[How WHI study influences women doctors' behaviour towards menopause]. / Impact de l'étude WHI sur le comportement des femmes médecins vis-à-vis de la ménopause.

OBJECTIVE: A survey entitled FEMME was conducted during 2002 in order to evaluate among French women doctors their own actual or future menopause perception and this before the WHI publication. The results of this American trial possibly modified the perception of these French women doctors. Therefore the same experts group conducted a new survey, from May to September 2003. The main aim of this survey was to evaluate the possible changes in the medical management of the actual or future menopause of these women, and secondarily to evaluate the changes in their patients' behaviour towards hormone replacement therapy (HRT). POPULATION AND METHODS: Postal auto administered questionnaires were sent to the same 10 000 French women doctors (GP or gynaecologist) whatever their menopausal status or their age. 1365 women doctors (respectively 18,5 or 11% of the gynaecologists or GPs contacted) were volunteers to participate in this survey. Among them, 1120 (84,9%) had already participated in the first part of this survey which took place before the WHI publication. RESULTS: 80% of these women doctors have been informed on WHI results principally by professional press or conferences. 70,9% changed their own actual or future menopause perception as follows. No additional selection of non hormonal treatment have been mentioned in comparison with the first part of the survey. On the other hand for HRT, selections of free estrogen plus progestin associations increased whereas those of fixed combinations decreased: this might be linked to the greater variety of estrogen doses, types of progestin and schedules of treatment (mostly with bleeding) offered by this kind of associations. Finally, duration of HRT is included between three and ten years in most cases. DISCUSSION AND CONCLUSION: Thus, unlike most of their patients, these women's physicians always preferred hormonal treatment for their own actual or future menopause. Only the conditions of these treatments have changed.

[Methodology of the inquiry MISSION (menopause, breast cancer risk, morbidity and prevalence)]. / Méthodologie de l'enquête MISSION (Ménopause, rISque de cancer du SeIn, mOrbidité et prévaleNce).

OBJECTIVE: The ambition of this article is to detail and to explain the methodology of the study named MISSION (Menopause: breast cancer risk, morbidity and prevalence). The aims of MISSION are to determine the prevalence of breast cancer and global morbidity in France among menopausal women treated or not with hormone replacement therapy (HRT) and followed by a gynecologist. MATERIAL AND METHOD: 6600 menopausal women [3300 with HRT -- ie for estrogen: only estradiol via oral or transdermal administration; for progestogen: natural progesterone or assimiled or one pregnane derived (excluding medroxyprogesterone acetate) or non-pregnane derived -- and 3300 without HRT] will be enrolled in France between January 5 2004 and February 28 2005 by 825 gynecologists, members or not of the National Federation of Medical Gynecologists (FNCGM). This study design is a historico-prospective with case randomization. MISSION is conducted by a Theramex-Merck Laboratories initiative in collaboration with a WHO (World Health Organization) Collaborating Center for Public Health Aspects of Rheumatic Diseases and a multidisciplinary expert group. CONCLUSION: First results of this study will contribute to better knowledge of women health.

Continuous hormone replacement therapy for menopause combining nomegestrol acetate and gel, patch, or oral estrogen: a comparison of amenorrhea rates.

This open-label, prospective, randomized, multicenter trial compared the incidence of amenorrhea in 54 postmenopausal women (mean age, 54.9 +/- 0.6 years) who underwent six 4-week cycles of continuous hormone replacement therapy combining a progestin-nomegestrol acetate 2.5 mg/d--plus one of three estrogens: percutaneous 17beta-estradiol gel (1.5 mg/d, group A), transdermal 17beta-estradiol patch (50 microg/d, group B), or oral estradiol valerate (2 mg/d, group C). Based on an intent-to-treat analysis, the rate of amenorrhea varied significantly according to which estrogen preparation was used. Calculated cycle by cycle, rates of amenorrhea were 67% to 83% for group A, 25% to 56% for group B, and 53% to 61% for group C. Overall rates of persistent amenorrhea were not statistically different between groups for cycles 1 through 3, but for cycles 4 through 6, significantly more women in groups A and C (67% and 46%, respectively) experienced amenorrhea than did those in group B (12%). Amenorrhea rates for the entire six-cycle period were 78% for group A, 48% for group B, and 60% for group C. These differences were not statistically significant. The differences in rates could not be attributed to endometrial atrophy, since when measured by transvaginal sonography, endometrial thickness did not differ significantly between groups. Of the original population, 7% withdrew prematurely because of bleeding. The data for all three groups confirmed that in two out of three women, the occurrence of amenorrhea during the first three cycles predicted continuation of amenorrhea during subsequent cycles and that for 51% of women, < or =10 days of bleeding during the first three cycles predicted amenorrhea during the last three cycles. Calculated as a function of the number of women included in the trial, the percentage of amenorrheic women (evaluated cycle by cycle or for the second three-cycle period) was highest when the progestin was combined with percutaneous 17beta-estradiol gel, although findings were similar with estradiol valerate. The percutaneous 17beta-estradiol gel was also associated with a higher percentage of amenorrheal cycles than was estradiol valerate or transdermal estrogen, although differences were significant only in comparison with the transdermal formulation. This difference may have positive clinical implications.

Acute changes in serum calcium and parathyroid hormone circulating levels induced by the oral intake of five currently available calcium salts in healthy male volunteers.

Several calcium supplements are currently available and many of them are marketed without proper comparison of the bioavailability of the actual preparations. The aim of the present trial was to evaluate and compare the acute changes in serum calcium (Ca) and parathyroid hormone (PTH) levels following the oral administration of a vehicle and of five calcium salts currently prescribed in Western Europe. No significant changes in serum Ca or PTH levels were observed after administration of the vehicle. All calcium salts induced significant increases in serum Ca and decreases in serum PTH compared to baseline values. Comparison of the six response curves revealed a significantly greater increase in serum Ca and a greater decrease in serum PTH after each of the calcium salts than observed after the vehicle. However, no statistically significant differences were observed between the different calcium salts for serum Ca increments. The decrease in serum PTH observed after administration of an ossein-hydroxyapatite complex was significantly less important than after the four other calcium salts, even if statistically different than after vehicle. When assessing the area under the curve (AUC) of PTH values, we observed that calcium carbonate and citrate induce a significantly greater decrease in serum PTH than the other calcium salts which are, however, statistically more active than the vehicle. Serum PTH is decreased under the lower limit of the normal range (10 pg/ml), between t60 and t120 for calcium carbonate and citrate and between t60 and t90 for calcium gluconolactate while the mean PTH values remain within the normal range throughout the study with calcium pidolate, the ossein-hydroxyapatite complex and the vehicle. In conclusion, all calcium preparations significantly increase serum calcium and decrease serum parathormone, compared to what is observed after oral intake of a vehicle. However, significant differences in suppression of parathormone are observed between the different calcium preparations and might be of importance for their clinical use.

[Evaluation of the efficacity and speed of action of sertaconazole nitrate suppository and cream combined treatment for vulvovaginal candidiasis]. / Evaluation de l'efficacité et de la rapidité d'action d'un traitement associant un ovule et une crème de nitrate de sertaconazole dans la candidose vulvovaginale.

OBJECTIVE: To assess efficacy and speed of action of a monodose sertaconazole vaginal suppository administered as a single treatment or combined with sertaconazole cream applied to the vulvar area. METHODS: This prospective, multicentric, randomised open study was conducted on 77 women with vulvovaginal candidiasis confirmed by mycological examination. They were either treated with one sertaconazole monodose vaginal suppository only (group O) or treated with the suppository combined with sertaconazole cream applied to the vulvar area for 7 days (group OC). The patients who were not clinically cured at D7 received a second phase of treatment. RESULTS: Clinical cure rates were higher in group OC than in group O at D7 (76% versus 68%), and D14 (100% versus 80%). The efficacy on symptoms was faster in group OC, with 78% of the patients relieved of pruritus as early as D2 versus 61% in group O, although these differences were not significant. Clinical local tolerance was very good, with 95% of patients not experiencing any local side effects. CONCLUSION: When candidiasis is both vulvar and vaginal, the combination of sertaconazole cream with a monodose sertaconazole vaginal suppository tends to improve clinical cure at D7 and D14 and to relieve more patients as early as D2 than the vaginal suppository used as a single treatment.

[Comparison of changes in biochemical markers of bone turnover after 6 months of hormone replacement therapy with either transdermal 17 beta-estradiol or equine conjugated estrogen plus nomegestrol acetate]. / Comparaison de l'évolution des marqueurs biologiques du remodelage osseux après six mois de traitement hormonal substitutif par 17 beta-estradiol cutané ou estrogènes sulfoconjugués équins et acétate de nomégestrol.

OBJECTIVE: To compare changes in biochemical markers of bone turnover in postmenopausal women who received sequential discontinuous hormone replacement therapy (HRT) with either transdermal 17 beta-estradiol gel (group 1) or oral equine sulfoconjugated estrogen (group 2), plus nomegestrol acetate. PATIENTS AND METHOD: Prospective, open, randomized, controlled trial, conducted on 3 parallel groups of 106 postmenopausal women. All treated groups received estrogen therapy for 25 consecutive days every month. The estrogen used was either 1.5 mg/day of transdermal 17 beta-estradiol gel (group 1) [N = 42, average age (AA) = 51.6 years, average duration of menopause (ADM = 21.5 months)], or 0.625 mg/day of oral equine sulfoconjugated estrogen (group 2) [N = 39, AA = 51.3 years, ADM = 16.8 months]. In all cases nomegestrol acetate 5 mg/day was added for 12 consecutive days every month. The control group comprised 25 patients, [AA = 53.4 years, ADM = 33.7 months]. Two bone resorption markers: urinary cross-linked N-telopeptide and C-telopeptide of type I collagen (U-NTX/Cr, U-CTX/Cr), and a bone formation marker: serum bone specific alkaline phosphatase activity were measured before and 6 months after treatment start. RESULTS: Significant decreases from baseline values were observed for the 3 biochemical markers in both treated groups compared with control (P < 0.001). There were no significant differences in changes between the 2 treated groups for the 3 biochemical markers. The mean percentage change in the 3 biochemical markers was: from -9.3 to -45.5% in group 1, from -20.5 to -39% in group 2, and from -3.3 to 2% in control group. In group 1, the mean percentage decreases in U-CTX reached optimal threshold of bone turnover change (-45%) which is considered by the International Osteoporosis Foundation as clinically relevant because it predicts an increase in BMD greater than 3% when treatment is maintained over a long term. DISCUSSION AND CONCLUSION: Both treated groups induced a significant comparable decrease of bone turnover markers after 6 months of intervention, compared with control. The group treated with cyclic administration of transdermal 17 beta-estradiol (1.5 mg/day) and nomegestrol acetate (5 mg/day) showed a bone resorption markers decrease corresponding to the threshold of clinical relevance described in the international literature and predictive of positive BMD response in long term.

[Biological and clinical safety of nomegestrol acetate administered alone then associated in inverse sequence with transdermal 17 beta estradiol, in women at risk of dyslipoproteinemia type IIa]. / Tolérance biologique et clinique du Nomégestrol acétate, administré seul puis associé en séquentiel inversé au 17 beta estradiol cutané, chez des femmes à risque présentant une dyslipoprotéinémie de type IIa.

In this study including 26 patients with dyslipoproteinemia classified IIa, we evaluated biochemical and clinical safety of Nomegestrol acetate (Lutenyl) used for its antigonadotrophin property. It was administered alone, during 3 cycles at the dose of 5 mg/d for 21 days by cycle and then it was associated (at the same sequence and dose), without any wash out, for the next 6 cycles, with a 17 beta estradiol patch (Estraderm TTS 50), 50 micrograms/d from the 11th to the 21st day of each cycle. Nomegestrol acetate, alone, had no significant effect on glycemia, antithrombin III, triglycerides, total cholesterol, apoprotein A1, and LpA1 values compared to those at baseline but apoprotein B and Lp (a) values tended to decrease slightly. Serum progesterone levels were collapsed, and FSH values were low. Weight and blood pressure remained constant. Adding 17 beta estradiol enabled to significantly decrease and normalize the apoprotein B values after the first 3 cycles compared to the baseline values, then these values remained constant during the next 3 cycles. There was no effect on the other parameters (except for a significant increase in plasmatic estradiol values) on the antigonadotrophin property of Nomegestrol acetate, nor on weight and blood pressure which remained constant. Moreover, we observed an important decrease in the rate of amenorrheic cycles compared to those with Nomegestrol acetate alone.

[Determination of acceptability of 2 cutaneous estradiol gels, in a dose of 1.5 mg daily]. / Appréciation de l'acceptabilité de deux gels d'estradiol cutané, à la dose d'1,5 mg par jour.

OBJECTIVE: The aim was to compare acceptability of a percutaneous 0. 1% estradiol gel (Gel A, Estreva(R) Gel, Laboratoire Théramex, Monaco) to that of an 0.06% estradiol gel (Gel B, Oestrodose(R), Laboratoires Besins-Iscovesco) in its new formulation and packaging. MATERIAL AND METHODS: This randomized, crossed, simple-blind study was carried out in 48 volunteer healthy postmenopausal women. The volunteers applied on one forearm 1.5 mg/day of cutaneous estradiol in the form of either gel, according to randomized allocation, for four days without free period between the two therapeutic periods. The application and drying times of the two gels were measured during the first application; gel subjective women assessment was collected at the beginning and at the end of the study. RESULTS: Mean application and drying times with Gel A are significantly reduced, compared to Gel B (p=0.0259 and p=0.0001, respectively) with drying time 61% shorter; these data are confirmed by subjective women evaluation. The two gels are not significantly different regarding several criteria as consistency, ease of application and sensation of lasting stickiness. However, a significant difference is found in favour of Gel A on the following items: practicality of application (p=0.007), ease of penetration (p<0.001), quantity of gel to apply (p<0.001) after the first application. After four days of administration, a same significant difference is observed concerning practicality of the gel (p=0.0078), duration of use (p<0. 001), packaging, women opinion on the gel (p=0.022) and the product, gel and packaging (p<0.001). At the end of the study, gel A utilization is considered by women more practical (p=0.001) with an easier application (p<0.001) and less restricting while applying (p=0.001), compared to Gel B; 72.9% of women prefer the Gel A and 12. 5% of women prefer the Gel B. CONCLUSION: A better acceptability of the 0.1% estradiol gel and of its packaging compared to that of the 0.06% estradiol gel in this new formulation and packaging is observed in this study.

Comparison of calcium retention measured using a radionuclide method after administration of 1000 mg elemental calcium in two different galenic forms, in one or two doses.

A randomized, open, crossover, two-phase study was conducted to compare body retention of calcium measured using a radionuclide method after acute oral administration of 1 000 mg elemental calcium in two different galenic forms, in one or two doses. In the first phase of the study, which included 14 volunteers, the two treatments were one dissolve-in-the-mouth tablet of calcium carbonate in the morning and one in the evening (Orocal 500 mg) (treatment A1) and one effervescent tablet calcium carbonate (Cacit 1000) (treatment B). In the second phase in 8 volunteers, treatment A1 (Orocal 500 mg) was compared to two tablets of the same preparation in a single dose (Orocal 500 mg) (treatment A2). Each treatment contained a tracing dose of 47Ca. Body retention, expressed as the percentage of the total dose and measured seven and 14 days after each treatment, was significantly greater with Orocal 500 mg than with Cacit 1000 (24.21 +/- 3.38 versus 11.96 +/- 2.50 on day 7; 20.22 +/- 3.26 versus 9.67 +/- 2.56 on day 14; p < 0.001). Retention after administration of Orocal 500 mg was slightly better with two doses than with one dose (24.66 +/- 3.44 versus 21.32 +/- 7.63 on day 7; 20.19 +/- 3.28 versus 17.29 +/- 6.63 on day 14). Twenty-five per cent of the difference in calcium retention between treatments A1 (Orocal 500 mg) and B (Cacit 1000) was ascribable to the dosing schedule difference and 75% to the differences in galenic characteristics.

[The cyclic administration of nomegestrol acetate does not alter the vasodilating effects of estradiol on the uterine artery]. / L'administration cyclique de nomégestrol acétate n'altère pas les effets vasodilatateurs de l'estradiol sur l'artère utérine.

Uterine artery blood flow was analyzed in 8 menopausal women receiving hormonal replacement therapy consisting of transdermal E2 (0.05 mg/24 h) administered without interruption for 12 weeks in combination with a cyclical supply of Nomegestrol acetate (5 mg/24 h) for the last 13 days of each four week treatment cycle. Uterine artery flow was analyzed using transvaginal pulsed Doppler making semi quantitative measurements of Doppler flow waves by calculation of the pulsatility index (PI). Before treatment (baseline) uterine artery PI was elevated at 3.7 +/- 0.7 (mean +/- SD) and decreased significantly under the influence of E2 to reach 1.9 +/- 0.8 after 2 weeks of treatment. This effect of E2 was not altered by the cyclical addition of Nomegestrol acetate. On the 3rd month of treatment, uterine artery PI values were lower than seen during the first month and no difference was observed between measurements made while receiving E2 (week 10) or E2 and Nomegestrol acetate (week 12). These data indicate that cyclical administration of the progestin Nomegestrol acetate does not interfere with the vascular effects of E2 lowering the uterine artery PI a reflector of the impedance to flow.

Validation of OSIRIS, a prescreening tool for the identification of women with an increased risk of osteoporosis.

According to the recent recommendations of the European Community and the World Health Organization, identification of risk factors for fracture or low bone mineral density (BMD) should help health professionals to make a better use of bone densitometry. This includes helping patients to modify their behaviour and act on modifiable risk factors (correction of low calcium intake and vitamin D deficiencies, etc.) and also to provide evidence-based guidance for starting a treatment when necessary. In this context, we previously developed a clinical scoring index, OSIRIS (OSteoporosis Index of RISk), for classifying women into three categories of risk of osteoporosis. In order to evaluate the discriminatory performance of OSIRIS, we performed the present prospective study in a sample of 889 postmenopausal women from France. The osteoporosis risk depends on the OSIRIS category. Thus, 62% of women in the 'high-risk' category (OSIRIS < or = -3) were osteoporotic, compared to 34% of women in the 'intermediate-risk' category (OSIRIS ranged between -3 and +1) and only 16.8% of women in the 'low-risk' category (score OSIRIS > 1). These results might contribute to the development of more efficient screening strategies for osteoporosis. The patients in the low-risk category do not require immediate BMD testing; women with 'intermediate risk' have to be carefully followed by their doctor with BMD testing decided on a case-by-case basis; for those within the high-risk category, treatment may be initiated immediately and BMD testing performed either to assess the efficacy of the treatment or to increase the long-term compliance of the patient. In conclusion, for clinical practice, a user-friendly tool has been developed. This tool, called OSIRIS, as far as a simple rule allows, identifies the level of osteoporosis risk in women.

Influence of daily calcium and vitamin D supplementation on parathyroid hormone secretion.

Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures, which were alternated at weekly intervals. After a 'blank' control procedure, when they were not exposed to any supplements, they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses, or one water-soluble effervescent powder pack of Cacit vitamin D3, taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols), veinous blood was drawn every 60 minutes for up to 9 hours, for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation, a statistically significant decrease in serum parathyroid hormone was observed with both regimens, compared with baseline and the control procedure. During this first period, no differences were observed between the two treatment regimens. However, between the 6th and the 9th hour, serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration, while they returned to baseline values with the once-daily Cacit D3 preparation. During this period, the percentage decrease in serum parathyroid hormone relative to baseline was significantly greater with Orocal D3 than Cacit D3 (p = 0.0021). We therefore conclude that the twice-daily administration of 500 mg calcium and 400 IU vitamin D3 at 6-hour intervals provides a more prolonged decrease in serum parathyroid hormone levels than the administration of the same total amount of calcium and vitamin D, as a single morning dose in young healthy.

Influence of daily regimen calcium and vitamin D supplementation on parathyroid hormone secretion.

Calcium and vitamin D supplementation has been shown to reduce secondary hyperparathyroidism and play a role in the management of senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we have compared the administration of a similar amount of Ca and vitamin D, either as a single morning dose or split in two doses, taken 6 hours apart. Twelve healthy volunteers were assigned to three investigational procedures, at weekly intervals. After a blank control procedure, when they were not exposed to any drug intake, they received two calcium-vitamin D supplement regimens including either two doses of Orocal D3 (500 mg Ca and 400 IU vitamin D) 6 hours apart or one water-soluble effervescent powder pack of Cacit D3 in a single morning dose (1000 mg Ca and 880 IU vitamin D). During the three procedures (control and the two calcium-vitamin D supplementations), venous blood was drawn every 60 minutes for up to 9 hours, for serum Ca and serum PTH measurements. The order of administration of the two Ca and vitamin D supplementation sequences was allocated by randomization. No significant changes in serum Ca were observed during the study. During the 6 hours following Ca and vitamin D supplementation, a statistically significant decrease in serum PTH was observed with both regimens, compared with baseline and with the control procedure. Over this period of time, no differences were observed between the two treatment regimens. However, between the sixth and the ninth hour, serum PTH levels were still significantly decreased compared with baseline with split dose Orocal D3 administration, while they returned to baseline value with the Cacit D3 preparation. During this period, the percentage decrease in serum PTH compared with baseline was significantly more pronounced with Orocal D3 than with Cacit D3 (P = 0.0021). We therefore conclude that the administration of two doses of 500 mg of calcium and 400 IU of vitamin D3 6 hours apart provides a more prolonged decrease in serum PTH levels than the administration of the same total amount of Ca and vitamin D as a single morning dose in young healthy volunteers. This might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover in elderly subjects.

Development and assessment of the Osteoporosis Index of Risk (OSIRIS) to facilitate selection of women for bone densitometry.

A simple questionnaire would be useful to identify individuals most in need of bone mineral density (BMD) testing. We designed a new predictive model and risk assessment instrument based on an extensive review of the literature evaluating risk factors for osteoporosis, and tested its performance in a large cohort of postmenopausal women in whom BMD was measured by dual x-ray absorptiometry. In total, 1303 postmenopausal women from an outpatient osteoporosis clinic participated in this study. The Osteoporosis Index of Risk (OSIRIS) is based on four variables: age, body weight, current hormone replacement therapy use and history of previous low impact fracture. The sensitivity and specificity for an OSIRIS value of +1 were respectively 78.5% and 51.4%. The AUC under the ROC curve of OSIRIS was 0.71. Three categories were arbitrarily created using OSIRIS, with cutoff of +1 and -3. The low risk category (OSIRIS > +1) represented 41% of all women; only 7% of the women in this category had osteoporosis. The prevalence of osteoporosis was very high (66%) among the group at high risk (OSIRIS < -3 representing 15% of all women). The prevalence of osteoporosis was 39% in the intermediate risk group (-3 < OSIRIS < +1, 44% of all women). In conclusion, OSIRIS is a simple index based on four easy-to-collect variables from postmenopausal women, it shows a high degree of accuracy, and performed well for classifying the degree of risk of osteoporosis in western European women of Caucasian lineage. Based on this instrument it is possible to propose a strategy that would initiate treatment in women with very high risk, postpone BMD measurement in women with low risk and limit BMD measurement to women with intermediate risk of osteoporosis, this would spare more than 55% of the densitometry bill compared with a mass screening scenario.