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Background: During the menopausal transition, around 25% of women experience a particularly accelerated loss of bone mineral density. These so-called "fast bone losers" represent a group of patients with an increased risk of osteoporosis. The precise mechanisms underlying this extraordinary level of bone mass reduction have not yet been conclusively elucidated. The PeKnO study ( Perimenopausale Knochendichte und Ovulation ; Perimenopausal Bone Density and Ovulation) was a 2-year prospective study investigating menstrual cycle changes, hormonal levels, markers of bone metabolism, and changes in bone mineral density (BMD) in perimenopausal women. The PeKnO study specifically focused on the questions of when the maximum of bone loss occurs, whether the decreasing number of ovulatory cycles correlates with increased bone density loss, and which hormones play a role during these processes., Methods: Healthy women aged ≥45 years with menstrual cycles of ≤42 days and without any exogenous hormonal intake continually self-assessed the lengths of their menstrual cycles and the occurrence of LH peaks with the help of a commercially available electronic fertility monitoring device. At baseline and at 6, 12, 18, and 24 months, hormones (LH, FSH, 17β-estradiol, progesterone, cortisol) and markers of bone metabolism (bone-specific alkaline phosphatase (BAP), osteocalcin (OC), and CTX (C-terminal telopeptide) were assessed during the luteal phase. Trabecular bone density was measured in the lumbar spine (vertebrae L1 through L3) by means of quantitative computed tomography (QCT) at the beginning and at the end of the 2-year study period. Patients were divided into 3 groups according to the changes in bone mineral density (BMD) that occurred within the period of 2 years: group I with an increase in BMD, group II with a decrease in BMD of ≤7%, and group III with a decline in BMD of >7%. Women in the latter group were defined as fast bone losers., Results: From a total of 72 recruited patients with an average age of 48.1 (±2.4) at baseline, complete 2-year data were available from 49 participants. Over the course of 24 months, mean bone mineral density decreased by -4.26 (±4.65). In the same time period, the proportion of ovulatory cycles declined from 67% to 33%. The decrease in the ovulatory rate significantly correlated with an enhanced BMD loss (r = 0.68; p < 0.05). Twelve of the forty-nine participants (24.3%) showed a BMD loss of >7% and were identified as fast bone losers. Levels of the luteal phase hormones LH, FSH, 17β-estradiol, and progesterone were significantly different between the three groups., Conclusion: The PeKnO study confirms a marked decline of the ovulatory rate during perimenopause, which is associated with an increased bone density loss while estrogen levels are still adequate.

Objective: To assess whether progesterone (P4) or osteoblast P4 receptor-acting progestin (P) contributed to estrogen (E) therapy-related increased areal bone mineral density (BMD) in randomized controlled trials (RCT) with direct randomization to estrogen (ET) or estrogen-progestin (EPT) therapy., Methods: Systematic literature searches in biomedical databases identified RCT with direct randomization and parallel estrogen doses that measured spinal BMD change/year. Cyclic P4/P was included in this random effects meta-analysis only if for ≥ half the number of E-days., Results: Searches yielded 155 publications; five met inclusion criteria providing eight dose-parallel ET-EPT comparisons in 1058 women. Women averaged mid-50 years, ⟨five years into menopause and took conjugated equine E daily at 0.625 mg with/without 2.5 mg medroxyprogesterone acetate (MPA). The weighted mean EPT minus ET percentage difference in spinal BMD change was +0.68%/year (95% CI 0.38, 0.97%) (P=0.00001). This result was highly heterogeneous (I²=81%) but this may reflect the small number of studies., Conclusion: Estrogen with an osteoblast P4R-acting progestin (EPT) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET. These data have implications for management of vasomotor symptoms and potentially for osteoporosis treatment in menopausal women.

Background Some studies have already proposed an inverse association between vitamin D levels and breast density. As breast density is already considered an established risk factor for breast cancer, such a connection could offer a new starting point for the prevention of breast cancer. Material and Methods To investigate this suggested connection, a total of 412 pre- and 572 post-menopausal women for whom mammography was indicated were recruited into this cross-sectional study. In addition to a questionnaire-based interview on the patient's general and gynecological medical history, her eating habits and lifestyle, serum levels of 25-hydroxyvitamin D [25(OH)D], calcium, phosphate and creatinine were determined. Breast density was determined by mammography and categorized as 1 to 4 according to the ACR classification. In addition to performing descriptive analysis to get a better overview of the data, a number of multivariate regression models were developed to determine the impact of confounders and the connection between vitamin D and mammographic density. Results More than half of all participants had low levels of 25(OH)D (< 20 ng/ml) and only a small minority of women (5.7 %) had what are currently considered to be optimal serum levels of 25(OH)D of at least 30 ng/ml. The significant majority of the cohort had a medium mammographic density (n = 463 had ACR 2; n = 343 had ACR 3). Logistic regression analysis showed that lower 25(OH)D serum levels were associated significantly more often with high rather than medium breast density. This association remained, even after adjusting for other factors which influence breast density such as age, BMI and menopausal status (p = 0.032 for ACR 4 vs. ACR 2; p = 0.028 for ACR 4 vs. ACR 3). When the same analysis was done separately for pre-menopausal and post-menopausal women, BMI in both groups was found to be inversely correlated with breast density and this inverse correlation was highly significant. In post-menopausal women, age was found to be similarly correlated while 25(OH)D did not appear to be associated with ACR. In pre-menopausal women the opposite was the case: although there was no correlation between age and breast density, higher vitamin D levels tended to be associated with lower breast density (p = 0.06 for ACR 2 vs. ACR 4) in this smaller sample (n = 412). When vitamin D-rich food and food supplements were also taken into account, regular intake of vitamin D preparations was associated with lower breast density; this association achieved borderline statistical significance (p = 0.05 for ACR 3 vs. ACR 4). When the analysis also took menopausal status into account, the breast density of pre-menopausal women was lower following regular vitamin D intake and this lower breast density of pre-menopausal women was statistically highly significant (p < 0.001 for ACR 1 and ACR 2 vs. ACR 4, respectively). This effect was not found in post-menopausal women. Frequent intake of vitamin D-containing nutrition had no significant impact on ACR in either of the groups. Conclusion These results reinforce the assumption previously proposed by several authors that higher levels of 25(OH)D pre-menopause and vitamin D substitution are associated with lower breast density and could reduce the risk of breast cancer. The findings did not confirm any post-menopausal association between vitamin D and mammographic breast density.

Introduction: Pleiotropic immune-modulatory and anti-proliferative effects of vitamin D and hopes to stop cancerogenesis have led to an increased interest in possible reduction of breast cancer with higher vitamin D levels. Mammographic density is an established risk factor for breast cancer risk, and its association with serum vitamin D is complex, as recent studies have shown. Patients and Methods: In this cross-sectional study, 1103 participants were recruited in the breast diagnostic unit of the Klinikum rechts der Isar, TU Munich. A standardised questionnaire and blood samples for 25-OH-vitamin D were taken on the day of mammography. Histologic results of biopsies in suspicious mammographies were documented. Results: In the 1090 data-sets analysed, vitamin D-deficiency was common among women under 40. Highest vitamin D values were observed in participants aged 60-69 years, but average values for all age cohorts were below 20 ng/ml of vitamin D. 15.6 % of all participants had very low vitamin D values (< 10 ng/ml), 51.3 % were vitamin D-deficient (10-19 ng/ml) and only 5.7 % were above 30 ng/ml, i.e. showed sufficient vitamin D. Patients with malignant results had vitamin D < 10 ng/ml more often (16.9 %; p = 0.61), and only 3.4 % in this group had sufficient vitamin D supply (> 30 ng/ml). There were no significant differences in vitamin D-levels between density groups according to the American College of Radiology (ACR) criteria. Conclusion: Vitamin D values were lower than in comparable US women. Up to now, there is no direct clinical evidence for a relationship between the risk for breast cancer and a specific vitamin D value.

Introduction: Several authors have linked subclinical ovulatory disturbances in normal length menstrual cycles to premenopausal fracture risk and bone changes. This study systematically examined the influence of ovulation and anovulation on the bone metabolism of premenopausal women. Participants and Methods: In 176 cycles in healthy premenopausal women, FSH, 17β-estradiol (E2) and progesterone (P4) as well as bone alkalic phosphatase (BAP), pyridinoline (PYD) and C-terminal crosslinks (CTX) were measured during the follicular and during the luteal phase. The probability and timing of ovulation was self-assessed by a monitoring device. In addition, bone density of the lumbar spine was measured by quantitative computed tomography (QCT) at baseline and at the end of the study. Analysis was restricted to blood samples taken more than three days before the following menstruation. Results: 118 cycles out of the 176 collected cycles were complete with blood samples taken within the correct time interval. Of these, 56.8 % were ovulatory by two criteria (ovulation symbol shown on the monitor display and LP progesterone > 6 ng/ml), 33.1 % were possibly ovulatory by one criterion (ovulation symbol shown on the monitor display or LP progesterone > 6 ng/ml), and 10.2 % were anovulatory by both criteria). Ovulation in the previous cycle and in the same cycle did not significantly influence the mean absolute concentrations of the bone markers. However, bone formation (BAP) was higher in the luteal phase of ovulatory cycles than in anovulatory cycles (n. s.) and the relative changes within one cycle were significantly different for bone resorption (CTX) during ovulatory vs. anovulatory cycles (p < 0.01). In 68 pairs of cycles following each other directly, both ovulation in the previous cycle and ovulation in the present cycle influenced CTX, but not the differences of other bone markers. Conclusion: Ovulatory cycles reduce bone resorption in their luteal phase and that of the following cycle. The interaction between ovulation and bone metabolism is complex. Since anovulation may occur in low estrogen states such as pre-anorexic dietary restraint, as well as with high estrogenic circumstances e.g. from functional perimenopausal ovarian cysts, the association with bone changes has been variable in the literature. Accumulating physiological and clinical evidence however point towards a role for ovulation in enhancing bone formation and limiting bone resorption.

Introduction: The impact of pregnancy and parenthood on the long-term course of PCOS (polycystic ovary syndrome is still not known. The LIPCOS study (Lifestyle Intervention for Patients with Polycystic Ovary Syndrome [PCOS] - using the example of pregnancy and parenthood) systematically investigates long-term changes in PCOS symptoms. Method and Patients: The LIPCOS pilot study sent out a questionnaire to 403 patients who had presented with oligomenorrhea between 1991 and 2002. The prospective LIPCOS main study systematically investigated 64 women using structured interviews about lifestyle changes in the last 10 years, created a detailed hormone profile of these women and carried out vaginal ultrasound to calculate ovarian score. Results: Ovarian volume and ovarian score were not significantly lower for women with children (n = 25) compared to women with PCOS who had not had children (n = 39; p = 0.226). More women with children than women who did not have children currently reported a regular daily lifestyle, and the difference was statistically significant (92 % [n = 23/25] vs. 61.5 % [n = 24/39]; p = 0.009). Ten years ago or before the birth of their first child, respectively, no such difference was found between both groups (52 vs. 51.3 %). Over the last 10 years, women with children were more likely to have shorter cycles compared to women without children (p = 0.441). 88 % of women with children compared to 69.2 % of women without children reported that currently they had a "healthy diet" (p = 0.130). Serum testosterone levels were slightly lower for women with children (67.6 % of the upper limits of normal ranges) compared to women without children (80 % of the upper limits of normal ranges), but because of the small subgroup sizes the difference was not statistically significant (p = 0.106). Conclusion: The LIPCOS study shows for the first time that pregnancy and parenthood may have an impact on the long-term course of PCOS. Women with children reported shorter cycles and had lower testosterone levels compared to women without children.

Background: The German statutory health insurance (GKV) reimburses all health care services that are deemed sufficient, appropriate, and efficient. According to the German Medical Association (BÄK), individual health services (IGeL) are services that are not under liability of the GKV, medically necessary or recommendable or at least justifiable. They have to be explicitly requested by the patient and have to be paid out of pocket., Research Questions: The following questions regarding IGeL in the outpatient health care of GKV insurants are addressed in the present report: What is the empirical evidence regarding offers, utilization, practice, acceptance, and the relation between physician and patient, as well as the economic relevance of IGeL?What ethical, social, and legal aspects are related to IGeL? FOR TWO OF THE MOST COMMON IGEL, THE SCREENING FOR GLAUCOMA AND THE SCREENING FOR OVARIAN AND ENDOMETRIAL CANCER BY VAGINAL ULTRASOUND (VUS), THE FOLLOWING QUESTIONS ARE ADDRESSED: What is the evidence for the clinical effectiveness?Are there sub-populations for whom screening might be beneficial?, Methods: The evaluation is divided into two parts. For the first part a systematic literature review of primary studies and publications concerning ethical, social and legal aspects is performed. In the second part, rapid assessments of the clinical effectiveness for the two examples, glaucoma and VUS screening, are prepared. Therefore, in a first step, HTA-reports and systematic reviews are searched, followed by a search for original studies published after the end of the research period of the most recent HTA-report included., Results: 29 studies were included for the first question. Between 19 and 53% of GKV members receive IGeL offers, of which three-quarters are realised. 16 to 19% of the insurants ask actively for IGeL. Intraocular tension measurement is the most common single IGeL service, accounting for up to 40% of the offers. It is followed by ultrasound assessments with up to 25% of the offers. Cancer screening and blood or laboratory services are also frequent and represent a major proportion of the demand. The ethical, social, and legal aspects discussed in the context of IGeL concern eight subject areas: autonomous patient decisions versus obtrusion,commercialization of medicine, duty of patient information, benefit, evidence, and (quality) control, role and relation of physicians and patients,relation to the GKV, social inequality,formally correct performance. For glaucoma screening, no randomized controlled trial (RCT) is identified that shows a patient relevant benefit. For VUS three RCT are included. However, they do not yet present mortality data concerning screened and non-screened persons. VUS screening shows a high degree of over-diagnosis in turn leading to invasive interventions. To diagnose one invasive carcinoma, 30 to 35 surgical procedures are necessary., Conclusion: IGeL are a relevant factor in the German statutory health care system. To provide more transparency, the requests for evidence-based and independent patient information should be considered. Whether official positive and negative-lists could be an appropriate instrument to give guidance to patients and physicians, should be examined. Generally, IGeL must be seen in the broader context of the discussions about the future design and development of the German health care system.