Tibolone, oral or transdermal hormone replacement and colour Doppler analysis: a prospective, randomised pilot study

Objective: To compare the plasma thromboxane, the plasma viscosity and the Doppler flow modifications induced by tibolone and by oral or transdermal continuous combined hormone replacement therapy. Methods: Forty-two post-menopausal patients underwent either on: oral daily treatment with tibolone (2.5 mg) (Group I; n=14); or continuous oral administration of 0.625 mg conjugated equine estrogens + medroxyprogesterone 5 mg per day (Group II; n=14); or continuous estradiol transdermal supplementation, at a dose of 50 μg per day, + medroxyprogesterone 5 mg per day (Group III; n=14). The duration of the study was 6 months and the patients were submitted to transvaginal ultrasonographic evaluation of pelvic organs; Doppler analysis of the uterine, internal carotid and ophthalmic arteries; thromboxane and plasma viscosity assays in basal condition, and at 1, 3 and 6 months from the beginning of the study. Results: Although the endometrial thickness increased significantly, there were no cases in which it exceeded the normal range (≤5 mm). In all the three groups, the pulsatility index of the uterine, internal carotid and ophthalmic arteries significantly decreased during the therapy showing a reduced impedance since the first month of treatment. Similar variations were observed for the peak systolic blood flow velocity of the internal carotid and ophthalmic arteries. Hormone replacement therapy and tibolone induced a deep, significant and rapid decrease in plasma thromboxane and plasma viscosity levels. Conclusions: Hormone replacement therapy and tibolone seem to have beneficial effects on vascular and hemorrheological parameters.     

Carotid and uterine vascular resistance in short-term hormone replacement therapy postmenopausal users

Objective: To compare the short-term effects of oral hormone replacement therapy (HRT) and placebo on carotid and uterine vascular impedance. Methods: 80 postmenopausal women selected from the outpatient clinic of the Hospital Leonor Mendes de Barros in São Paulo, Brazil, were randomized to oral HRT (estradiol 2 mg/norethisterone acetate 1mg—Kliogest^r) or placebo. Carotid and uterine arteries pulsatility indices (PIs) were assessed by color Doppler at baseline, after 4 and 12 weeks of treatment. Seventy-six women completed the trial, 38 in each group. Results: The carotid PI did not decrease significantly in either group. In the uterine arteries, the drop in PI was steeper and greater for HRT women. Drops occurred despite the supposed counteracting effect of norethisterone acetate. In placebo group, there was no significant difference between 4 and 12 weeks of treatment compared with the baseline. The results did not change when analyzed in a real treatment approach. Conclusion: Oral continuous HRT are effective at 12 weeks in reducing impedance to flow in uterine, but not in carotid circulation. These results suggest that the effects of HRT vary by vascular site, and do not have a detectable short-term vascular effect in the carotid area.     

Effects of continuous combined hormone replacement therapy and clodronate on bone mineral density in osteoporotic postmenopausal women: A 5-year follow-up

Objective

To determine the effects of HRT with or without clodronate on bone mineral density (BMD) change and bone turnover markers.

Design

Prospective, partly randomized trial.

Setting

Kuopio University Hospital, Finland.

Population

167 osteoporotic women (61 ± 2.7 years; T-score ≤ −2.5 SD).

Methods

Estradiol 2 mg + NETA 1 mg, randomization to additional 800 mg clodronate (n = 55, HT + C-group) or placebo (n = 55, HT-group); if contraindications to HRT, clodronate (n = 57, C-group).

Main outcome measures

BMD by DXA after 1, 3 and 5 years, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) at the baseline and after 3 years.

Results

After 5 years, adjusted lumbar BMD increased by 4.2% in the HT-group and 3.7% in the HT + C-group. The C-group showed a decrease of −1.1%, the total difference being 5.3% and 4.8% between HT, HT + C vs. C-group, respectively (p < 0.001). In the femoral neck, the adjusted 5-year BMD benefit was 1.3% and 2.4% in the HT- and HT + C-groups, respectively, the net loss of BMD in the C-group was −3.3% (p < 0.05 between HT + C vs. C). By 3 years, OC decreased by 55.0%, 70.3% and 53.8% in the HT-, HT + C- and C-groups, respectively (p < 0.001 vs. baseline). The significant decreases of BAP were 39.4% in the HT-group, 42.1% in the HT + C-group and 30.2% in the C-group with no significant differences between the groups after adjustments.

Conclusions

In postmenopausal women with osteoporosis, HRT increased spinal and femoral BMD, but the combination of HRT and clodronate did not offer an extra gain of bone mass.     

Diurnal variation in uterine artery blood flow in post-menopausal women on oestrogen hormone replacement therapy.

Doppler ultrasound was used to investigate circadian variations in uterine artery blood flow in 20 post-menopausal women in the oestrogen-only phase of combined oestrogen hormone replacement therapy with cyclical oral norethisterone or dydrogesterone. All women were examined between 0800 and 0830 h and then again between 1800 and 1830 h on the same day. Mean arterial blood pressure, heart rate and a blood sample for measurement of serum oestradiol were taken at each visit. Indices of uterine artery blood flow included the pulsatility index, resistance index, peak systolic velocity and time-averaged maximum velocity. No significant differences in the mean arterial blood pressure, pulse rate and oestradiol concentrations were detected between morning and evening visits. Significant fluctuation was observed in the pulsatility index (P < 0. 001), resistance index (P < 0.001) and time-averaged maximum velocity (P < 0.01). The assessment of uterine artery blood flow in post-menopausal women should take into account the presence of circadian variations to ensure accuracy and reproducibility of Doppler investigations.     

Percutaneous estradiol gel with an intrauterine levonorgestrel releasing device or natural progesterone in hormone replacement therapy

Objective: To evaluate the bleeding patterns and clinical compliance associated with postmenopausal amenorrhea-inducing forms of hormone replacement therapy using either percutaneous estradiol-gel and a levonorgestrel-releasing intrauterine device or an oral/vaginal natural progesterone. Methods: Sixty postmenopausal women with an intact uterus were followed over 12 months in this open, non-randomised, parallel group study. All patients continuously received a gel containing 1.5 mg of estradiol daily. The women were divided into three groups on the basis of progestin administration. Twenty women (group I) had a levonorgestrel-releasing device (LNG-IUD) inserted at the beginning of the study. Twenty-one women (group II) received oral natural micronised progesterone (oral P) 100 mg daily during 25 calendar days each month, and 19 women (group III) used vaginal natural micronised progesterone (vaginal P) 100–200 mg daily during 25 calendar days each month (higher dose if spotting occurred). Clinic visits were at 0, 3, 6 and 12 months. Bleeding patterns were recorded by the patient in a diary and clinical compliance was evaluated at control visits during the treatment. Symptoms were recorded using a modified Kuppermann index. The serum estradiol concentration was determined at the 0, 6 and 12 month control visits. Results: 80% (n = 16) of the patients in the LNG-IUD group, 67% (n = 14) in the oral P group II and 53% (n = 10) in the vaginal P group were without bleeding at 12 months. Spotting was common during the first 3 months. Symptom relief was good in each group. The LNG-IUD did not cause any serious side-effects. Compliance was good for LNG-IUD and oral progesterone but not for vaginal progesterone. Conclusions: Percutaneous estradiol-gel associated with LNG-IUD is an appropriate method of hormone replacement therapy. The combination of oral natural progesterone with estradiol-gel is also useful, although bleeding episodes complicated the treatment in one third of the patients. The vaginal administration of natural progesterone was impractical due to bleeding disorders..     

Perspective on hormone therapy 10 years after the WHI

The Women's Health Initiative (WHI) hormone trials are among the most influential and debated research studies in women's health in recent medical history 0005 and 0010. This year (2013) marked the 10th anniversary of the publication of the WHI results and this past decade has been nothing less than revolutionary. We have witnessed a transformative evolution in our understanding of, and in the practice of, menopause management and herein summarize the strides the field has traversed over the past 10 years.     

Doppler colour flow analysis of uterine and ovarian arteries prior to and after surgery for tubal sterilization: a prospective study

Female sterilization by tubal ligation is a very common methodof birth control. A relationship between tubal sterilizationand subsequent development of menstrual disorders has been describedin the literature but a biological mechanism explaining suchan association has not yet been demonstrated. The aim of thisstudy was to evaluate the influence of tubal ligation by thePomeroy technique on ovarian and uterine artery blood flow usingpre- and post-surgical Doppler assessments. We studied prospectively20 patients undergoing laparotomy for tubal ligation. All patientshad a Doppler blood flow assessment before and after surgery,conducted in the mid-foUicular phase of their cycle. The pulsatilityindex (PI) of the right uterine artery ranged from 1.44 to 3.86(mean 2.23) when measured prior to surgery and from 136 to 2.85(mean 2.13) when measured after surgery. In the left uterineartery, the PI ranged from 1.67 to 3.17 (mean 2.17) and from1.69 to 2.88 (mean 2.22) before and after surgery respectively.The difference was not statistically significant The PI of theright ovarian artery ranged from 138 to 3.48 (mean 2.41) priorto surgery and from 1.48 to 3.23 (mean 2.29) after surgery.In the left ovarian artery, the PI ranged from 1.36 to 3.62(mean 234) and from 1.85 to 4.00 (mean 2.61) before and aftersurgery respectively. Again, the difference was not statisticallysignificant Our results suggest that tubal sterilization performedby Pomeroy‘s technique does not induce immediate alterationsin the vascular flow of either ovarian or uterine arteries.     

Use of hormone replacement therapy (HRT) among women aged 45-64 years in the German EPIC-cohorts

OBJECTIVE: To describe the prevalence and to assess type and indicators of hormone replacement therapy (HRT) use in the two German EPIC-cohorts. METHODS: Approximately 30,000 women predominantly aged 35-65 years were recruited in EPIC-Heidelberg and EPIC-Potsdam between 1994 and 1998. Information on diet and lifestyle, medical history and use of hormone therapy was collected at recruitment. Prevalence and type of HRT-regime was described and logistic regression models used to examine correlates of HRT-use. RESULTS: Among women aged 45-64 years, 37.9% in Heidelberg and 35.8% in Potsdam were current HRT users. Among current users without bilateral oophorectomy, 40.5% in Heidelberg and 23.7% in Potsdam used HRT for at least 5 years. Most women in Heidelberg were taking cyclic combined or estrogen monotherapy, whereas in Potsdam both continuous combined and cyclic combined therapies were most frequently used. In both centres, older age, ever use of oral contraceptives, and alcohol consumption were indicators for both current and ever HRT-use. HRT-use was less frequent in obese women as compared to women with lower BMI. In Potsdam, but not in Heidelberg, higher education and current smoking were associated with HRT-use. CONCLUSION: In both German EPIC-cohorts, the prevalence of medication with HRT is high compared to other European countries. Types of exogenous hormones used differed by centre. Various reproductive and lifestyle characteristics were identified as correlates of HRT-use.     

Power and colour Doppler ultrasonography for the evaluation of the vasculature of the human corpus luteum

We used power Doppler imaging to examine neovascularizationin the corpus luteum (CL) in 12 healthy volunteers. We alsoinvestigated whether CL blood flow reflected luteal function.The ratio of the area of vessels in the CL to the area of asectional plane at the maximum diameter of the CL observed bypower Doppler (FA ratio) was used as a quantitative index ofthe vascularity of the CL. The pulsatility index (PI) was significantlylower in ovarian arteries with CL than without CL (P <0.05).Changes in ovarian arterial and intra-luteal PI appeared toreflect physiological changes in the vasculature of the CL.There was no correlation between the volume of the CL or theFA ratio and the concentration of progesterone. The patternof changes in the product of the FA ratio and the CL volumeand in the progesterone concentration was similar. The progesteroneconcentration was positively correlated with this product (r= 0.74, P < 0.01). The product of the FA ratio and the CLvolume plateaued during the mid- to late luteal phase, suggestingthe presence of functional and structural luteolysis. Thesefindings suggest that colour Doppler ultrasonography, includingpower Doppler imaging, can detect physiological changes in theblood flow of the ovary in the luteal phase, and may be a usefulnon-invasive tool for evaluating CL function.     

Effects of bezafibrate and simvastatin on plasma lipoproteins in hypercholesterolemia resistant to hormone replacement therapy

Objectives: Estrogen replacement therapy has favorable effects on serum lipoprotein levels in postmenopausal women with hypercholesterolemia. However, there are some patients who fail to respond to hormone replacement therapy (HRT) to lower the serum cholesterol level. In these cases, a conventional lipid-lowering therapy will be applied in addition to HRT, while the effects of these drugs are not well understood. In this study, we studied the effects of simvastatin and bezafibrate administered in addition to HRT. Methods: Patients who were hypercholesterolemic even after HRT were randomly assigned to three treatment groups: HRT only (control group, n=10), HRT+simvastatin (10 mg/day, n=10), or HRT+bezafibrate (400 mg/day, n=10). Serum lipids and lipoprotein levels were measured throughout 12 weeks. Results: The serum triglyceride levels were decreased by 24±28 and 38±13% in the HRT+simvastatin and HRT+bezafibrate groups, respectively. HRT+simvastatin decreased the total cholesterol (21±10%) and low-density lipoprotein cholesterol (28±12%) levels without affecting the high-density lipoprotein cholesterol (HDL-C) level, while HRT+bezafibrate increased the HDL-C level (12±11%). Conclusions: Treatment with simvastatin or bezafibrate in addition to HRT should be considered in cases of postmenopausal hypercholesterolemia in which HRT alone fails to lower the serum lipoprotein levels.     

Effects of hormone replacement therapy on ocular function in postmenopause

OBJECTIVE: To evaluate the effect of hormone replacement therapy on climacteric ocular complaints, lacrimal secretion, intraocular pressure (IOP), and corneal thickness. DESIGN: A prospective, controlled, randomized study on 50 healthy women (mean age 53.4 +/- 3.8 years) at least 1 year after spontaneous menopause. Twenty-five women (group A) were treated with transdermal 17beta-estradiol (50 microg/day) and medroxyprogesterone acetate (10 mg/day) for 12 days per cycle. Twenty-five untreated women (group B) were used as a control group. All participants underwent eye examination at the beginning of the study and after 3 and 6 months of therapy to detect ocular diseases and to measure lachrymal secretion, IOP, and corneal thickness. RESULTS: No significant differences were observed between the two groups at the beginning of the study. After 3 and 6 months of treatment, we observed a significant reduction in the percentage of women in group A affected by ocular symptoms and in the severity of symptomatology in comparison with baseline and with group B (P < 0.01). A significant increase of both basal and stimulated lachrymal secretion was observed after 3 months of therapy in group A in comparison with baseline (P < 0.01). There was a significant decrease of IOP (P < 0.01) after 3 months of therapy in group A (P < 0.01), and a slight, nonsignificant increase of corneal thickness was observed in group A at 3 and 6 months in comparison with basal values. CONCLUSION: Our data suggest that hormone replacement therapy may exert a beneficial effect on ocular symptomatology, increase lachrymal secretion, reduce IOP, and increase corneal thickness.     

Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women

Objective: at the onset of menopause, weight-gain and the aggravation of certain cardiovascular risk factors are frequently observed. The aim of this study was to examine the metabolic effects of combined hormone replacement therapy (17β-oestradiol transdermic 50 μg for 21 days and oral medroxyprogesterone acetate 5 mg from day 10 to 21) using, in particular, indirect calorimetry. Methods: patients (21; 12 substituted and nine controls) were studied twice (3 months apart) during an oral glucose load (75 g). Results: total body weight was unaltered after 3 months in the control group, whereas a fat-loss of 2.1±0.2 kg and a decrease of the waist:hip ratio were observed in the substituted group. In the latter group, a significant increase in lipid oxidation was observed (0.58±0.06 mg/kg/min before and 0.75±0.04 mg/kg/min after substitution P<0.05), whilst total energy expenditure and thermogenesis were also increased. Glucose, lipid and protein oxidation remained stable during three months in the control group. The insulin response to an oral glucose load diminished by 30% with hormone replacemnet therapy (102.3±32.8 mμ/l versus 71.4±20.0 mμ/l). Total and LDL-cholesterol improved after hormone replacement therapy whereas plasma triglycerides were not altered. Conclusions: combined hormone replacement therapy not only prevented weight-gain, but favored weight-loss by significantly increasing lipid oxidation after 3 months of treatment. It also favourably influenced the insulin response, plasma lipids and energy expenditure.     

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response.     

Effect of hormone replacement therapy on lipids in perimenopausal and early postmenopausal women

Objective: To determine the effects of oral sequential hormone replacement therapy (HRT) on lipid-profile in perimenopausal and early postmenopausal women. Methods: We performed a single-center, randomized, placebo-controlled trial. The trial was double blind with respect to 17β-estradiol/desogestrel (17β-E-D) and placebo and open with respect to conjugated estrogens/norgestrel (CEE-N). A total of 125 healthy perimenopausal and early postmenopausal women, aged 43–58 years, were recruited from the general population in Zoetermeer, the Netherlands. The intervention consisted of 6 months treatment with 1.5 mg 17β-estradiol/0.15 mg desogestrel (n=53), 0.625 mg conjugated estrogens/0.15 mg norgestrel (n=36) or placebo (n=36). At baseline, cycle 1, 3 and 6, overnight fasting blood samples were obtained in which lipids were determined. We used linear regression analysis to calculate differences in mean change from baseline in lipids in the active treatment groups compared to placebo. Results: In both treatment groups significant (P<0.05) falls in low-density-lipoprotein (LDL)-cholesterol (17β-E-D: −7.8% and CEE-N: −8.4%) and lipoprotein(a) (17β-E-D: −11.7% and CEE-N: −28.3%) were found compared to placebo. Apolipoprotein A1 (17β-E-D: 6.8% and CEE-N: 7.3%) and HDL-cholesterol (17β-E-D: 6.4% and CEE-N: 8.0%) significantly increased compared to placebo. No significant changes were found in the other lipids. Mean changes from baseline in total cholesterol, LDL-cholesterol and apolipoprotein B were significantly more pronounced in postmenopausal women compared to perimenopausal women, adjustment for age-differences did not change the results. Conclusion: Treatment of perimenopausal and early postmenopausal women with 17β-E-D or CEE-N changes their lipid-profile in a potentially anti-atherogenic direction. Changes appear to be more pronounced in postmenopausal women compared to perimenopausal women.     

The effect of hormone replacement therapy on the number and the proliferation index of endometrial leukocytes

This study aimed to determine the changes in endometrial leukocyte subpopulations under sequential hormone replacement therapy (HRT) during the late progestogenic phase. The number of leukocytes was determined using immunohistochemistry utilizing monoclonal antibodies to CD45 (total leukocytes), CD56 (endometrial granulated lymphocytes), CD3 (T-cells), and CD68 (macrophages). Leukocyte proliferation was demonstrated using in-situ hybridization with a histone probe, and the proliferation index was determined using double labelling for Ki67 (Mib1). Compared to the corresponding phase of the physiological cycle, sequential HRT-treated endometrium exhibited a 95% increase in CD45(+) cells (P < 0.05), a 130% increase in CD56(+) cells (P < 0.05), and a 113% increase in CD3 cells. There was a non-statistically significant drop in the number of CD68(+) cells. The number of proliferating leukocytes increased in sequential HRT endometrium.     

Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy

Objective: To evaluate the incidence of breast symptoms in a population treated with various hormone replacement therapy (HRT) regimens and to detect the variations in breast symptomatology after HRT changing to tibolone administration. Methods: This prospective placebo-controlled clinical trial was conducted on healthy women on HRT reporting breast symptoms. A questionnaire was given to each woman to detect breast symptomatology. Breast tenderness and mastalgia were evaluated using a visual analogue scale (VAS). According to the choice of the each woman with breast symptoms, the HRT was changed to tibolone (2.5 mg/day per os) or to calcium carbonate (1 tab/day, placebo group). The duration of treatment was of 12 months. After 6 and 12 months breast symptomatology was re-evaluated. Results: Among the 600 screened women, 64 (10.7%) were suffering from breast symptomatology. After 6 and 12 months of treatment with tibolone or placebo, mean VAS score for breast tenderness and for mastalgia resulted significantly (P<0.05) decreased, without differences between groups, in comparison with basal value. Only one woman had no improvement from the breast symptoms with tibolone administration. Conclusions: Shifting from classical HRT to tibolone is followed by a significant reduction of breast symptomatology in postmenopausal women with breast complaints similar to that obtained with treatment withdrawal.     

Diagnostic techniques: Blood flow changes in uterine and ovarian vasculature, and predictive value of transvaginal pulsed colour Doppler ultrasonography in an in-vitro fertilization programme

The role of transvaginal pulsed colour Doppler ultrasound inthe prediction of the outcome of in-vitro fertilization (IVF)therapy was assessed longitudinally in 30 patients during stimulatedcycles. The pulsatility index (PI) of the uterine arteries didnot change significantly until the mid-luteal phase. Within6 days after the beginning of stimulation the maximum peak systolicvelocity of the uterine blood flow had increased significantlyfrom 27.6 ± 8.9 to 36 ± 12.8 cm/s. No differencewas found in uterine PI between pregnant and non-pregnant women.The PI of intra-ovarian flow was also similar in both groups.However, there was an insignificant increase in uterine receptivitywhen the PI of the uterine artery was between 2.0 and 2.99 onthe day of embryo transfer. Nevertheless, the appraisal of theprognostic outcome of the treatment could not be made with Doppler.     

Colour Doppler analysis of ovarian and uterine arteries in women with hypoestrogenic amenorrhoea

BACKGROUND: This is a clinically-controlled study designed to investigate uterine and ovarian blood flow in patients with hypoestrogenic amenorrhoea. METHODS: Twelve women with hypoestrogenic amenorrhoea and 13 eumenorrhoeic subjects (controls) were enrolled. Colour and pulsed Doppler was used to visualize the uterine and ovarian arteries and the blood vessels within the ovarian stroma in both groups. Four blood flow indices were calculated: the pulsatility index, the resistance index, the peak systolic velocity and the end-diastolic velocity. RESULTS: Peak systolic velocity underwent the most significant change in amenorrhoeic patients, being significantly lower in comparison with that of controls, both in the uterine (P = 0.0009) and ovarian (P = 0.001) arteries. Compared with controls, the end-diastolic velocity of the ovarian artery was significantly lower (P = 0.039) in amenorrhoeic patients, and was also lower in the uterine artery (though not statistically significantly so). A reduction in blood flow was also evident in the ovarian stroma in amenorrhoeic patients. CONCLUSIONS: The significant reduction in blood flow observed in hypoestrogenic amenorrhoea suggests that estrogens play an important role in regulating both uterine and ovarian blood flow.