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June 2003


A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.

OBJECTIVE: To study the effects of long-term combined continuous oral hormone replacement therapy (HRT) on vascular function in healthy postmenopausal women. BACKGROUND: The cardiovascular effects of HRT are controversial. Improvement in vascular function is a proposed mechanism of estrogen action but there are no long-term controlled human trials in this area. In this study, we examined the effects of HRT on lipid profiles and vascular function, encompassing both biomechanical arterial properties [systemic arterial compliance (SAC) and pulse wave velocity (PWV)] and endothelial function [flow-mediated vasodilation (FMD)]. METHODS: In this two-year, double-blind, placebo-controlled study, 59 healthy postmenopausal women were randomized to oral combined continuous estrogen and progesterone [Kliogest, estradiol (2 mg), norethisterone (1 mg)] or placebo, with end-points measured at baseline, six weeks and after 6,12 and 24 months of treatment. RESULTS: Oral combined HRT reduced lipoprotein a [Lp(a)], although other lipid benefits were not observed. There were no significant changes in SAC, PWV or FMD with oral combined HRT, compared to placebo. CONCLUSION: In this long-term, randomized placebo-controlled trial, oral continuous HRT with combined estradiol and norethisterone in healthy postmenopausal women did not improve a spectrum of indices of arterial function compared to placebo. These results suggest that HRT might not be of cardiovascular benefit in postmenopausal women.

Clin Endocrinol (Oxf) 2001 Nov;55(5):673-8

Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss.

OBJECTIVE: To determine effectiveness of transdermal progesterone cream for controlling vasomotor symptoms and preventing postmenopausal bone loss. METHODS: We randomly assigned 102 healthy women within five years of menopause to transdermal progesterone cream or placebo. Study subjects and investigators were masked until data analysis was completed. An initial evaluation included complete history, physical examination, bone mineral density determination and serum studies (TSH, FSH, lipid profile and chemistry profile). Subjects were instructed to apply a quarter teaspoon of cream (containing 20 mg progesterone or placebo) to the skin daily. Each woman received daily multivitamins and 1200 mg of calcium and were seen every four months for review of symptoms. Bone scans and serum chemistries were repeated after one year. RESULTS: Thirty of the 43 (69%) in the treatment group and 26 of the 47 (55%) in the placebo group complained initially of vasomotor symptoms. Improvement or resolution of vasomotor symptoms, as determined by review of weekly symptom diaries, was noted in 25 of 30 (83%) treatment subjects and five of 26 (19%) placebo subjects (P amp;lt; .001). However, the number of women who showed gain in bone mineral density exceeding 1.2% did not differ (alpha = .05, power of 80%). CONCLUSION: Although we found no protective effect on bone density after one year, we did see a significant improvement in vasomotor symptoms in the treated group.

Obstet Gynecol 1999 Aug;94(2):225-8

Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women.

Peripheral vascular responses to acute administration of natural progesterone were studied in 12 postmenopausal women (mean +/- SD age 50.3 +/- 4.8 years) with no evidence of cardiovascular disease. According to a randomized, double-blind protocol, all subjects were given natural progesterone as a vaginal cream, able to produce a rapid peak and decay of plasma hormone concentrations, or matched placebo, with crossover after a one-week washout period. Forearm blood flow and peak flow after ischemic stress (ml/100 ml/min), local vascular resistance (mm Hg/ml/100 ml/min), venous volume (ml/100 ml), and venous compliance (ml/100 ml/mm Hg) were measured by strain-gauge venous occlusion plethysmography at baseline and after progesterone or placebo administration. Plasma norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection. Progesterone sharply decreased forearm blood flow (p amp;lt;0.01) through an increase in local vascular resistance (p amp;lt;0.01). Measures of venous function remained unchanged. Although the hormone increased circulating norepinephrine concentrations (p amp;lt;0.05), there were no significant changes in mean arterial pressure or heart rate. Furthermore, progesterone reduced the local vasodilator capacity, shown by a decrease in forearm delta flow (difference between peak flow and basal flow, p amp;lt;0.05). Compared with the well-known effect of estrogen, progesterone exerted an opposite action on peripheral vascular responsiveness. Peripheral circulatory changes may be attributed to a direct activity of progesterone on the arterial wall and may in part reflect a modulation of the hormone on peripheral sympathetic tone. Consideration must be given to the hypothesis that the addition of progestin may attenuate the beneficial effects of unopposed estrogen replacement therapy in postmenopausal women.

Am J Cardiol 1999 Jul 15;84(2):214-8

Effects of estrogen and progesterone on age-related changes in arteries of postmenopausal women.

1. Hormone replacement therapy (HRT) with estrogen or estrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima-medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non-HRT) and those women on long-term HRT with estrogen alone (HRT-E) or oestrogen plus progestin (HRT-EP). 2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure. 3. Plasma total cholesterol was reduced and high-density lipoprotein-cholesterol was increased in the HRT group compared with the non-HRT group; low-density lipoprotein-cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT-E and HRT-EP subgroups were similar. 4. Carotid IMT was significantly reduced in the HRT group compared with men and non-HRT groups. Results for HRT-E and HRT-EP subgroups were similar. 5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age; SAC was higher in both HRT-E and HRT-EP groups compared with the non-HRT group. Indices of carotid stiffness were similar in men and in non-HRT groups. The HRT-EP group showed increased carotid stiffness compared with the HRT-E group. 6. There is an apparent protective effect of long-term estrogen therapy on carotid IMT and age-related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.

Clin Exp Pharmacol Physiol 1997 Jun;24(6):457-9

Transition of ovarian arterial compliance during the human menstrual cycle, assessed by Doppler ultrasound-correlation with serum hormone levels.

Ovarian arterial velocimetry was performed using color and pulsed Doppler ultrasound. Seventy-one examinations were done on nine healthy women with regular menstrual cycles. The change in ovarian arterial compliance was based on the calculation of the pulsatility index (PI). In the active ovary carrying a dominant follicle or corpus luteum, PI in the early proliferative phase was significantly higher than that in the late proliferative phase (p less than 0.001), and PI in the early secretory phase was significantly lower than that in the late proliferative phase (p less than 0.001). PI became significantly higher in the late secretory phase than that in the early secretory phase (p less than 0.001). In the inactive ovary without a follicle of corpus luteum, no changes were seen among the values for PI, in any menstrual phase. There was a significant difference between the values for PI in the active ovary and the inactive ovary in the late proliferative, the early and the late secretory phases (p less than 0.001), respectively. The PI values for the active ovary significantly correlated with the serum progesterone levels (r = -0.53, p less than 0.05) but not with the estradiol levels. These findings provide a useful foundation for assessing ovarian hemodynamics during the menstrual cycle.

Nippon Sanka Fujinka Gakkai Zasshi 1990 Jul;42(7):662-6

Estrogen and thyroid hormone receptor interactions: physiological flexibility by molecular specificity.

The influence of thyroid hormone on estrogen actions has been demonstrated both in vivo and in vitro. In transient transfection assays, the effects of liganded thyroid hormone receptors (TR) on transcriptional facilitation by estrogens bound to estrogen receptors (ER) display specificity according to the following: 1) ER isoform, 2) TR isoform, 3) the promoter through which transcriptional facilitation occurs and 4) cell type. Some of these molecular phenomena may be related to thyroid hormone signaling of seasonal limitations upon reproduction. The various combinations of these molecular interactions provide multiple and flexible opportunities for relations between two major hormonal systems important for neuroendocrine feedbacks and reproductive behaviors.

Physiol Res 2002 Oct;82(4):923-44

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