. 8.6 +/- 2.0 micromol/L; mean change, -4.4%). No significant changes were observed in the transdermal E2 group. After four washout cycles, the homocysteine concentration had returned to baseline values in all groups. CONCLUSION(S): Oral E2 therapy reduced the homocysteine concentration more than did therapy with transdermal E2 or oral E2 plus gestodene. This finding may indicate a role of liver metabolism and suggests that gestodene has a negative effect on these changes.     

Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlled trial

OBJECTIVE: To investigate the efficacy of micro-dose transdermal estrogen in relieving menopausal vasomotor symptoms. METHODS: A randomized, double-blind, placebo-controlled, multi-center trial. Healthy postmenopausal women with at least seven moderate or severe hot flushes per day for at least 1 week, or at least 50 per week, applied transdermal patches with a nominal delivery of 0.023 mg/d 17beta-estradiol and 0.0075 mg/d levonorgestrel (low-dose E2/levonorgestrel; n=145), 0.014 mg/d E2 (micro-dose; n=147), or placebo (n=133) for 12 weeks. The coprimary efficacy variables were the mean changes from baseline in frequency and severity of moderate and severe hot flushes at the week 4 and 12 endpoints. RESULTS: At the week 12 endpoint, mean weekly frequencies of moderate and severe hot flushes were significantly reduced compared with placebo with low-dose E2/levonorgestrel (-51.80; P<.001) and micro-dose E2 (-38.46; P<.001). Severity scores were also significantly reduced with both treatments compared with placebo. At week 12 endpoint, 41.3% of women receiving micro-dose E2 were treatment responders (75% or more reduction from baseline in hot flush frequency; P=.003 compared with 24.2% placebo). In this group, the mean reduction in moderate and severe hot flushes from baseline was approximately 50% after 2, 70% after 4, 90% after 8, and 95% after 12 weeks. There were no differences between active treatments and placebo regarding adverse events. CONCLUSION: Micro-dose E2 (0.014 mg/d) was clinically and statistically significantly more effective than placebo in reducing the number of moderate and severe hot flushes, with a 41% responder rate, supporting the concept of the lowest effective dose. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00206622     

Effect of pulsed estrogen therapy on hemostatic markers in comparison with oral estrogen regimen in postmenopausal women

BACKGROUND/AIMS: Hormone replacement therapy (HRT) is associated with an increased risk of thromboembolism dependent on the type of HRT; therefore, we compared therapy effects of intranasal with oral estrogens on coagulation and fibrinolysis markers in postmenopausal women. METHODS: A randomized study in which 29 healthy hysterectomized women received intranasal 17beta-estradiol or oral estrogens for 3 months. RESULTS: There were no significant differences in the baseline characteristics between groups. Those women receiving intranasal estradiol showed a mild increment in plasminogen activator inhibitor-1 (PAI-I) (from 6.8 +/- 3.5 to 9.6 +/- 3.9 U/ml, p < 0.01); however, fibrinogen, factor VII-tissue factor complex (VIIa-rTF), antithrombin III (ATIII), protein C (PC) activity, protein S (PS) activity, plasminogen (PLG), and tissue-type plasminogen activator antigen (t-PA) were unchanged. In contrast, oral unopposed estrogens elevated t-PA (from 4.9 +/- 2.9 to 9.6 +/- 5.1 ng/ml, p < 0.01) in parallel with a decrement in PAI-I (from 5.2 +/- 4.0 to 2.7 +/- 1.7 U/ml, p < 0.05) and VIIa-rTF (from 201.2 +/- 181.0 to 140.6 +/- 108.7 mU/ml, p < 0.05). Fibrinogen, ATIII, PC, PS, and PLG were unchanged. CONCLUSIONS: Nasal 17beta-estradiol had no effect on the coagulation markers, except a moderate increment in PAI-1. In contrast, oral estrogens elicited a decrement in both VIIa-rTF and PAI-1; however, those changes did not surpass normal limits.     

Continuous low-level topical heat in the treatment of dysmenorrhea

OBJECTIVE: To compare the efficacy of topically applied heat for menstrual pain with oral ibuprofen and placebo treatment. METHODS: We conducted a randomized placebo and active controlled (double dummy), parallel study using an abdominal patch (heated or unheated) for approximately 12 consecutive hours per day and oral medication (placebo or ibuprofen 400 mg) three times daily, approximately 6 hours apart for 2 consecutive days. Pain relief and pain intensity were recorded at 17 time points. There was at least 85% power to detect a true one-unit difference in the 2-day pain relief treatment means for comparisons with the unheated patch plus oral placebo group using a one-tailed test at the.05 level of significance, based on an observed within-group standard deviation of 1.147. RESULTS: Eighty-four patients were enrolled and 81 completed the study protocol. Over the 2 days of treatment, the heated patch plus placebo tablet group (mean 3.27, P <.001), the unheated patch plus ibuprofen group (mean 3.07, P =.001), and the combination heated patch plus ibuprofen group (mean 3.55, P <.001) had significantly greater pain relief than the unheated patch plus placebo group (mean 1.95). Greater pain relief was not observed for the combination heated patch plus ibuprofen group compared with the unheated patch plus ibuprofen group (P =.096); however, the time to noticeable pain relief was statistically significantly shorter for the heated patch plus ibuprofen group (median 1.5 hours) compared with the unheated patch plus ibuprofen group (median 2.79 hours, P =.01). CONCLUSION: Continuous low-level topical heat therapy was as effective as ibuprofen for the treatment of dysmenorrhea.     

Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol

OBJECTIVE: To investigate uterine effects of unopposed ultralow-dose transdermal estradiol administered to postmenopausal women for 2 years. METHODS: Postmenopausal women (n = 417), aged 60-80 years, with a uterus and with bone mineral density that was normal for age (z score >or=-2.0) were randomly assigned to receive unopposed transdermal estradiol (14 microg per day) or identical placebo patch. We evaluated effects on endometrial histology, vaginal bleeding, and vaginal epithelial cell maturation. RESULTS: At baseline, estradiol and placebo groups were similar in age (67 +/- 5 years) and in median baseline serum estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/mL). In the estradiol group, median estradiol level increased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, P < .001). In the estradiol group, focal atypical endometrial hyperplasia developed in 1 woman, and adenosarcoma of the uterus developed in 1 woman. The placebo group had no endometrial hyperplasia. Endometrial proliferation occurred in 8.5% of the estradiol group and in 1.1% of the placebo group (P = .06). Incidence of vaginal bleeding was 12.4% in the estradiol group and 8.6% in the placebo group (P = .3). Vaginal epithelial cells showed greater maturation in the estradiol group than in the placebo group (P < .001) but less than typically observed with standard doses of estrogen. CONCLUSION: During 2 years of treatment with ultralow-dose unopposed estradiol, treatment and placebo groups had similar rates of endometrial hyperplasia, endometrial proliferation, and vaginal bleeding. This therapy apparently causes little or no endometrial stimulation. LEVEL OF EVIDENCE: I.     

The effect of transdermal estradiol on hormone and metabolic dynamics over a six-week period

Seventeen healthy postmenopausal women who had subjectively noted eight or more hot flashes per day and who objectively demonstrated four or more vasomotor flushes of 1.0C or more during eight hours of continuous thermography were studied. They were randomly allocated in a double-blind fashion to either 50 micrograms/day of transdermal estradiol (E2) patch or placebo. Application of the first patch was followed immediately by repeat eight-hour thermography, with hourly measurements of E2 and luteinizing hormone (LH). In the transdermal E2 group only, significant elevations of E2 (mean 91 pg/mL) were noted at two hours, and LH was suppressed after eight hours (P less than .05). There was no immediate effect on vasomotor flushes. Treatment was continued for six weeks, with daily subjective recording of hot flash frequency. Patients on transdermal E2 reported a significant (P less than .001) fall in hot flashes over four weeks, after which the rate stabilized. An initial decline in the placebo group was not statistically different from baseline. Eight-hour thermography was repeated after six weeks of treatment. Patients on transdermal E2 demonstrated an 85% decrease from baseline in vasomotor flushes (P less than .01). No effect on total cholesterol or its subfractions, renin substrate, or aldosterone was found. Serum E2 levels fell by 50% in 24 hours after patch removal. Endometrial histology and vaginal cytology showed an estrogen effect.     

The influence of hormone replacement therapy containing transdermal 17-beta estradiol and oral medroxyprogesterone acetate on coagulation and fibrinolysis]

OBJECTIVE: The aim of the study was to evaluate some coagulative and fibrinolytic changes in women taking hormone replacement therapy (HRT). MATERIALS AND METHODS: In 29 women aged 45-64 years with osteoporosis and climacteric symptoms several fibrinolytic and coagulative parameters were measured. These measurements were performed three times in each women--before and after three and six months of HRT containing transdermal 17 beta-estradiol (50 mg per day) and oral medroxyprogesterone acetate (2.5 mg per day). RESULTS: PAI-1 (antigen) and factor VII (activity) were decreased significantly during the trial. No other significant modifications in the examined parameters (fibrinogen, antithrombin III, protein C, protein S, thrombin-antithormbin III complexes, t-PA and D-dimers) were detected. CONCLUSIONS: The hormone replacement therapy can reduce the risk of coronary heart disease thanks to decreased levels of PAI-1 and factor VII. No other changes in coagulation and fibrinolysis were observed during the treatment.     

Low-dose oral combination of 17beta-estradiol and norethisterone acetate in postmenopausal women decreases factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1.

OBJECTIVE: Controversies still persist concerning hormone replacement therapy (HRT) and its effects upon blood coagulation and fibrinolysis. This study was carried out to evaluate possible effects of continuously administered low-dose 17beta-estradiol (E2) and norethisterone acetate (NETA) on coagulation and fibrinolytic factors. METHODS: We conducted a randomized double-blind, placebo-controlled, 1-year study in 120 healthy postmenopausal women. The three groups consisted of a placebo group (n = 40), a group receiving oral continuous combined E2 1 mg and NETA 0.25 mg (n = 40) and a group receiving oral continuous combined E2 1 mg and NETA 0.5 mg (n = 40). RESULTS: The two low doses of E2-NETA induced significantly lower plasma levels of factor VII, fibrinogen, antithrombin and plasminogen activator inhibitor-1 (PAI-1), compared with placebo treatmen CONCLUSIONS: Low-dose E2 (1 mg) in combination with NETA resulted in favorable changes of factor VII activity and fibrinogen, compared with placebo. The lower plasma levels of PAI-1 may lead to increased fibrinolytic activity. These findings suggest a decreased risk of developing coronary heart disease. Antithrombin activity was also reduced, which may increase the risk of developing venous thromboembolism. The clinical significance of the lower levels of these factors remains to be clarified.     

Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial

OBJECTIVE: To assess the efficacy of the combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol (3-mg drospirenone/20-microgram ethinyl estradiol) administered as 24 consecutive days of active treatment after a 4-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris. METHODS: Healthy females aged 14-45 years with moderate acne were randomized in this double-blind study to 3-mg drospirenone/20-microgram ethinyl estradiol (n=270) or placebo (n=268) for six cycles of 28 days. The primary outcome measures of acne lesion counts and Investigator Static Global Assessment scale ratings were assessed at baseline and during cycles 1, 3, and 6. RESULTS: The percentage reduction from baseline to endpoint for total lesions is 46.3% for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6% for placebo group (P<.001). The likelihood of participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen group having "clear" or "almost clear" skin as rated by the investigators at endpoint was about threefold (odds ratio 3.13, 95% confidence interval 1.69-5.81; P=.001) greater than in the placebo group. The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen was well tolerated. CONCLUSION: The low-dose combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol administered in a 24/4 regimen significantly reduced acne lesion counts more effectively than placebo and demonstrated greater improvement in the Investigator Static Global Assessment rating of acne. The safety profile was consistent with low-dose combined oral contraceptive use.     

Randomized comparison between orally and transdermally administered hormone replacement therapy regimens of long-term effects on 24-hour ambulatory blood pressure in postmenopausal women

OBJECTIVE: The aim of this study was to assess whether oral delivery and transdermal delivery of sequential combined hormone replacement therapy have similar effects on systemic blood pressure, as measured by 24-hour automated ambulatory recordings. STUDY DESIGN: Eighty-two healthy postmenopausal women, of whom 73 completed the study, were randomly assigned to start hormone replacement therapy with either orally (n = 38) or transdermally (n = 35) administered medication. Ambulatory blood pressure was recorded for a 24-hour period before the start of hormone replacement therapy and again 2 and 6 months later. Analysis of variance was used for data analysis. RESULTS: Hormone replacement therapy by both oral and transdermal routes was associated with slight but nonsignificant drops in mean 24-hour systolic and diastolic ambulatory blood pressure. Daytime systolic ambulatory blood pressure (mean +/- SE) fell significantly (P <.05) and similarly at 2 months in the oral (3.8 +/- 0.2 mm Hg) and transdermal (4.0 +/- 0.3 mm Hg) treatment groups. The daytime ambulatory blood pressure remained significantly lower than baseline at 6 months in the oral treatment group (-3.6 +/- 0.3 mm Hg), whereas the fall at 6 months in the transdermal group (-3.1 +/- 0.3 mm Hg) was not significant. Mean daytime diastolic ambulatory blood pressure was reduced in both the oral (-1.8 +/- 0.8 mm Hg) and transdermal (-3.5 +/- 0.7 mm Hg; P <.05) treatment groups at 2 months but not at 6 months. Nighttime ambulatory blood pressures in both groups remained unaffected by hormone replacement therapy. CONCLUSION: Sequential combined hormone replacement therapy delivered by both oral and transdermal routes caused significant falls in the daytime ambulatory blood pressure of normotensive postmenopausal women at 2 months of treatment. This fall persisted as long as 6 months of treatment in the oral treatment group but not in the transdermal treatment group.     

Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial

OBJECTIVE: To evaluate eszopiclone 3 mg for treatment of insomnia in perimenopausal and early postmenopausal women, as well as the impact of insomnia treatment on mood, menopause-related symptoms, and quality of life. METHODS: This was a double-blind, placebo-controlled study with 410 women (aged 40-60; perimenopausal or early postmenopausal) who reported insomnia defined as sleep latency of at least 45 minutes and total sleep time less than or equal to 6 hours per night for at least 3 nights per week over the previous month. Patients were randomly assigned to eszopiclone 3 mg or placebo nightly for 4 weeks. Sleep data were collected once a day. Physician global assessments of menopause, menopause-specific questionnaire, Greene Climacteric Scale, the Montgomery Asberg Depression Rating Scale, and the Sheehan Disability Scale were collected at baseline and end of treatment. RESULTS: Patients receiving eszopiclone reported improvements in sleep induction, sleep maintenance, sleep duration, sleep quality, and next-day functioning relative to placebo (P<.05). Patients receiving eszopiclone reported fewer total awakenings and awakenings due to hot flushes (P<.05). Eszopiclone use led to greater improvement in Montgomery Asberg Depression Rating Scale scores (P<.05) and physician global assessments of menopause scores (P<.001); total Greene Climacteric Scale score and the vasomotor and psychological sub-scores (P<.05); vasomotor and physical domains of the menopause-specific questionnaire (P<.05); and family life/home domain of the Sheehan Disability Scale (P<.05). CONCLUSION: In this study, eszopiclone provided significant improvements in sleep and positively impacted mood, quality of life, and menopause-related symptoms in perimenopausal and early postmenopausal women with insomnia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00366093 LEVEL OF EVIDENCE: I.     

Transdermal versus oral estrogen therapy in postmenopausal smokers: hemodynamic and endothelial effects

OBJECTIVE: To test the hypothesis that, in postmenopausal smokers, transdermal estrogen would be more effective than oral estrogen in reducing blood pressure (BP) and vascular and norepinephrine responses to stress and in increasing endothelial function and vascular beta2-adrenoceptor responsivity. METHODS: By using a randomized, double-blind, placebo-controlled design, 82 healthy postmenopausal smokers were tested before and after 6 months of therapy with transdermal estrogen (0.05 mg/d) plus a progestin (2.5 mg/d; n = 31), oral conjugated equine estrogen (0.625 mg/d) plus a progestin (2.5 mg/d; n = 30), or placebo (n = 21). Dependent measures included resting and stress-induced increases in BP, total peripheral resistance, and plasma norepinephrine, as well as endothelial function and beta-adrenoceptor responsivity. RESULTS: When compared with placebo, the transdermal estrogen group showed more consistent reductions in total peripheral resistance at rest and in response to mental stress than the oral estrogen group. Only the transdermal group showed treatment-related reductions in behavioral stress norepinephrine, baseline rest, and behavioral stress BP levels, and increases in vascular beta2-adrenoceptor responsivity and endothelium-dependent vasodilation. Posttreatment concentrations of serum estradiol and estrone were lower and the serum estradiol/estrone ratio closer to pre-menopausal values in the group receiving transdermal estrogen compared with oral estrogen. CONCLUSION: Six months of transdermal estrogen therapy is associated with greater reductions in measures reflecting vascular sympathetic tone than oral estrogen therapy in healthy postmenopausal smokers. Thus, transdermal estrogen may be associated with a more favorable risk/ benefit ratio in postmenopausal smokers, a group at high risk of osteoporosis and cardiovascular disease.     

Evaluation of coagulation and fibrinolysis systems in women at peri- and postmenopausal age qualified for hormone replacement therapy

OBJECTIVE: The aim of the study was to evaluate coagulation and fibrinolysis systems in peri- and postmenopausal women who were qualified for hormone replacement therapy. MATERIALS AND METHODS: In sixty eight peri- and postmenopausal women qualified for hormone replacement therapy under study some coagulation and fibrinolysis parameters were measured in serum--platelet count, prothrombin time, prothrombin ratio, INR, APTT, thrombin time (TT), fibrinogen, D-dimers, TAT, factor VII, activity of antithrombin III, activity of protein C and protein S, PAI-1 and t-PA concentration. Controls were 26 healthy, reproductive women. RESULTS: Out of fifteen examined coagulation and fibrinolysis parameters in six cases there were statistically significant differences between menopausal women and controls:--APTT and TT were shortened (but within normal range) in menopausal group than in controls;--concentration of fibrinogen in menopausal group (also within normal range) was higher than in controls;--activity of factor VII was risen (and outside normal range) in the examined group in comparison to the controls;--activity of protein S was lower in menopausal than in reproductive women;--also concentration of t-PA was lower in the examined group. CONCLUSIONS: 1. Differences in the values of coagulation and fibrinolytic parameters between the menopausal and reproductive groups of women may testify to the increased risk of thrombus formation in women at peri- and postmenopausal age. 2. Impaired fibrinolysis (low t-PA, high PAI-1) together with the rise in activity of factor VII can contribute to the development of ischaemic heart disease in menopausal women.     

Effects of oral and transdermal hormone replacement therapy on internal carotid artery pulsatility indices in postmenopausal women. A prospective, randomized, comparative study.

OBJECTIVE: To compare the effects of oral and transdermal hormone replacement therapy on the internal carotid artery pulsatility index in postmenopausal women. STUDY DESIGN: Thirty-seven women were randomized to six months of treatment with oral (n = 19) or transdermal (n = 18) sequential combined hormone replacement therapy. The internal carotid artery pulsatility index was assessed by color Doppler ultrasound at baseline and after six months of treatment. RESULTS: Carotid artery pulsatility indices were significantly lower than the mean of 0.939 +/- 0.139 at 0.860 +/- 0.084 in the oral hormone replacement group and significantly lower than the mean of 0.928 +/- 0.092 at 0.891 +/- 0.046 in the transdermal hormone replacement therapy group (P = .042) after six months of treatment. The mean changes in the carotid artery pulsatility index between the oral and transdermal hormone replacement groups were nonsignificant (-0.078 +/- 0.131 and -0.037 +/- 0.067, respectively; P = .53). There was a significant negative correlation between the change in pulsatility index during treatment and baseline values in the carotid artery (r = -.81, P = .001), but no correlation was found with time since menopause and serum estradiol level. CONCLUSION: Oral and transdermal sequential hormone replacement therapy are similarly effective at six months in reducing impedance to flow in the internal carotid artery.     

Predictors of Early Discontinuation of Effective Contraception by Teens at High Risk of Pregnancy

Study ObjectiveIn the United States, teen pregnancy rates are declining. However, the United States still has the highest teen pregnancy rate among high-income countries. Understanding factors that predict discontinuation of effective contraception might help to further decrease teen pregnancy. We aimed to assess predictors of early discontinuation of effective contraception during typical use by high-risk teens.Design, Setting, Participants, Interventions, and Main Outcome MeasuresWe recruited 145 women aged 13-20 years (mean, 17.7 ± 1.8 years); 68% (99/145) Hispanic; 26% (38/145) black; 14% (20/145) ever pregnant; and 4% (6/145) high school dropouts who chose an effective contraceptive method during a health care visit and we prospectively assessed use of the method after 6 months. Contraceptive choices of the 130 participants who were reassessed at 6 months (90% retention) were: intrauterine device (IUD), 26% (34/130); depot medroxyprogesterone acetate (DMPA), 8% (10/130); combined oral contraceptives (COCs), 48% (62/130); transdermal patch (Patch), 13% (17/130); and intravaginal ring (Ring), 5% (7/130).ResultsAfter 6 months, only 49 of 130 (38%) continued their chosen method; 28 of 130 (22%) never initiated the method; and 53 of 130 (40%) discontinued. Users and nonusers at 6 months did not differ according to cultural and/or social characteristics (age, ethnicity, acculturation, education, health literacy) but differed according to contraceptive method type. For the 102 of 130 who initiated a method, 88% continued use of the IUD, 20% DMPA, 43% COC, 17% Patch and Ring (P < .001). Using Cox proportional hazards multivariable analysis, compared with IUDs, all other methods predicted discontinuation: DMPA (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.2-26.7; P < .05); COCs (HR, 6.6; 95% CI, 1.8-25; P < .01); Patch and Ring (HR, 12; 95% CI, 3.0-48; P < .001). Discontinuation was also predicted by past use of hormonal contraceptives (HR, 1.9; 95% CI, 1.0-3.6; P < .05) and high school dropout (HR, 8.2; 95% CI, 1.6-41; P < .01).ConclusionContraceptive method type is the strongest predictor of early discontinuation; compared with IUDs, all other methods are 6-12 times more likely to be discontinued. Cultural and/or social characteristics, with the exception of school dropout, are of little predictive value. Increasing the use of IUDs by high-risk teens could decrease discontinuation rates and possibly teen pregnancy rates.     

Hemostatic variables, carbohydrate metabolism and lipid profile in women with low body mass index.

The aim of this study was to evaluate hemostatic variables in women according to different body mass index (BMI) values, and then correlate them with some metabolic parameters - fasting insulin and glucose, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Eighty-four female patients aged 18-39 years were recruited, and agreed to participate in the study. The study group was divided into three subgroups according to BMI: low BMI (BMI < 18.5 kg/m2; n = 43), normal-weight (control) (BMI 18.5-24.99 kg/m2; n = 21) and overweight/obese (BMI > 25 kg/m2; n = 20). BMI was calculated, and the following measurements were taken: International Normalized Ratio, antithrombin III, tissue plasminogen activator (t-PA) activity, t-PA-antigen, plasma fibrinogen level, factor VII, Plasminogen activator inhibitor (PAI)-1 activity and antigen and metabolic parameters: fasting insulin and glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides. The results were statistically analyzed. In the low BMI group, a negative correlation between fasting insulin and PAI-1 activity, and a positive correlation between fasting glucose and PAI-1 antigen were observed. Also, a strong negative correlation between PAI-1 activity and insulin/glucose index was found. Plasma insulin levels were significantly lower in the low-BMI women than in the overweight/obese group (p < 0.001) and with no difference compared to the control group. We did not find any difference in fasting glucose level between all groups. HDL-cholesterol showed the highest levels in the normal BMI group and was significantly higher than in the low BMI and obese groups (p < 0.05 and p < 0.01, respectively). PAI-1 activity in the low BMI women revealed increased activity in comparison to control and overweight/obese women (p < 0.001 and p < 0.05, respectively). Lower antigen levels were also shown as compared to both these groups (p < 0.001 and p < 0.001, respectively). Similar results were obtained with t-PA antigen levels (p < 0.001 and p < 0.001, respectively). There were no differences in activity of t-PA in all groups. Obese women showed significantly higher fibrinogen levels than other BMI groups (p < 0.001 and p < 0.001 respectively). Analysis of hemostatic variables in women with a low BMI testify to the impaired fibrinolysis in this group, also showing a strong correlation with carbohydrate metabolism.     

The effects of transdermal estrogen therapy on bone mass and turnover in early postmenopausal smokers: a prospective, controlled study

OBJECTIVE: The purpose of this study was to investigate whether smoking reduces the effects of transdermal estrogen replacement therapy on bone. STUDY DESIGN: One hundred forty-eight women (0.5-5 years after menopause, aged 46-58 years) completed the study. Smokers were assigned randomly to receive either 1.0 mg (n=32 women) or 1.5 mg (n=31 women) of transdermal estradiol in gel daily, and nonsmokers (n=46 women) were assigned to receive 1.0 mg of transdermal estradiol for 2 years. The control group consisted of 17 smokers and 22 nonsmokers. Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover was assessed by measurements of urinary aminoterminal telopeptide of type I collagen and serum aminoterminal propeptide of type I procollagen. RESULTS: Lumbar spine bone mineral density increased similarly in smoking (+3.6%) and nonsmoking (+2.6%) estrogen users (P<.0001 to a decrease of 2.5% in the control group). Femoral neck bone mineral density increased 2.2% to 2.4% in smoking and nonsmoking estrogen users but decreased 0.2% in control subjects (P<.05). Urinary aminoterminal telopeptide of type I collagen decreased similarly in all estrogen-using groups (P<.05 to control group), but serum aminoterminal propeptide of type I procollagen decreased more in smoking than in nonsmoking estrogen users (P=.006). Serum 25-hydroxyvitamin D was 20% lower (P=.004) in smokers than in nonsmokers. CONCLUSION: Transdermal estrogen treatment protects smoking women as effectively as nonsmokers from osteoporosis. Smoking worsens the vitamin D state of postmenopausal women.