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OBJECTIVE: To assess the effect of perimenstrual estradiol supplements on menstrual attacks of migraine associated with estrogen withdrawal. METHODS: Women with regular menstrual cycles and menstrual migraine or menstrually related migraine completed an initial three-cycle assessment confirming eligibility for a six-cycle crossover study using estradiol or placebo to prevent menstrual attacks of migraine. Women collected early morning samples of urine daily for laboratory assay and used a fertility monitor to identify peak fertility associated with ovulation. Estradiol gel or placebo was first applied on the tenth day following the first day of peak fertility and continued daily until, and including, the second full day of menstruation. Women kept a daily migraine diary and continued their usual treatment for migraine. The main outcome was the number of days during gel use on which a migraine occurred. RESULTS: Data from 35 women were available for a paired analysis. Percutaneous estradiol was associated with a 22% reduction in migraine days (RR 0.78, 95% CI 0.62 to 0.99, p = 0.04); these migraines were less severe and less likely to be associated with nausea. This was, however, followed by a 40% increase in migraine in the 5 days following estradiol vs placebo (RR 1.40, 95% CI 1.03 to 1.92, p = 0.03). CONCLUSION: Although perimenstrual percutaneous estradiol showed benefit during treatment, this was offset by deferred estrogen withdrawal, triggering post-dosing migraine immediately after the gel was stopped. Further work could assess if this could be avoided by extending the duration of treatment with estradiol.

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OBJECTIVE: To investigate the association between urinary hormone levels and migraine, with particular reference to rising and falling levels of estrogen across the menstrual cycle in women with menstrual and menstrually related migraine. METHODS: Women with regular menstrual cycles, who were not using hormonal contraception or treatments and who experienced between one and four migraine attacks per month, one of which regularly occurred on or between days 1 +/- 2 of menstruation, were studied for three cycles. Women used a fertility monitor to identify ovulation, conducting a test each day as requested by the monitor, using a sample of early morning urine. Urine samples were collected daily for assay of estrone-3-glucuronide, pregnanediol 3-glucuronide, follicle-stimulating hormone, and luteinizing hormone. All women kept a daily migraine diary and continued their usual treatment for migraine. RESULTS: Of 40 women recruited, data from 38 women were available for analysis. Compared with the expected number of attacks, there was a significantly higher number of migraine attacks during the late luteal/early follicular phase of falling estrogen and lower number of attacks during rising phases of estrogen. CONCLUSION: These findings confirm a relationship between migraine and changing levels of estrogen, supporting the hypothesis of perimenstrual but not postovulatory estrogen "withdrawal" migraine. In addition, rising levels of estrogen appear to offer some protection against migraine.

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BACKGROUND: The rise in FSH (FSHr) that leads to the recruitment of a cohort of follicles during the menstrual cycle occurs during the luteal-follicular transition, however, it is unclear whether it consistently occurs on one particular day, or is subjected to reproductive ageing. METHODS: We determined the FSHr in 836 complete menstrual cycles from 102 women with regular menses using an algorithm, and additionally compared the relative variation in FSH during the last 14 days of the cycle. Possible effects of reproductive ageing on the onset of FSHr were also investigated. RESULTS: The day of FSHr follows a normal distribution with a median value of -4 (relative to first day of menses), mean -4.1 and SD 2.1. Analysis of the relative changes in FSH during the last 14 days of the cycle revealed the first significant rise on day -4 (P=0.0033), coinciding with the first significant drop in estrogens (P=0.0002). No effect of chronological age, or initial FSH levels, on FSHr was found, however, there was an inverse relationship between total follicular phase length (from day of FSHr to LH peak) and initial FSH levels (P<0.0001). CONCLUSIONS: The initial FSH rise in the cycle occurs consistently 4 days before menses, is related to a drop in estrogen levels, and is not affected by reproductive ageing.

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The menopausal transition is characterized by the appearance of elongated cycles, which become longer and more frequent as menopause approaches. Several endocrine abnormalities have been attributed to these cycles; however, no quantitative studies of their causes and consequences exist to date. This study is based on sequential daily urinary concentrations of FSH, LH, estrone 3-glucuronide (E1G), and pregnanediol 3-glucuronide (PdG) from 34 women with perimenopausal menstrual irregularity (total of 289 cycles). The timing of ovarian response was determined as the day of E1G take-off (ETO). Other parameters measured were the mean FSH concentration before ETO (FSH(ETO)) and the midluteal levels of PdG, E1G, and LH. There was a strong parallelism between ETO and cycle length variability. FSH(ETO) levels increased gradually with ETO. Both ETO and FSH(ETO) were inversely related to luteal PdG and directly related to E1G. PdG and LH levels were inversely related. All comparisons were highly significant (P < 0.0001). We conclude that delayed ovarian response underlies the elongation of the menstrual cycle in the menopausal transition, which is likely to be caused by a temporary lack of ovarian responsiveness to FSH. A progressive decline in luteal PdG with increased E1G occurs in association with these trends.

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Although reproductive aging has been separately related to elevated FSH and shorter follicular phase (FP), the direct association between both parameters has not been investigated. Also, the exact effects of increased FSH on estrogen production are yet to be established.A large database of daily urinary concentrations of FSH, LH, and estrone 3-glucuronide (E1G) from 37 regularly menstruating women (median 11 cycles per patient) was used. Initial FSH levels (iFSH) were estimated as the mean value of d 1-5. The day of E1G take-off (ETO) was determined by an algorithm, and accordingly, the FP was divided into early (d 1 to ETO) and late (ETO+1 to LH peak). FP maximum and integrated E1G were calculated. Subjects were distributed according to their mean iFSH into three categories (5 to 10, and >10 IU/liter). There was a gradual decrease in FP length with increasing category (15.2 +/- 3.8, 14.1 +/- 3.6, and 13 +/- 2.6 d, respectively; P < 0.0001). A similar effect occurred in early FP (7.5 +/- 4, 6.4 +/- 3.7, and 5.4 +/- 2.7; P < 0.0001); in contrast, late FP was unaffected (7.7 +/- 2.1, 7.7 +/- 2.1, and 7.6 +/- 2.4; P = 0.86). No consistent increase in E1G was found with advancing iFSH category; however, women with mean initial LH higher than 6 IU/liter had significantly elevated maximum (P < 0.0001) and integrated (P = 0.002) E1G.FP length decreases in parallel with increasing iFSH, with a selective effect on the early FP. Increased FSH does not affect E1G; however, elevated initial LH level was related to higher E1G.

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The outcome from a Double-Blind Placebo-Controlled Food Challenge is often of a subjective nature and cannot be measured directly. Reactions to placebo challenges are frequently observed, implying that some of the responses in the study are in fact 'false responses'. In order to adjust for these false responses, previous studies have used various methods, including removing subjects from the analysis who reacted to the placebo. Simply ignoring the false responses can lead to misleading estimates for the true proportion of sensitised individuals. This paper outlines two models which can account for these false responses. In the single challenge study, a simple model is developed which enables the estimation of the rate of false responses in the study, as well as the true proportion of sensitised subjects. This model is very easy to apply in practice. For a repeated challenge study, a more complicated model is developed which again enables the estimation of the rate of false responses and the true proportion of sensitised subjects.

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Psychopharmacological studies using caffeinated beverages or caffeine have rarely considered temporal effects on psychological and physiological function or the specific contribution of caffeine, hot water, or beverage type to the observed effects. The effect of 400 ml hot tea, coffee, and water consumption on systolic and diastolic blood pressure (SBP and DBP), heart rate, skin conductance (a measure of sympathetic nervous system activation), skin temperature, salivary cortisol, and mood were monitored in 16 healthy caffeine-withdrawn (14 h) subjects in a complete crossover design. Beverages were ingested with/without 100 mg caffeine and milk (tea/coffee only). Hot beverage ingestion rapidly increased skin conductance and temperature (+1.7 degrees C) with peak effects observed only 10-30 min post-consumption. Caffeine in the beverage rapidly augmented skin conductance responses but, in contrast to the effect of hot water, reduced the skin temperature response and increased SBP (+2.8 mmHg) and DBP (+2.1 mmHg) 30-60 min post-consumption. Both caffeine and milk addition to beverages independently improved mood and reduced anxiety 30 and 60 min post-consumption. Milk addition had no other effects apart from attenuating the transient increase in physiological responses associated with the drinking phase. There were no effects of beverage consumption on salivary cortisol or of beverage vehicle on salivary caffeine levels, the latter indicating that caffeine pharmacokinetics was similar in both tea and coffee, and not different from caffeinated water. In keeping with this, the responses to tea and coffee ingestion were similar and largely accounted for by the effects of hot water and caffeine. However, tea potentiated the increase in skin temperature compared to coffee and water indicative of a greater vasodilatory response plausibly related to the presence of flavonoids in tea. We conclude that ingestion of hot caffeinated beverages stimulates physiological processes faster than hitherto described, primarily via the effects of hot water and caffeine, but with beverage type and milk playing important modulatory roles.

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We examined the prognostic value of early serum CA125 assay in 58 patients with advanced epithelial ovarian cancer together with residual disease, age, tumour grade, performance status, and the presence of ascites or adhesions at primary surgery. CA125 was a highly significant predictor of both progression free and overall survival after the first cycle and throughout primary chemotherapy. After the first cycle, CA125 was by far the most significant predictor of progression free survival (P < 0.0005). At this time, CA125 was a highly significant predictor of survival (P < 0.005), but did not add to performance status (P < 0.001) in multivariate analysis. We were able to identify three statistically-distinct prognostic groups. Patients in the upper quartile, with CA125 levels greater than 450 U ml-1, had a very poor median survival of 7 months. Patients in the lower quartile, with CA125 levels less than 55 U ml-1 had a good median survival of 23 months. Those in the two interquartile groups, who had CA125 levels ranging from 58-221 U ml-1 and 228-434 U ml-1, had relatively intermediate median survival times of 16 months and 15 months respectively. Although CA125 levels provided significant prognostic information, in the majority of patients CA125 merely confirmed overall clinical impression.

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We assayed serum HMFG2 in serial samples from 215 primary epithelial ovarian cancer patients using an 'in-house' single determinant ELISA, 45% of patients with stage I, 54% with stage II, 61% with stage III and 75% with stage IV disease had elevated serum HMFG2. Post-operative levels were significantly related with residual tumour volume (P < 0.005), and fell in the majority of responders, although the association with response to first-line chemotherapy was not significant. HMFG2 had a sensitivity of 50% specificity of 83%, accuracy of 61%, PVP of 86% and PVN of 45% for disease at second-look laparotomy. Serial levels gave a lead time to clinical relapse in 47% of patients who responded to therapy, including one patient with negative CA125 levels. HMFG, paralleled CA125 in many respects, although it was elevated in fewer patients. In a stepwise discriminant analysis, HMFG2 added to the discrimination of CA125 (r = 0.183, P < 0.005), although additional accurate information was only given in patients with advanced poorly differentiated serous cystadenocarcinoma. Given that HMFG2 is expressed in few patients who are CA125 negative it is unlikely that it will have a significant clinical impact upon patient management.

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Serum CA125 measurement has an established role in monitoring epithelial ovarian cancer patients, assisting in determining response to chemotherapy and providing a lead time to clinical relapse. Over the past few years there has been a decrease in the use of second-look laparotomy to determine response; however, this is largely due to the lack of impact that this procedure has on survival rather than the growing use of less invasive scanning techniques or CA 125 assay to determine disease status. The value of a marker lead time depends ultimately on a patient's remaining therapeutic options; the influence on survival of therapeutic intervention at pre-clinical diagnosis of relapse remains to be tested in a randomized controlled trial. The third area where CA 125 may help patient management is in predicting progression-free survival and overall survival. Treating patients with aggressive chemotherapy regimes would not be justified (given the deterioration in the quality of life for a period of months that may result from such therapy) if a poor outcome could be predicted. Deciding when to stop ineffective treatment is extremely difficult for the clinician given patients' desire for active therapy. The prognostic value of CA 125 needs to be further clarified before it can influence such treatment decisions. The aim of this study was to help clarify the role of CA 125 in patient management and to assess several other putative EOC markers, including determinants found on the polymorphic epithelial mucin (PEM)--the most promising alternative marker protein to date.

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