Folic acid supplementation in postmenopausal women with hot flushes: phase III randomised double-blind placebo-controlled trial.

OBJECTIVE: To assess whether folic acid supplementation ameliorates hot flushes. DESIGN: Double-blind, placebo-controlled randomised trial. SETTING: Nine hospitals in England. POPULATION: Postmenopausal women experiencing ≥50 hot flushes weekly. METHODS: Women (n = 164) were randomly assigned in a 1:1 ratio to receive folic acid 5 mg tablet or placebo daily for 12 weeks. Participants recorded frequency and severity of hot flushes in a Sloan Diary daily and completed Greene Climacteric and Utian Quality of Life (UQoL) Scales at 4-week intervals. MAIN OUTCOME MEASURES: The change in daily Hot Flush Score at week 12 from randomisation based on Sloan Diary Composite Score B calculation. RESULTS: Data of 143 (87%) women were available for the primary outcome. The mean change (SD) in Hot Flush Score at week 12 was -6.98 (10.30) and -4.57 (9.46) for folic acid and placebo group, respectively. The difference between groups in the mean change was -2.41 (95% CI -5.68 to 0.87) (P = 0.149) and in the adjusted mean change -2.61 (95% CI -5.72 to 0.49) (P = 0.098). Analysis of secondary outcomes indicated an increased benefit in the folic acid group regarding changes in total and emotional UQoL scores at week 8 when compared with placebo. The difference in the mean change from baseline was 5.22 (95% CI 1.16-9.28) and 1.88 (95% CI 0.23-3.52) for total and emotional score, respectively. CONCLUSIONS: The study was not able to demonstrate that folic acid had a statistically significant greater benefit in reducing Hot Flush Score over 12 weeks in postmenopausal women when compared with placebo. TWEETABLE ABSTRACT: Folic acid may ameliorate hot flushes in postmenopausal women but confirmation is required from a larger study.

Microsatellite variation of ESR1, ESR2, and AR in Serbian women with primary ovarian insufficiency.

OBJECTIVE: This study aimed to investigate the potential role of microsatellite polymorphisms of the estrogen receptor alpha gene (ESR1) TA repeat, estrogen receptor beta gene (ESR2) CA repeat, and androgen receptor gene (AR) CAG and GGN repeats among Serbian women with primary ovarian insufficiency (POI). These microsatellites have been reported to be associated with POI in different racial/ethnic populations. METHODS: A cohort of 196 POI cases matched with 544 fertile controls was recruited by the Institute for Endocrinology, Diabetes and Metabolic Disorders of Serbia between 2007 and 2010. DNA was extracted from saliva. The four microsatellites were genotyped using a PCR-based assay to determine the repeat lengths. RESULTS: POI patients carried shorter repeat lengths of ESR2 (CA)n than controls (P = 0.034), but the difference was small. ESR1 (TA)n was on the borderline of statistical differences between groups (P = 0.059). AR (CAG)n and (GGN)n showed no association with POI. CONCLUSIONS: We cautiously conclude that microsatellite polymorphisms of gonadal steroid receptor genes might contribute to the genetic basis of POI in Serbian women, but a larger-scale study and family-based studies are warranted to validate our findings even though the sample size in this study is larger than any previously published in this field.

Lack of association between ESR1 gene polymorphisms and premature ovarian failure in Serbian women.

OBJECTIVE: It has previously been reported that estrogen receptor-alpha (ERα) gene (ESR1: estrogen receptor 1) polymorphisms are associated with premature ovarian failure (POF). The aim of this study was to investigate whether these genetic polymorphisms of ESR1 are associated with POF in Serbian women. METHODS: A series of 197 POF cases matched with 547 fertile controls was recruited by the Institute for Endocrinology, Diabetes and Metabolic Disorders of Serbia between 2007 and 2010. Genomic DNA was extracted from saliva using Oragene® DNA sample collection kits. Two single-nucleotide polymorphisms (SNPs), PvuII and XbaI, in ESR1 were genotyped by dynamic allele-specific hybridization. Haplotype analyses were performed with the restriction fragment length polymorphism method. SNP and haplotype effects were analyzed by logistic regression models. RESULTS: No significant difference was found in the distribution of ESR1 PvuII and XbaI polymorphisms or haplotypes between the POF and control groups. CONCLUSION: The two ESR1 SNPs, PvuII and XbaI, are not commonly associated with POF in Serbian women and may not contribute to the genetic basis of the condition.

Therapeutic options for postmenopausal female sexual dysfunction.

BACKGROUND: Female sexual dysfunction (FSD) is a multidimensional problem combining biological, psychological and interpersonal elements of multiple etiologies. Menopause-related sexual dysfunction may not be reversible without therapy. Hormonal deficiency does not usually decrease in severity over time. Many options are available for the successful treatment of postmenopausal FSD. OBJECTIVE: To review the pharmacological and non-pharmacological therapies available for postmenopausal FSD, focusing on practical recommendations for managing postmenopausal women with sexual complaints, through a literature review of the most relevant publications in this field. PSYCHOSOCIAL THERAPY: This type of therapy (basic counselling, physiotherapy and psychosexual intervention) is considered an adaptable step-by-step approach for diagnostic and therapeutic strategies, normally combined with biomedical interventions to provide optimal outcomes. PHARMACOLOGICAL THERAPY: For postmenopausal FSD, many interventional options are now available, including hormonal therapies such as estrogens, testosterone, combined estrogen/testosterone, tibolone and dehydroepiandrosterone. CONCLUSIONS: Menopause and its transition represent significant risk factors for the development of sexual dysfunction. FSD impacts greatly on a patient's quality of life. Consequently, it is receiving more attention thanks to the development of effective treatments. Non-pharmacological approaches should be used first, focusing on lifestyle and psychosexual therapy. If required, proven effective hormonal and non-hormonal therapeutic options are available.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study.

OBJECTIVE: To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 microg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). METHODS: A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. RESULTS: The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. CONCLUSIONS: TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Immunolocalisation of oestrogen receptor beta in human tissues.

Oestrogens exert their actions via specific nuclear protein receptors that are members of the steroid/thyroid receptor superfamily of transcription factors. Recently, a second oestrogen receptor (ERbeta) has been cloned, and using reverse transcription-PCR and immunohistochemistry it has been shown to have a wide tissue distribution in the rat that is distinct from the classical oestrogen receptor, ERalpha. Using commercial polyclonal antisera against peptides specific to human ERbeta, we have determined the sites of ERbeta expression in archival and formalin-fixed human tissue and compared its expression with that of ERalpha. ERbeta was localised to the cell nuclei of a wide range of normal adult human tissues including ovary, Fallopian tube, uterus, lung, kidney, brain, heart, prostate and testis. In the ovary, ERbeta was present in multiple cell types including granulosa cells in small, medium and large follicles, theca and corpora lutea, whereas ERalpha was weakly expressed in the nuclei of granulosa cells, but not in the theca nor in the copora lutea. In the endometrium, both ERalpha and ERbeta were observed in luminal epithelial cells and in the nuclei of stromal cells but, significantly, ERbeta was weak or absent from endometrial glandular epithelia. Epithelial cells in most male tissues including the prostate, the urothelium and muscle layers of the bladder, and Sertoli cells in the testis, were also immunopositive for ERbeta. Significant ERbeta immunoreactivity was detected in most areas of the brain, with the exception of the hippocampus - a tissue that stained positively for ERalpha. In conclusion, the almost ubiquitous immunohistochemical localisation of ERbeta indicates that ERbeta may play a major role in the mediation of oestrogen action. The differential expression of ERalpha and ERbeta in some of these tissues suggests a more complex control mechanism in oestrogenic potential than originally envisioned.

Identification of a cycle-modulated 200-kDa endometrial antigen by a monoclonal antibody LDS60.

We have developed a mouse monoclonal antibody, LDS60, against a cycle-dependent antigen by immunising (MF1 x BALB/c)F1 mice with a human endometrial membrane preparation. In formalin fixed paraffin embedded sections, LDS60 identified an epithelial specific antigen which exhibited a specific pattern of expression during the menstrual cycle. It was only occasionally expressed during the proliferative phase. During the early-secretory phase, there was intracytoplasmic staining in about half of the glands examined. This was in the form of small microvesicles, either near the base of the cell or supranuclear. In the mid-secretory phase the same proportion of glands exhibited staining in the form of micro-vesicles that were noted to accumulate nearer to the cell apices. In the late-secretory phase, there was no intracytoplasmic staining and the antigen was localised to the luminal border of the glandular epithelium and some staining appeared within the gland lumen of approximately 20% of glands. It is also diffusely expressed in some mucous secreting cells in the tongue, stomach and colon, as well as lung pneumocytes. The antigen has a molecular weight of approximately 200 kDa as identified by immunoblotting. This antigen exhibits similarities to MUC-1 which is involved in uterine receptivity and could therefore have a similar role. Its cycle modulation suggests that it could be used to monitor the uterine response to steroids.

Trimegestone: expanding therapeutic choices for the treatment of the menopause.

UNLABELLED: Trimegestone is a novel norpregnane progestin, which has a potent progesterone receptor and very low androgen receptor affinities but no detectable affinity to oestrogen receptor. Trimegestone has been developed for use in conjunction with oestrogen for postmenopausal hormone replacement therapy (HRT). The dose of trimegestone required for endometrial safety was optimised in a dose ranging study. Oral trimegestone was administered at 0.05, 0.1, 0.25 and 0.5 mg/day, days 15 - 28 along with continuous oral micronised oestradiol at 2 mg daily. The majority of women in the four dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle. The incidence of pre-menstrual tension-like symptoms was low and did not differ between the four dose groups. After 6 months of treatment, the bleeding pattern showed a clear dose-dependent modulation such that the higher the dose of trimegestone administered the more predictable was the day of onset of bleeding and the shorter and lighter the bleeding episodes became. This was further confirmed in another study comparing trimegestone in 0.5 and 0.25 mg doses to norethisterone acetate, where women on the 0.5 mg dose experienced more favourable bleeding pattern compared with the lower dose of 0.25 mg or to norethisterone acetate. In the dose ranging study, 96% of endometrial specimens obtained at the end of the study had secretory changes. The lipoprotein profile measured at baseline, 3 and 6 months during the dose ranging study confirmed the fact that trimegestone, irrespective of the dose, did not negate the beneficial effects of oestrogen on lipids. CONCLUSION: trimegestone is an effective and well-tolerated new progestin, which does not negate the beneficial effects of oestrogen on lipids.

Sex hormone status and bone metabolism in men with Crohn's disease.

BACKGROUND: Men with Crohn's disease (CD) are at risk of osteoporosis, but the factors contributing to low bone mineral density and its optimum treatment have not been established. AIM: To investigate the sex hormone status of men with CD, and to establish the influence of sex hormones on their bone metabolism. METHODS: Bone density was measured by dual energy X-ray absorptiometry at the hip and lumbar spine in 48 men with CD. Total serum testosterone and gonadotrophins were measured in all subjects and the free androgen index calculated in men with low or borderline total testosterone. Serum osteocalcin, pro-collagen carboxy-terminal peptide, bone specific alkaline phosphatase and urinary deoxypyridinoline were measured as markers of bone turnover. RESULTS: Eight (17%) men had osteoporosis, and a further 14 (29%) had osteopenia. Three (6%) men had a low free androgen index and normal gonadotrophins consistent with secondary hypogonadism, two of whom had osteopenia of the hip and spine. Age (P = 0.002) and small bowel Crohn's disease (P = 0.02) were the only independent predictors of serum testosterone. There was a significant association between total testosterone and osteocalcin (r = 0.53, 95%, CI: 0.29-0.71, P = 0.0001) which was independent of age and current steroid use (P = 0.0001). CONCLUSIONS: Previously undiagnosed hypogonadism is an uncommon cause of low bone density in men with CD. The independent association between testosterone and the bone formation marker osteocalcin suggests sex hormone status influences bone metabolism in men with CD. The results suggest testosterone replacement might be effective treatment for some men with osteoporosis and Crohn's disease.

Increased bone resorption in patients with Crohn's disease.

BACKGROUND: Patients with Crohn's disease are at risk of osteoporosis and premature fracture. However, the pathophysiology underlying bone loss remains poorly understood and the optimum treatment has not been established. AIM: To investigate mechanisms of bone loss in Crohn's disease using biochemical markers of bone turnover. METHODS: Bone mineral density was measured at the hip and spine using dual-energy X-ray absorptiometry in 117 patients (48 male) with Crohn's disease. Bone turnover was assessed by measuring serum osteocalcin (BGP), pro-collagen carboxy-terminal propeptide (PICP), bone specific alkaline phosphatase (BALP) and urinary deoxypyridinoline (DPD); and compared to age-matched healthy controls (n = 28). RESULTS: Bone mineral density was reduced (z-score < -1) in 48 (41%) patients with Crohn's disease. Mean values for bone formation markers in patients with Crohn's disease were all within the normal reference range (BGP 8.92 (+/- 3.23) ng/mL (normal range 3.4-10.0), BALP 17.6 (+/- 12.6) U/L (normal range 11.6-43.3), PICP 95.1 (+/- 46.5) ng/mL (normal range 69-163)) and were not significantly different to the control population. However, mean urinary DPD was significantly higher in patients with Crohn's disease compared to healthy controls (10.97 (+/- 9.22) nM DPD/mM creatinine vs. 5.02 (+/- 1.03) nM DPD/mM creatinine, difference in means = 5.95, 95% CI: -9.6 to -2.3, P = 0.00001) and compared to the UK reference range DPD levels were increased in 74 (63%) patients. CONCLUSIONS: Bone resorption as evidenced by urinary DPD was frequently increased in patients with Crohn's disease and was significantly higher than in an age-matched control population. The high levels of urinary DPD suggest increased bone collagen degradation may contribute to osteoporosis in patients with Crohn's disease. These results suggest anti-resorptive agents such as the bisphosphonates may be effective treatment for osteoporosis in Crohn's disease.

The Leicester Endometrial Needle Sampler: a novel device for endometrial and myometrial junctional zone biopsy.

A 48-cm-long, fine (16 gauge) needle was purpose-built to our design for full-thickness endometrial sampling. It is driven by a high-speed cutting device that has a two-step action-loaded spring, and is adjusted to a penetration depth of 16 mm. Pain and tolerance were assessed on a visual analogue scale. The histologic diagnosis obtained by this device, the Leicester Endometrial Needle Sampler, was compared with that of Pipelle endometrial sampling in 40 patients at the end of panoramic hysteroscopy under local anesthesia. The patients' mean age was 51 years (range 39-60) and the mean parity was 2.4 (range 0-6). The mean (+/-standard deviation) pain score was 3.7 +/- 2.2 and the mean tolerability score was 4.4 +/- 3.6. The technique helped to procure a full-thickness endometrial biopsy in all cases, from targeted areas including the myometrial junctional zone, with 100% efficiency.

Differing responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapy.

OBJECTIVE: To examine the effects of oral and transdermal estrogen replacement therapy (ERT) on ambulatory 24-hour blood pressure (BP) recordings. METHODS: In a nonrandomized, prospective study, 90 normotensive, oophorectomized women, ages 30-59 years, underwent ambulatory 24-hour BP measurements at study entry and after 3 and 6 months of either oral (n = 50) or transdermal (n = 40) ERT. RESULTS: In the women receiving transdermal estrogen, we observed a change in mean nighttime systolic BP of -4.2 mmHg (95% confidence interval [CI] -7.7, -0.7; P = .039) after 6 months, treatment. There was a change in mean daytime diastolic BP after 3 months (-3.3 mmHg; 95% CI -5.5, -0.9; P = .016) and 6 months (-4 mmHg; 95% CI-6.8, -1.2; P = .014), and in mean nighttime diastolic BP after 3 months (-3.8 mmHg; 95% CI -6.6, -0.9; P = .027) and 6 months (-4.4 mmHg; 95% CI -7.1, -1.7; P = .005). No significant BP changes were observed in the women taking oral estrogen. Although the statistical power to detect a change of 4 mmHg at the 5% significance level was 90% for diastolic BP, it was weaker for systolic BP (63%) in this group. However, in more than one-third of the women receiving either treatment, a statistically significant increase in BP was observed. CONCLUSIONS: Transdermal ERT was associated with a reduction in mean ambulatory BP, whereas oral treatment did not alter BP. Although the overall effect of estrogen was to lower BP, individual responses were variable, and BP increased in more than one-third of the women on either treatment. Therefore, long-term monitoring of ambulatory measurements may be required.

Continuous combined hormone replacement therapy compared with tibolone.

OBJECTIVE: To compare relief of vasomotor symptoms, changes in lipoproteins, and bleeding patterns in postmenopausal women receiving either continuous combined hormone replacement therapy (HRT) of estradiol valerate and norethisterone or tibolone 2.5 mg/day. METHODS: In a multicenter, randomized, open-label study, 235 postmenopausal women received one of the above-mentioned treatments. Fasting lipoproteins were measured at baseline and at 3, 6, and 12 months. At each visit, participants completed Greene climacteric questionnaires and recorded any bleeding episodes. Data are presented as mean +/- standard deviation if normally distributed, median and interquartile range if non-normally distributed, or as frequency count. For menopausal symptoms and diary card data, the differences were tested by Wilcoxon rank-sum test. RESULTS: One hundred sixteen women received continuous combined HRT and 119 women received tibolone; 72 and 76 women, respectively, completed 12 months of therapy. Both treatments effectively relieved vasomotor symptoms and reduced serum total cholesterol. Continuous combined HRT, but not tibolone, significantly reduced low-density lipoprotein levels. Both treatments reduced high-density lipoprotein levels, but the effect was more profound with tibolone. The initial bleeding score was higher for women taking continuous combined HRT; however, by the end of the study, the percentages of amenorrheal women were comparable. Endometrial histology was similar for both treatments at the end of the study, although two cases of proliferative endometrium were found in the tibolone group. CONCLUSION: Estradiol valerate-norethisterone continuous combined HRT controls symptoms and is associated with a safe lipid profile.

Abnormal uterine bleeding on hormone replacement: the importance of intrauterine structural abnormalities.

OBJECTIVE: To examine the importance of submucous myomas and endometrial polyps before and after menopause and in abnormal withdrawal bleeding on hormone replacement therapy (HRT). METHODS: Between May 1991 and May 1993, women presenting with abnormal withdrawal bleeding on HRT (n = 106), menstrual problems in pre-menopause (n = 92), or postmenopausal bleeding (n = 33) underwent diagnostic outpatient hysteroscopy for the presence of intrauterine structural abnormalities. The findings were compared with a control group of post- and perimenopausal women without bleeding problems (n = 183). RESULTS: When compared with women who had normal uterine cavities, the presence of submucous myomas was associated with a threefold increase in the risk of abnormal menstrual bleeding in premenopausal women (odds ratio [OR] 3.34, 95% confidence interval [CI] 1.77-6.43; P < .001) and a twofold increase in the risk of abnormal withdrawal bleeding in post- and perimenopausal women (OR 2.4, 95% CI 1.25-4.53; P = .004). This did not seem to be related to the number of myomas detected. The frequency of endometrial polyps was not found to be significantly higher in women who had menstrual disorders or abnormal withdrawal bleeding on HRT. Postmenopausal bleeding without hormonal stimulation was not significantly associated with submucous myomas or polyps. CONCLUSION: As increasingly more women request HRT, bleeding problems presenting pre-menopause can no longer be expected to resolve "naturally" after menopause. In the presence of submucous myomas, these women will continue to have a higher risk of abnormal withdrawal bleeding when treated with hormone replacement, whereas endometrial polyps are not associated with an increased bleeding risk. Hysteroscopic assessment of the uterine cavity and subsequent counseling as to the risk of heavy or prolonged bleeding will be helpful in their future management and may improve compliance.

Long-term hormone implant therapy--hormonal and clinical effects.

Long-term effects of hormone implants (estradiol or estradiol plus testosterone) were examined in 75 menopausal women. Both therapies relieved vasomotor symptoms with a return of significant flushing after six months, thus reimplantation was performed every six months. Estradiol levels had not returned to baseline by six months, and significant accumulation of estradiol occurred by three years. The patients given testosterone experienced a similar accumulation of testosterone. There was no significant change in mean weight, blood pressure, or liver function tests during three years. Both therapies reversed the bone biochemical changes of menopause, and in both groups there was no significant loss in bone density. Supplementation of estradiol with testosterone in implant therapy was not observed to provide additional benefit in terms of the parameters studied.

The relation of hand skin-fold thickness to bone mineral density in patients with Crohn's disease.

OBJECTIVES: In healthy postmenopausal women, the association of skin-fold thickness (SFT) with bone mineral density (BMD) is well described, and a low SFT is a useful predictor of osteoporosis. In this study the association between hand SFT and BMD in patients with Crohn's disease was assessed; and the potential for hand SFT as a screening test for osteoporosis evaluated. DESIGN/METHODS: In a cross-sectional study, BMD was measured at the hip and lumbar spine by dual energy x-ray absorptiometry (DEXA). SFT was measured on the dorsum of the right hand using Holtain Tanner Whitehouse calipers. One hundred and seventeen patients (48 male) with Crohn's disease and 50 (25 male) controls were studied. RESULTS: There was a significant correlation between hand SFT and BMD (expressed as t scores) at all four measured sites (lumbar spine r = 0.41, P < 0.0001, 95% CI 0.25-0.55, Ward's triangle r = 0.38, P < 0.0001, 95% CI 0.21-0.53, trochanter r = 0.33, P < 0.0001, 95% CI 0.16-0.48, femoral neck r = 0.38, P < 0.0001, 95% CI 0.21-0.53). On stepwise regression analysis, the association remained significant after correcting for age, weight, menstrual status and current steroid use (P < 0.05). Hand SFT was significantly lower in patients with Crohn's disease than controls (difference in means 0.51 mm, 95% CI 0.3-0.72, P < 0.0001). Mean hand SFT was significantly lower in patients with osteoporosis compared to patients with normal BMD (difference in means 0.74 mm, 95% CI 0.33-1.15, P < 0.001), as was that of osteopenic patients compared to patients with normal BMD (difference in means 0.28 mm, 95% CI 0.01-0.55, P < 0.05). In the diagnosis of osteoporosis, the sensitivity of hand SFT ranged from 29% to 93%, with specificities of 54% to 95%. CONCLUSIONS: Hand SFT is independently associated with BMD in Crohn's disease and is lower than in age-matched healthy subjects. Hand SFT in combination with other easily measurable confounding variables might be useful in screening for osteoporosis in patients with Crohn's disease.

Screening for osteoporosis in Crohn's disease. A detailed evaluation of calcaneal ultrasound.

OBJECTIVES: To compare calcaneal broadband ultrasonic attenuation (BUA) and velocity of sound (VOS) in patients with Crohn's disease with an age-matched control population. The validity of BUA as a screening tool for osteoporosis was evaluated and the relationship between BUA and previous fracture studied. DESIGN: Cross-sectional study. BACKGROUND: Since patients with Crohn's disease are at risk of osteoporosis and premature fracture, routine assessment of bone mineral density (BMD) is recommended. Quantitative ultrasound of the calcaneum is an inexpensive and radiation-free means of assessing bone density which also provides information on bone microstructure. METHODS: BUA (dB/MHz) and VOS (m/s) were measured at the calcaneum (CUBAclinical, McCue Ultrasonics, Winchester, UK) and compared with bone mineral density at the hip and lumbar spine measured by dual-energy X-ray absorptiometry (DEXA); 100 patients (42 men) with Crohn's disease and 52 age-matched healthy controls (23 men) were studied. RESULTS: BUA was significantly reduced in patients with Crohn's disease compared with age-matched controls [76.53 dB/MHz (+/-17.3) vs 87.29 dB/MHz (+/-17.9), difference in means = 10.76, 95% CI -16.67, -4.85, P = 0.0004] and was significantly associated with BMD at the spine (r = 0.49, 95% CI 0.32, 0.63, P< 0.0001) and femoral neck (r = 0.54, 95% CI 0.38, 0.67, P < 0.0001). In the diagnosis of osteoporosis (t score <-2.5) BUA had a sensitivity of 66.7% at the femoral neck, with a specificity of 85.6%; sensitivity of BUA at the spine was 75% with specificity 89%. CONCLUSION: Patients with Crohn's disease have reduced BUA compared with an age-matched control population. Calcaneal BUA is significantly associated with BMD at the hip and spine but the correlation is insufficient to recommend ultrasound as a screening tool for DEXA.

Investigation of the bleeding patterns of postmenopausal women treated with Estrapak-50.

Diary cards of patients in two similar trials of Estrapak-50 hormone replacement therapy were analysed with regard to the characteristics of progestogen-associated bleeding (PAB) and breakthrough bleeding (BTB). Forty out of 52 patients in Study A and 74 out of 92 patients in Study B had diaries suitable for analysis. One patient in Study A and two patients in Study B who withdrew from treatment did so because of unacceptable bleeding problems. Similar results were obtained from both trials. After 6 months of treatment approximately 90% of patients in study A and approximately 70% of patients in study B had PAB on or before day 11. Twenty-seven percent and 49% in studies A and B, respectively, bled prior to day 8, which in the majority of instances affected one treatment cycle. Duration of PAB varied from 1 to 14 days (median 7 days) and the pattern of bleeding in the second cycle was predictive of bleeding in subsequent cycles. Although over 1/3 of women reported some heavy bleeding days, this usually only affected one treatment cycle, and the majority of bleeding was only spotting or light flow. BTB patterns did not raise suspicions of endometrial pathology. Bleeding patterns were both acceptable to patients and, in as much as the current literature indicates that bleeding patterns can be interpreted, were consistent with adequate progestogenic protection of the endometrium.