Changes of menopausal hormone therapy use pattern since 2000: results of the Berlin Spandau Longitudinal Health Study.

BACKGROUND: There are virtually no prospective cohort studies in Germany regarding the changes of menopausal hormone therapy (HT) use pattern and factors associated with HT discontinuation after the release of the Women's Health Initiative (WHI) trial results. METHODS: We assessed HT prevalence and use pattern as well as factors associated with HT discontinuation in a cohort of 903 women 40 years of age and older, who participated in two consecutive follow-up visits in a 20-year prospective health study from July 2000 to February and from August 2002 to December 2004. RESULTS: Overall, the prevalence of HT users in the cohort declined significantly from 35.4% in 2000-2002 to 22.5% in 2002-2004. Adjusting for aging of the population, a statistically significant decrease in HT user prevalence was consistently observed across subgroups of HT users defined by type and duration of HT use. The decline was most pronounced with respect to women using combined estrogen-progestin regimens (-10.5%), higher-dose estrogens (-11.6%), oral preparations (-11.1%), as well as long-term HT users (-8.4%). The prevalence of women indicating HT use for climacteric symptoms decreased significantly (-12.4%), whereas the prevalence of women reporting use of HT for the prevention of osteoporosis increased (+1.8%) significantly. Irrespective of hysterectomy status, half of the women who continued HT changed their HT preparations and switched to lower estrogen doses (11.5%), topical estrogens (8.2%), or phytohormones (3.8%). We did not observe any significant differences between women who continued and discontinued HT regarding health-related characteristics of the study population as of 2000-2002. However, women seeing a gynecologist in the 12 months preceding the 2002-2004 visit were significantly less likely to discontinue HT use in bivariate and multivariate analyses. CONCLUSIONS: Substantial declines in HT user prevalence as well as changes in HT use patterns to lower-dose estrogen preparations and non-oral routes of administration are likely to reflect effects of the publication of the WHI results. Consulting a gynecologist appeared to be relevant for a woman's decision to continue HT.

Cell migration: don't tread on me.

During directed cell migration, telling cells to avoid certain areas may be as important as attracting them to others. The recently identified wunen gene is involved in the repulsive guidance of migrating primordial germ cells in Drosophila.

Regulation of zygotic gene expression in Drosophila primordial germ cells.

Activation of the zygotic genome is a prerequisite for the transition from maternal to zygotic control of development. The onset of zygotic transcription has been well studied in somatic cells, but evidence suggests that it is controlled differently in the germline. In Drosophila, zygotic transcription in the soma has been detected as early as one hour after egg laying (AEL) [1]. In the germline, general RNA synthesis is not detected until 3.5 hours AEL (stage 8) [2] and poly(A)-containing transcripts are not observed in early germ cell nuclei [3]. However, rRNA gene expression has been demonstrated at this time [4]. Therefore, either there is a general, low level activation of the genome in early germ cells, or specific classes of genes, such as those transcribed by RNA polymerase (RNAP) II, are repressed. We addressed this issue by localizing the potent transcriptional activator Gal4-VP16 to the germline, and we find that Gal4-VP16-dependent gene expression is repressed in early germ cells. In addition, localization of germ plasm to the anterior reveals that it is sufficient to repress Bicoid-dependent gene expression. Thus, even in the presence of known transcriptional activators, RNAP II dependent gene expression is actively repressed in early germ cells. Furthermore, once the germ cell genome is activated, we find that vasa is expressed specifically in germ cells. This expression does not require proper patterning of the soma, indicating that it is likely to be controlled by the germ plasm.

Susceptibility to diphtheria in adults: prevalence and relationship to gender and social variables.

Recent outbreaks of diphtheria have drawn attention to the re-emergence of this disease. This study investigated susceptibility to diphtheria in north-east Germany and its relationship to gender and social factors. A study population of 4275 individuals recruited for the population-based Study of Health in Pomerania (SHIP) was available for analysis. IgG antibodies against diphtheria toxin were determined by ELISA and were used to define susceptibility to diphtheria (i.e., IgG titres < 0.1 IU/mL). The prevalence of susceptibility to diphtheria was 32.4%. Multivariate analysis revealed 45% increased odds of women being susceptible to diphtheria. Women who had not received diphtheria toxoid vaccination during the previous 10 years had four-fold increased odds of being susceptible to diphtheria toxin compared with unvaccinated men. None of the social factors investigated was associated with susceptibility status. It was concluded that a high proportion of middle-aged adults was susceptible to diphtheria. Women lacked seroprotection more often than men, which might be explained, in part, by gender-specific immune responses following vaccination. There is a need for information campaigns to improve public awareness of these problems.

Impact on uterine bleeding and endometrial thickness: tibolone compared with continuous combined estradiol and norethisterone acetate replacement therapy.

OBJECTIVE: To evaluate endometrial thickness and the incidence of uterine bleeding in postmenopausal women using either tibolone 2.5 mg or continuous combined 2 mg estradiol and 1 mg norethisterone acetate (E+NETA) daily as hormone replacement therapy. DESIGN: We compared diary records of self-reported uterine bleeding and measurements of endometrial thickness, area, and volume by transvaginal sonography at baseline and after 1, 3, 6, and 12 months in a 1-year, prospective, randomized, double-blind, single-center trial of 100 postmenopausal women aged 46-69 years. Bleeding frequencies and endometrial thickness were assessed by Chi-square tests and analysis of covariance, respectively. RESULTS: Self-reported bleeding was significantly less in the tibolone group. Bleeding episodes were reported by 27.7% of women in the tibolone group and by 59.2% in the E+NETA group. The mean number of days with bleeding was 5.8 +/- 27.0 in the tibolone group and 35.6 +/- 58.6 in the E+NETA group. Six women in the tibolone group and seven in the E+NETA group discontinued the study; three in the E+NETA group because of bleeding. The mean endometrial thickness at baseline was 2.56 +/- 0.81 mm in the tibolone group and 2.58 +/- 1.04 mm in the E+NETA group. After 1 year, the corresponding figures were 3.32 +/- 1.58 mm and 3.07 +/- 1.68 mm. Thus, 86% of women in the tibolone group and 93% in the E+NETA group had an endometrial thickness of less than 5 mm. CONCLUSIONS: Use of tibolone 2.5 mg daily for 1 year was associated with significantly less bleeding and spotting compared with daily continuous combined 2 mg estradiol and 1 mg norethisterone acetate in postmenopausal women in the presence of both minimal and nonprogressive increase of endometrial thickness associated with the two regimens.

Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy.

OBJECTIVE: To determine serum parameters reflective of androgen status in postmenopausal women using two types of hormone replacement therapy (HRT). DESIGN: Randomized, double-blind, prospective 1-year trial of two oral HRT regimens. SETTING: University hospital, department of obstetrics and gynecology, menopause clinic. PATIENT(S): 100 postmenopausal women > or = 45 years. INTERVENTION(S): Daily use of the progestogen tibolone (2.5 mg; n = 50) or continuous combined 17-beta-estradiol (2 mg) and norethindrone acetate (E+NA, 1 mg; n = 50). MAIN OUTCOME MEASURE(S): Measurements of total testosterone (total T), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), FSH, and sex-hormone-binding globulin (SHBG), and calculations of free testosterone (free T). Assessment of changes from baseline within and between groups after 6 and 12 months. RESULT(S): We found significant differences (% changes) in the tibolone group compared to baseline within the groups after both 6 and 12 months, respectively. Levels of free T doubled, total T decreased slightly, and SHBG decreased by half; DHEAS increased by approximately 20%; and FSH decreased. In the E+NA group, levels of free T, total T, androstenedione, and FSH all decreased, and SHBG increased. Pre-trial levels of DHEAS, A, and total T were significantly higher in the E+NA group. Between groups throughout the study, the changes from baseline were significant due to the different extent of FSH reduction, and opposite changes of free T, SHBG, and DHEAS. CONCLUSION(S): Both regimens modify plasma androgens, DHEAS, and SHBG differently. Tibolone decreased the levels of SHBG, and substantially increased free T and to a lesser extent increased DHEAS; this may reflect a modification of adrenal androgen production. Continuous combined estradiol and norethindrone acetate HRT suppressed the peripheral plasma androgens mediated by increased levels of SHBG.

Hormonal replacement regimens and bleeding.

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.

Long-term compliance of continuous combined estrogen and progestogen replacement in postmenopausal women.

The occurrence of uterine bleeding usually associated with hormonal replacement therapy is not acceptable for many women. Our objective was to review data on compliance and bleeding patterns in 70 postmenopausal women on oral replacement with estradiol 2 mg, estriol 1 mg, and norethisterone acetate 1 mg daily administered in a continuous combined fashion to avoid withdrawal bleeding. After 1 year, compliance was 97%, after 5 and 9 years 76% and 58%. The most common reason for discontinuation was spotting. Reproductive history, body weight and pretreatment estradiol and FSH concentrations were not different between the subgroups with bleeding-19%- and without bleeding-81%. The probability to maintain amenorrhoe on HRT did not increase with the length of the postmenopausal interval or weight. Endometrial histology revealed one case of a highly differentiated in situ adenocarcinoma of the endometrium. In the women with bleeding, induced serum estradiol levels were significantly and pretreatment SHBG-levels lower compared to the non-bleeders. Whether these findings may be significant for election of patients for continuous combined HRT remains to be determined. In conclusion, we demonstrate that adherence to this treatment regimen apparently provides a choice patients considering long-term HRT should be informed about. However, the lack of parameters to elect patients in conjunction with the problem of uterine bleeding does not permit the recommendation to regard continuous combined HRT as first line therapy for long-term HRT. Criteria need to be developed when to obtain an endometrial histology once uterine bleeding occurs, as the optimal surveillance of this mode of HRT is presently unknown.

Are the antioxidative effects of 17 beta-estradiol modified by concomitant administration of a progestin?

OBJECTIVE: Estrogens are known to exhibit antioxidative effects. At present little information exists on the influence of co-administered progestins upon this effect. Therefore we investigated the influence of levonorgestrel, a potent antiestrogenic progestin, on the inhibition of the low-density lipoprotein (LDL) oxidation by 17 beta-estradiol or 17 beta-estradiol valerate in vitro and ex vivo. METHODS: After isolation from blood, the in vitro oxidation of LDL was induced by copper ions and measured continuously by monitoring the formation of conjugated dienes. In 21 female ovariectomized White New Zealand rabbits the antioxidative action of 17 beta-estradiol alone or in combination with levonorgestrel after subcutaneous infusion for 3 days was determined using the copper-induced LDL-oxidation as an endpoint. Eleven postmenopausal women were exposed to sequential estrogen-progestin replacement therapy (day 1-21:2 mg estradiol valerate/day, day 10-21: 0.15 mg levonorgestrel/day). Blood samples were collected at three times: on day 1, on day 10, on day 22 (after the combination phase). The lag time of ex vivo oxidation of LDL, the plasma estradiol and estrone levels were estimated. RESULTS: In the chosen cell-free system, 17 beta-estradiol increased the lag time of the LDL-oxidation in a dose-dependent manner. Levonorgestrel showed neither pro-oxidative nor antioxidative effects when administered alone in different concentrations. Co-administration of different doses of levonorgestrel did not modify the antioxidative action of estrogen either. The two ex-vivo models confirmed these results. In rabbits the co-administered 19-nortestosterone derivative levonorgestrel did not impair or reverse the estradiol-dependent effect. In postmenopausal women the daily oral administration of levonorgestrel in conjunction with 17 beta-estradiol valerate did not diminish the antioxidative action of this estrogen given for the first 9 days. CONCLUSION: The antioxidative potential of estradiol and estradiol valerate is maintained in the presence of levonorgestrel.

Therapeutic value and long-term safety of pulsed estrogen therapy.

OBJECTIVES: To demonstrate equivalent efficacy for menopausal symptoms between Aerodiol nasal spray and reference oral estradiol therapy, and to investigate the endometrial safety and tolerability of Aerodiol in the long term. METHODS: The efficacy of Aerodiol 300 microg, once daily, was compared with oral estradiol 2 mg/day in a randomized, double-blind trial. A statistical test of noninferiority was performed on the mean absolute Kupperman index (KI) obtained after 14 and 23 weeks of the two treatments. Long-term safety was assessed in a 1-year open-label study. The initial Aerodiol dose was 300 microg/day, and was adjusted if required. Endometrial biopsies were obtained at inclusion and at the end of the trial and examined independently by two pathologists. RESULTS: In the equivalence trial, the KI improved similarly in the Aerodiol group (n=317) and the oral estradiol group (n=342). Aerodiol was shown statistically to be at least as effective as oral therapy (P<0.001), but the incidences of mastalgia and withdrawal bleeding were significantly lower in the Aerodiol group (P<0.01 and P<0.001, respectively). In the long-term safety trial (n=408), the rate of Aerodiol treatment continuation at 12 months was 85%, and there was no incidence of endometrial hyperplasia or cancer. Aerodiol dose adaptation was performed by 29% of women. CONCLUSIONS: Aerodiol was shown to have equivalent efficacy to reference oral estradiol therapy, but with better gynaecological acceptability. The endometrial safety of Aerodiol was confirmed in the long term, and the ability to adjust the dosage easily was of benefit to a substantial proportion of women.

Estrogen-progestogen replacement therapy in postmenopausal women--is 1 mg estradiolvalerate sufficient to maintain axial trabecular bone density?

An oral estrogen-progestogen replacement therapy consisting of 1 mg estradiolvalerate +2 mg estriol/day for 21 days in combination with 0.25 mg levonorgestrel/day for the last 10 days sequentially may be sufficient to maintain lumbar trabecular bone density in climacteric pre- and postmenopausal women as demonstrated by serial bone density measurements (single-energy quantitative computed tomography of the lumbar spine) in 7 individuals with longitudinal follow-up for up to 5 years. At present, only postmenopausal women with induced estradiol levels of at least > or = 220 pmol/l (> or = 60 pg/ml) provided by estrogen replacement therapies containing higher daily estradiol doses as the above described preparation have been shown to be protective against loss of trabecular bone at the lumbar spine. Preliminary pharmacokinetic results obtained from 14 postmenopausal women being treated with the low-dose estrogen-progestogen replacement demonstrated peak estradiol concentration of 120-160 pmol/l (32-43 pg/ml) 10 hours after oral ingestion, suggesting bone preserving properties by these considerably lower estradiol concentrations.

[Diagnostic value and interpretation of imaging bone densitometry based on quantitative CT]. / Aussagefähigkeit und Interpretation der bildgebenden Osteodensitometrie am Beispiel der quantitativen CT.

Quantitative CT of the axial skeleton (aQCT) may serve as an example of the evaluation and interpretation of bone densitometric data as it is the only state-of-the-art technique with valid longitudinal observations. The value of bone density measurements in interindividual cross sections refers to a grading derived from a representative reference population and provides an evaluation of fracture risk. The presence and rate of any bone loss can only be evaluated in an intraindividual longitudinal follow-up. Adequate follow-up for trabecular bone requires at least 3 to 5 years intervals to discriminate between different loss rates. Bone losses induced by steroid therapy or immobilisation may have faster kinetics apparent within months; bone density increase due to hormone substitution may be significant after one to two years. Morphological data allow critical evaluation of the quantitative measurements, eliminating false values and differentiating between rarefying and destructive osteopenia.

[The morphological analysis of the vertebral spongiosa in quantitative CT]. / Morphologische Analyse der Wirbelkörperspongiosa in der quantitativen CT.

The diagnostic ranking of trabecular morphology for the evaluation of osteoporosis in quantitative CT (QCT) is presented. 5 patterns of cancellous bone correlating with trabecular density may be discerned. However, these patterns may indicate osteoporotic changes in particular cases only, by confluent rarefactions if the density is still within the normal range. There is neither a predictive value for the degree of spontaneous or therapy-induced bone loss, nor for therapy response. The trabecular appearances remain unchanged in short term even under strong quantitative changes and are therefore of no value for follow-up.

[Estrogen substitution in the postmenopause--effect and compliance]. / Ostrogensubstitution in der Postmenopause--Wirkung und Compliance.

At least one of four women will suffer from osteoporosis with fractures of vertebrae, forearm or hip. Maintenance of bone mass is a crucial argument for long-term estrogen replacement for prophylaxis of osteoporosis. 2 mg estradiol or 0.625 mg conjugated estrogens orally or 50 to 100 micrograms estradiol percutaneously are equally sufficient for prevention of osteoporosis. The additional use of a progestogen in women with intact uterus may support the antiresorptive effects of estrogens. Improvement of patients' compliance-administered today by only 25% of postmenopausal women in Germany through sufficient information upon estrogen replacement therapy provided by the medical community is a rewarding task for physicians and scientists engaged in the field of menopause and prevention of osteoporosis.

[Basic principles of hormone replacement therapy in the postmenopause]. / Grundprinzipen der Hormonersatztherapie in der Postmenopause.

17 beta-estradiol, conjugated equine estrogens, esterified estrogens, and estriol constitute postmenopausal replacement therapy, all of which are in clinical use as oral preparations. Non-oral routes--matrix and reservoir patches, gel--were developed for estradiol, as was the intravaginal administration of estriol and estradiol. Daily doses of 1 mg estradiol(valerate) or 25 micrograms estradiol delivered via a patch or 0.5 mg gel or 0.3 mg conjugated equine estrogens are often sufficient to alleviate climacteric symptoms. Bone resorption may be effectively reduced and bone mineral density maintained by 1 mg estradiol or 25 micrograms transdermal estradiol. Maximal bone sparing dosages are 2 mg estradiol, 50 micrograms transdermal estradiol, 0.625 mg conjugated equine estrogens, and 1.25 mg estrone Estriol, predominantly used for the prevention and or treatment of urogenital symptoms, has no bone sparing effect at the doses in clinical use. Non-oral administration of estradiol may be superior in diabetic women and those with hypertriglyceridemia due to the different metabolism which does not mainly involve the hepatic first pass effect. Epidemiological data do not support any preference of oral versus non-oral routes of administration regarding side-effects such as venous thromboembolism. Progestogens--natural progesterone, derivatives structurally related to progesterone and testosterone, respectively--are necessary for endometrial protection. Sequential use of a progestogen for at least 10 days per month, preferably 12-14 days abolishes the increased incidence of endometrial hyperplasia which is likely to develop with unopposed use of estrogen. Observational studies do not suggest any superiority of a given progestogen regarding cardiovascular risk, prevention of osteoporosis, and cognitive function in postmenopausal women on estrogen replacement therapy. Tibolone, a derivative of norethindrone, is yet another option for replacement therapy. The recommended dose for treatment of climacteric symptoms and prevention of bone loss is 2.5 mg. Controlled clinical studies do not suggest that this compound is superior in achieving amenorrhea compared with continuous combined estrogen progestogen replacement therapy, as available data are inconsistent. In early postmenopause the sequential use of a progestogen in conjunction with an estrogen is the preferred treatment option. With advancing postmenopausal age either continuous combined replacement or tibolone may be choices in case withdrawal bleeding is no longer acceptable for women. However, there are no rigid age limit when to change treatments, the selection of which is largely influenced by the preference of the individual's acceptance of withdrawal bleeding.

Everything you always wanted to know about sex ... in flies.

'Everything you always wanted to know about sex' is a workshop organized as part of the annual Drosophila Research Conference of the Genetics Society of America. This workshop provides an intellectual venue for interaction among research groups that study sexual dimorphism from the molecular, evolutionary, genomic, and behavioral perspectives. The speakers summarize the key ideas behind their research for people working in other fields, outline unsolved questions, and offer their opinions about future directions. The 2010 workshop highlighted the power of the Drosophila model for understanding sexual dimorphism at levels ranging from cell biology and gene regulation to population genetics and genome evolution, and demonstrated the importance of cross-disciplinary interactions in the study of sex. In this respect, Drosophila sets a good example for research in other organisms, including humans and their mammalian relatives.