A direct comparison of women's perceptions and acceptability of micronised progesterone and medroxyprogesterone acetate in combination with transdermal oestradiol in the management of young postmenopausal women, under 45 years of age.

OBJECTIVE: To assess the acceptability and perception of postmenopausal women, to two different hormone replacement therapy regimens, in relation to the control of their symptoms and development of adverse effects. STUDY DESIGN: Prospectively recruited postmenopausal women, <45 years, were randomised to one of two treatment arms for 12-months: cyclical micronised progesterone or medroxyprogesterone acetate in combination with transdermal oestradiol. A self-reported questionnaire with matrix rating scales was completed and repeated after 3, 6 and 12-months. MAIN OUTCOME MEASURES: Symptom control and development of adverse effects. RESULTS: Seventy-one individuals were screened, with baseline data available for 67 subjects. A total of 190 questionnaires were returned. The most commonly reported symptoms were low energy levels, vasomotor symptoms and sexual dysfunction. The prevalence of adverse effects ranged between 57.89 and 87.50%, with a reduction seen in the transdermal oestradiol + micronised progesterone arm (73.91% at 3-months, decreasing to 57.89% at 12-months; p = 0.33), compared to the transdermal oestradiol + medroxyprogesterone acetate arm (76.92% at 3-months, increasing to 87.50% at 12-months; p = 0.69). The main reported adverse effects were bloating, weight change and psychological symptoms. A significant difference was documented between the groups after set intervals, with a greater proportion reporting breast tenderness after 3-months (p = 0.01), lower numbers reporting mood swings at 6-months (p = 0.01) and irritability at 12-months (p = 0.03) in the transdermal oestradiol + micronised progesterone arm compared to the transdermal oestradiol + medroxyprogesterone acetate arm. CONCLUSIONS: The acceptability of both regimens was high despite adverse effects, but tolerability of transdermal oestradiol combined with micronised progesterone appeared to be better with fewer women reporting psychological concerns.

Maximum Redshift of Gravitational Wave Merger Events.

Future generations of gravitational wave detectors will have the sensitivity to detect gravitational wave events at redshifts far beyond any detectable electromagnetic sources. We show that if the observed event rate is greater than one event per year at redshifts z≥40, then the probability distribution of primordial density fluctuations must be significantly non-Gaussian or the events originate from primordial black holes. The nature of the excess events can be determined from the redshift distribution of the merger rate.

Dynamics of Dwarf Galaxies Disfavor Stellar-Mass Black Holes as Dark Matter.

We study the effects of black hole dark matter on the dynamical evolution of stars in dwarf galaxies. We find that mass segregation leads to a depletion of stars in the center of dwarf galaxies and the appearance of a ring in the projected stellar surface density profile. Using Segue 1 as an example we show that current observations of the projected surface stellar density rule out at the 99.9% confidence level the possibility that more than 6% of the dark matter is composed of black holes with a mass of few tens of solar masses.

Indication of Gamma-Ray Emission from the Newly Discovered Dwarf Galaxy Reticulum II.

We present a search for γ-ray emission from the direction of the newly discovered dwarf galaxy Reticulum II. Using Fermi-LAT Collaboration data, we detect a signal that exceeds expected backgrounds between ∼2-10 GeV and is consistent with annihilation of dark matter for particle masses less than a few ×10^{2} GeV. Modeling the background as a Poisson process based on Fermi-LAT diffuse models, and taking into account trial factors, we detect emission with p value less than 9.8×10^{-5} (>3.7σ). An alternative, model-independent treatment of the background reduces the significance, raising the p value to 9.7×10^{-3} (2.3σ). Even in this case, however, Reticulum II has the most significant γ-ray signal of any known dwarf galaxy. If Reticulum II has a dark-matter halo that is similar to those inferred for other nearby dwarfs, the signal is consistent with the s-wave relic abundance cross section for annihilation.

Sperm donor recruitment, attitudes and provider practices--5 years after the removal of donor anonymity.

STUDY QUESTION: Has the change in donor anonymity legislation in UK affected the recruitment of men wanting to be sperm donors and also affected the attitudes of the practitioners who provide donor sperm treatment? SUMMARY ANSWER: We have performed fewer IUI and IVF treatments using donor sperm following the change in legislation in April 2005 than before. However, we have seen an overall increase in men wanting to donate their sperm, including a small increase in men from ethnic minorities. WHAT IS KNOWN ALREADY: Sweden, which removed donor anonymity in 1985, had an initial drop in men wanting to donate and then 10 years later started to have an increase. The Human Fertilisation and Embryology Authority (HFEA) and other studies in the UK have shown an overall downward trend, but have not been able to compare large time scales either side of the change in legislation. STUDY DESIGN, SIZE, DURATION: This was a retrospective descriptive study that looked at all men who approached the clinic between the years 2000 and 2010, i.e. 5 years either side of the change in legislation (April 2005). Overall, we had 24 men wanting to be donors prior to the rule change and 65 men after the rule change. We also investigated the total number of all treatments with donor sperm, and this included a total of 1004 donor sperm treatments prior to the change in legislation and 403 donor sperm treatments after the change in legislation. PARTICIPANTS, SETTING, METHODS: The study was set in an NHS IVF clinic in South East London. We compared the indicators of service provision, provider practices and donor attitudes, in the period between April 2000 and March 2005 (Group A) with those between April 2005 and March 2010 (Group B), i.e. 5 years either side of the change in legislation. MAIN RESULTS: There were 875 IUI treatments and 129 IVF or ICSI treatments in Group A and 325 IUI and 78 IVF/ICSI treatments in Group B with the use of donor sperm, of which, 11.9% (119 out of 1004) in Group A and 39.5% (159 out of 403) in Group B were with donor sperm recruited by our unit. The clinical pregnancy rate per cycle of treatment in Group A was (86 out of 875) 9.8% for IUI and (27 out of 129) 20.9% for IVF/ICSI and in Group B (32/325) 9.8% and (28 out of 78) 35.9%, respectively. There was a sharp yearly fall in donor sperm treatments from 2004. Twenty-four men were screened in Group A, of which 18 (75.0%) were recruited for long-term storage and 12 (50%) were registered as donors with the HFEA when the sperm was used, whereas in Group B, 65 men were screened, 53 (82.0%) were recruited and 24 (36.92%) were registered as donors. Six (24.0%) men in Group A failed in screening because of poor semen analysis when compared with 9 (13.8%) men in Group B. The majority of post-recruitment dropouts were because of loss of follow-up or withdrawal of consent. More donors in Group A were white (92.0 versus 77.0%) and born in UK (92.0 versus 68.0%) when compared with those in Group B. Donors in Group B were more likely to be single (46.0 versus 4.0%) and to have informed their relevant partner of donation (71.0 versus 54.0%) when compared with those in Group A. 83.0% of donors in Group A were heterosexual when compared with 69.0% in Group B. The primary reason for donating in both groups of potential donors was 'wanting to help' (46.0% 'altruistic donors' in Group A versus 72.0% in Group B). Fewer donors in Group B (37%) had specific restrictions about the use of their sperm when compared with 46.0% in Group A. LIMITATIONS, REASONS FOR CAUTION: As this was a retrospective study, there is a chance for the introduction of bias. WIDER IMPLICATIONS OF THE FINDINGS: We have shown that despite no active in-house recruitment procedures, we are managing to recruit more potential sperm donors after the change in UK legislation, and we are able to meet the demand for treatments with in-house recruited donor sperm that is a reassuring finding for donor sperm treatment services in the wider UK. FUNDING/COMPETING INTERESTS: No external funds were sought for this work. None of the authors have any competing interests to declare.

Large loop excision of transformation zone and cervical length in the prediction of spontaneous preterm delivery.

OBJECTIVES: To investigate the association between previous large loop excision of transformation zone (LLETZ) and risk for subsequent spontaneous preterm delivery (sPD) and whether this effect is reflected in the measurement of cervical length at mid-gestation. DESIGN AND SETTING: A secondary analysis of data from women recruited for clinical trials of interventions to prevent preterm labour. POPULATION: A total of 26,867 women with singleton pregnancies attending for routine antenatal care. METHODS: Transvaginal sonographic measurement of cervical length was carried out at 20(+0) to 24(+6) weeks. Logistic regression analysis was used to determine the significant predictors of sPD among maternal characteristics, obstetric history, previous history of LLETZ and cervical length. MAIN OUTCOME MEASURES: Spontaneous preterm delivery. RESULTS: In the 473 women who had undergone LLETZ, compared with the 25,772 without a history of LLETZ, the rate of sPD before 34 weeks of gestation was higher (3.4 versus 1.3%, P = 0.0002) and the median cervical length was shorter (32 mm versus 34 mm, P < 0.0001). Regression analysis demonstrated that in the prediction of sPD there were significant contributions from racial origin, cigarette smoking, previous preterm delivery and LLETZ and the detection rate of sPD was 29.8%, at a false-positive rate of 10%. However, after addition of cervical length, LLETZ did not remain a significant predictor in the model, which detected 52.6% of sPD, at a false-positive rate of 10%. CONCLUSIONS: LLETZ increases the risk of sPD, even after adjustment for maternal risk factors. The effect of a previous LLETZ on sPD in a subsequent pregnancy is reflected in the measurement of cervical length at mid-gestation.

Exclusion of canonical weakly interacting massive particles by joint analysis of Milky Way dwarf galaxies with data from the Fermi Gamma-Ray Space Telescope.

Dwarf spheroidal galaxies are known to be excellent targets for the detection of annihilating dark matter. We present new limits on the annihilation cross section of weakly interacting massive particles based on the joint analysis of seven Milky Way dwarfs using a frequentist Neyman construction and Pass 7 data from the Fermi Gamma-Ray Space Telescope. We exclude generic weakly interacting massive particle candidates annihilating into bb with a mass less than 40 GeV that reproduce the observed relic abundance. To within 95% systematic errors on the dark matter distribution within the dwarfs, the mass lower limit can be as low as 19 GeV or as high as 240 GeV. For annihilation into τ+ τ-, these limits become 19, 13, and 80 GeV, respectively.

Galactic substructure and energetic neutrinos from the sun and earth.

We consider the effects of Galactic substructure on energetic neutrinos from annihilation of weakly interacting massive particles that have been captured by the Sun and Earth. Substructure gives rise to a time-varying capture rate and thus to time variation in the annihilation rate and resulting energetic-neutrino flux. However, there may be a time lag between the capture and annihilation rates. The energetic-neutrino flux may then be determined by the density of dark matter in the Solar System's past trajectory, rather than the local density. The signature of such an effect may be sought in the ratio of the direct- to indirect-detection rates.

Contraception and medical gynaecology for HIV-positive women in a one-stop clinic.

HIV-positive women may be reluctant to attend gynaecology or family planning clinics for fear of divulging their condition. Therefore, a referral clinic was opened within the HIV clinic. Retrospective case-note reviews of 197 new patients revealed 109 with a variety of medical gynaecology conditions (menorrhagia being the commonest) and 88 sought contraception. The full range of contraceptives was used, including Mirena for the treatment of menorrhagia as well as contraception and the combined pill adjusted for interaction with liver enzyme-inducing antiretroviral drugs. The acceptance of contraceptive advice and gynaecological evaluation by the patients has resulted in improved reproductive health services for these HIV-positive women. In centres with large cohorts of HIV-positive women, this type of one-stop specialist clinic will be very effective in providing high-quality reproductive health care and hence, this type of clinic is recommended for such centres.

Outcome analysis of 4 years' follow-up of patients referred for colposcopy with one smear showing mild dyskaryosis.

OBJECTIVE: To assess the 4-year outcome of patients after one smear showing mild dyskaryosis with respect to smear regression rate, prevalence of cervical intraepithelial neoplasia (CIN) and the effect of age. METHODS: Retrospective analysis of patients diagnosed with initial mildly dyskaryotic smear during the year 2000 with a follow-up period of 48 months. These women had not had any previous abnormal smears. SETTINGS: Cytopathology Department and Colposcopy Unit, King's College Hospital, London, UK. RESULTS: We identified 524 patients of whom 375 patients with complete follow-up data are included. The age range was 19-67 years with a median of 29 years. There were 207 patients aged 35 years or less (55%). At 6 months, 258 smears were performed and 47.8% of them were negative (95% CI: 41.6-54.0%). The total number of negative follow-up smears in the first year was 198 out of a total of 397 smears performed (50%). This proportion has significantly increased between 1 and 4 years' follow-up to 67.5% (RR: 1.24; 95% CI: 1.14-1.35). Over the 4-year period, 791 smears were performed and 477 were negative (60.3%; 95% CI: 56.9-63.7%). Of the 477 negative smears there were only 61 smears (12.8%; 95% CI: 10-16%), in 54 patients (14%; 95% CI: 11-18%) that reverted back to low-grade cytological abnormality. In only one case the repeat smear showed high-grade abnormality after initial negative follow-up; however, on biopsy, histology showed CIN I. Out of the 375 patients, 70 required treatment with excisional biopsy (19%; 95% CI: 15.0-22.9%). Histology confirmed high-grade CIN in only 41 cases giving a prevalence of 11% (95% CI: 8.1-14.5%). There were no cases of microinvasive or invasive cancer detected. Age (< or =35 years versus >35 years) did not significantly affect either cytological or histological outcome. CONCLUSION: Sixty per cent of follow-up smears after initial mild dyskaryosis subsequently became negative; of them 87.2% remained negative over the 4 year follow-up. Treatment was only required in 19% of patients, with 11% prevalence of high-grade CIN. Age did not affect the outcome. These results are reassuring and indicate that colposcopic referral may not be necessary after only one mildly dyskaryotic smear.

A comparative study of glycodelin concentrations in uterine flushings in women with subseptate uteri, history of unexplained recurrent miscarriage and healthy controls.

OBJECTIVE: To compare the concentration of glycodelin in uterine flushing at the implantation window obtained from women with subseptate uteri, women with a history of recurrent first trimester miscarriage and fertile controls. STUDY DESIGN: Glycodelin concentration was assessed using Enzyme Linked Immunohistochemistry (ELISA) at The Early Pregnancy & Gynaecology Assessment Unit, King's College Hospital, London, England. Eight women with a subseptate uterus, 20 women with a history of unexplained recurrent first trimester miscarriage and 16 fertile controls had uterine cavity flushing, for glycodelin concentration, done 7 days after the luteinising hormone surge. RESULTS: Glycodelin concentrations in uterine flushing obtained from women with subseptate uteri (n=8) (median 32.9 ng/ml, range 17.1-52.4 ng/ml) and recurrent miscarriage (n=20) (median 26.8 ng/ml, range 9.7-78.5 ng/ml) were significantly lower than in the control group (n=16) (median 67.7 ng/ml, range 59.0-77.6 ng/ml) (chi(2)=19.565, p<0.001). CONCLUSION: Peri-implantation levels of glycodelin are lower in women at high risk of early pregnancy failure.

Proper motion of gamma rays from microhalo sources.

I discuss the prospects of detecting the smallest dark matter bound structures present in the Milky Way by searching for the proper motion of gamma-ray sources in the upcoming Gamma Ray Large Area Space Telescope all sky map. I show that for dark matter particle candidates that couple to photons the detection of at least one gamma-ray microhalo source with proper motion places a constraint on the couplings and mass of the dark matter particle.

Prospective evaluation of three different models for the pre-operative diagnosis of ovarian cancer.

OBJECTIVE: To test the accuracy of the risk of malignancy index, the revised risk of malignancy index and Tailor's regression model to diagnose malignancy in women with known adnexal masses. DESIGN: Prospective collaborative study. SETTING: Gynaecology Assessment Unit, Department of Obstetrics and Gynaecology, King's College Hospital, London. SAMPLE: Sixty-one women with known adnexal masses were examined pre-operatively. Women were recruited from three South London hospitals. METHODS: The demographic, biochemical and sonographic data recorded for each patient included: age; menopausal status; CA125 levels; tumour volume; ultrasound characteristics; and Doppler blood flow analysis (peak and mean blood velocities, the pulsatility and resistance indices). The diagnosis of malignancy was made for each woman using all three models and the results compared with the final histopathological diagnosis. RESULTS: Thirty-eight women had benign tumours and 23 had ovarian cancer. Women with malignant tumours were significantly older than those with benign masses. There were also significant differences in CA125 levels, locularity, presence of papillary proliferations and ascites between the two groups. Tailor's regression model achieved a 43% sensitivity and 92% specificity in the diagnosis of malignancy. This compared with a 74% sensitivity and 92% specificity with the risk of malignancy model, and a 74% sensitivity and 89% specificity with the revised risk of malignancy model. CONCLUSION: When applied prospectively all three diagnostic models performed less accurately than originally reported, despite clinical signs of malignancy being present in many cases. It is likely that their accuracy would be even less in a population of women in whom there was a substantial clinical uncertainty. Intra-tumoral blood velocity and CA125 levels were the best individual parameters for discrimination between benign and malignant tumours.

A comparison of 25 mg and 50 mg oestradiol implants in the control of climacteric symptoms following hysterectomy and bilateral salpingo-oophorectomy.

OBJECTIVES: 1. To compare the effects of 25 mg and 50 mg oestradiol implants on serum follicle stimulating hormone and oestradiol levels; and 2. to assess the relationship of the dose of oestradiol implant and serum oestradiol on the effectiveness and duration of climacteric symptom control. DESIGN: Randomised, double-blind investigation. PARTICIPANTS: Forty-four women, who had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy. METHODS: The women were randomised to receive either 25 mg (n = 20) or 50 mg (n = 24) oestradiol implants. Follow up consisted of prospective symptom enquiry and hormone assays. MAIN OUTCOME MEASURES: Primary: climacteric symptom control: duration and effectiveness; secondary: serum oestradiol and follicle stimulating hormone levels. RESULTS: Serum oestradiol was significantly higher and serum follicle stimulating hormone significantly lower after the fourth month of treatment in women receiving 50 mg implants. No significant difference in symptom control was noted in the two groups. The mean duration of symptom control was similar in the two groups: 5.9 months (SD 2.4) in those receiving 50 mg oestradiol and 5.6 months (SD 2.3) in those receiving 25 mg. CONCLUSION: The higher level, 50 mg oestradiol implants does not result in better control of symptoms nor in longer periods of symptom control compared with 25 mg oestradiol implants. In order to maximise compliance, 25 mg oestradiol implants should therefore be the treatment of choice for women with normal bone density seeking relief of climacteric symptoms.

Prospective evaluation of logistic regression models for the diagnosis of ovarian cancer.

OBJECTIVE: To test the accuracy of three logistic regression models in diagnosing malignancy in women with adnexal masses. METHODS: This was a prospective collaborative study. Women were recruited from three hospitals and all assessments were performed at the Gynaecology Ultrasound Unit, King's College Hospital. One hundred women with known adnexal masses were examined preoperatively. The demographic, biochemical, and sonographic data recorded for each patient included age, menopausal status, CA 125 levels, ultrasound morphology, and Doppler blood flow analysis. The diagnosis of malignancy was made for each woman using three logistic regression models previously described by Alcazar et al, Tailor et al, and Timmerman et al. Variables used in these models were then combined to form a new model. The results were compared with the final histopathologic diagnosis. RESULTS: Sixty-seven women had benign tumors and 33 had ovarian cancer. Women with malignant tumors were older than those with benign masses. There were significant differences in CA 125 levels, presence of papillary proliferations, and ascites between the two groups. The sensitivities and specificities achieved respectively by the models were as follows: 45% and 93% with Tailor et al's model, 9% and 99% with Alcazar et al's model, and 73% and 91% with Timmerman et al's model. There was no significant improvement over the performance of Timmerman et al's model and the new combined model. CONCLUSION: All models performed less well than originally reported. Combining the models did not lead to a significant improvement in performance. Larger sample sizes that incorporate all types of ovarian tumors are necessary to design more accurate diagnostic models.

The diagnostic value of endometrial thickness and volume measurements by three-dimensional ultrasound in patients with postmenopausal bleeding.

We compared endometrial thickness and volume in patients with postmenopausal bleeding, and examined the value of each parameter in differentiating between benign and malignant endometrial pathology. A total of 103 patients with a history of postmenopausal bleeding were recruited into the study. Patients who were taking hormone replacements therapy or other hormonal preparations with a known effect on the endometrium were excluded. Each patient underwent three-dimensional ultrasonography for the measurement of endometrial thickness and volume. In 97 cases both of these measurements were obtained and the results were compared to the histological diagnosis after endometrial biopsy or dilatation and curettage. Endometrial cancer was diagnosed in 11 patients. The mean endometrial thickness was 29.5 mm (SD 12.59) and the mean volume was 39.0 ml (SD 34.16). In the remaining 86 patients there were eight cases with endometrial hyperplasia and seven with endometrial polyps. The endometrial thickness and volume in patients with benign pathology was 15.64 mm (SD 5.26) and 5.47 ml (SD 6.32), respectively. In 71 patients with atrophic or normal endometrium the mean thickness and volume was 5.29 mm (SD 3.97) and 0.91 ml (SD 1.71), respectively. Receiver operating characteristic curves showed endometrial volume to be superior to endometrial thickness for the diagnosis of endometrial cancer. The optimal cut-off value of endometrial thickness for the diagnosis of cancer was 15 mm, with the test sensitivity of 83.3% and positive predictive value of 54.5%. With the cut-off level of 13 ml for endometrial volume measurement the sensitivity was 100% and the positive predictive value 91.7%. Both the thickness and volume were higher in patients with advanced and less differentiated cancers. The measurements of endometrial volume was superior to that of endometrial thickness as a diagnostic test for the detection of endometrial cancer in symptomatic postmenopausal women.

Bone loss after hysterectomy with ovarian conservation.

OBJECTIVE: To examine the long-term effects of hysterectomy with conservation of the ovaries on bone density of the lumbar spine and proximal femur. METHODS: A cross-sectional study of the bone density of 40 postmenopausal women who had undergone hysterectomy with ovarian conservation before menopause compared with a matched group of 40 women who had not had hysterectomy. The 40 women who had undergone hysterectomy were also compared with a control population, using multiple linear regression analysis. Bone density of the femoral neck and lumbar spine was measured by quantitative digital radiography. RESULTS: Bone density in the hysterectomy group was significantly reduced at the spine (P < .05) and at the femoral neck (P < .05) compared with the matched group. Comparisons of the hysterectomy group with the reference group demonstrated that in addition to significant reductions in bone density at the spine (P < .05) and hip (P < .05), bone density at the femoral neck (P < .05), trochanter (P < .05), Ward's triangle (P < .05), and the second (P < .05) and fourth (P < .05) lumbar vertebrae was also significantly less in the hysterectomy group. CONCLUSION: Premenopausal women who have hysterectomy will have significantly lower bone density than controls, despite conservation of both ovaries at the time of surgery.

Type III collagen content in the skin of postmenopausal women receiving oestradiol and testosterone implants.

OBJECTIVE: To investigate the effect of subcutaneous oestradiol and testosterone on the proportion of type III collagen in the skin of postmenopausal women. DESIGN: A cross sectional comparison. SETTING: Dulwich Hospital menopause clinic. SUBJECTS: Fourteen untreated women and 11 women who had received subcutaneous oestradiol and testosterone for a median 8.0 years (range 3-14). Ten of the untreated women received subcutaneous hormone implants and the effect on skin collagen was studied prospectively. MEASUREMENTS: The proportion of type III collagen in skin biopsies taken from the lateral aspect of the thigh. RESULTS: The median type III collagen content in the skin of the women who had received hormone replacement therapy (25.4%, range 21.4-30.2) was significantly higher (P < 0.01) than in the untreated women (19.6%, range 18.2-28.8). The proportion of type III collagen in the skin of 10 untreated women increased significantly (P < 0.01) from a median of 19.9% (range 18.2-23.9) to 22.4% (range 20.5-31.5) following 6 months of treatment with hormone implants. CONCLUSION: This study indicates an increase in the proportion of type III collagen in women receiving hormone replacement therapy.