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It is vital that flood risks from multiple sources to the national Strategic Road Network are well understood, to help minimise disruption, reduce risk to people and to help prioritise maintenance programmes. Highways England have undertaken research to update their current understanding of risk based on improved flood mapping, plus data collected on flooding ‘hot spots’ through a concerted programme to record flooding events, severity and causes over the last 5 years. Building on the previous risk assessment, the roads layer was interrogated against new flood hazard data for multiple sources of flooding. The road network was divided into 100m segments in order to capture a strong spatial understanding of predicted flood risk from each source, but also summarised on a 1km scale and a management area level to aid prioritisation at varying scales. The 1 km grids were then ranked across England according to each source of flooding, and also an overall rank was derived through summing these ranks together. This was validated against detailed spatial ‘hot spot’ database recorded by Highways England, based on over 12,300 records, collected over 5 years.

Objective: To determine the time relationship between the ingestion of progestogen during sequential hormone replacement therapy (HRT) and impedance to blood flow in the uterine arteries., Design: Nine postmenopausal women who had already received HRT for at least 6 months were treated with either transdermal 17 beta-E2, 0.1 mg/d, or conjugated equine estrogens (Es), 1.25 mg/d, to which norethindrone, 0.7 mg/d, was added for 12 days in a single 28-day cycle of therapy. Transvaginal ultrasonography with color flow imaging was used to measure the pulsatility index (PI) in the uterine arteries every 3 to 5 days over one 28-day treatment cycle., Results: The ingestion of norethindrone increased the mean uterine artery PI by 30% (SE 16.4%). The PI fell significantly within 4 days of ceasing norethindrone., Conclusion: Progestogen addition in sequential HRT causes changes in the uterine arterial tone, but the effect subsides within 4 days of progestogen withdrawal.

Objective: To assess the value of transvaginal ultrasonography with colour blood flow imaging in detecting early ovarian cancer in women with a family history of the disease., Design: Study of self referred symptomless women with a close relative who had developed the disease. Each woman was screened to detect persistent lesions and defined changes in ovarian volume. Morphological score and pulsatility index were recorded., Setting: Ovarian screening clinic., Subjects: 1601 self referred women., Interventions: Women with a positive screening result were recommended to have further investigations., Main Outcome Measures: Findings at surgery and histology of abnormal ovaries. Morphological score > or = 5 and pulsatility index < 1.0 at last scan., Results: Women were aged 17 to 79 (mean 47) years; 959 (60%) were premenopausal, 469 (29%) were naturally postmenopausal, and 173 (11%) had had a hysterectomy. 157 women had a pedigree suggestive of the site specific ovarian cancer syndrome and 288 of multiple site cancers. 61 women had a positive screening result (3.8%, 95% confidence interval 2.9 to 4.9%), six of whom had primary ovarian cancer detected at surgery (five stage Ia, one stage III). Use of a high morphological score or a low pulsatility index increased the odds of finding ovarian cancer from 1:9 to about 2:5 (1:1 in the highest risk groups). Five interval cancers were reported (three ovarian and two peritoneal). Eight of the 11 cancers developed in women with pedigrees suggestive of inherited cancer., Conclusions: Transvaginal ultrasonography with colour flow imaging can effectively detect early ovarian cancer in women with a family history of the disease. The screening interval should be less than two years.

Objective: To investigate the relationship between estradiol (E2), progestogen, and impedance to blood flow in the uterine artery., Subjects: Twelve postmenopausal women treated for two cycles with transdermal E2, 0.05 mg/d, with either norethindrone acetate, 0.7 mg, or medroxyprogesterone acetate, 10 mg added sequentially., Measurements: Transvaginal ultrasonography and color flow imaging were used to measure the pulsatility index in the uterine arteries before and during the E2-only and combined E2/progestogen phases., Results: The mean pulsatility index fell to 53% of its pretreatment value within 12 days E2 administration (P < or = 0.0001) and was 66% of its pretreatment value in the combined phase (P < 0.005). Similar changes were seen in cycle 2. Time since menopause was correlated with the pretreatment pulsatility index (r = 0.674, P < 0.05) and change in pulsatility index on treatment (r = 0.856, P < 0.001)., Conclusion: Gonadal hormones have a profound effect on arterial tone in postmenopausal women; this action may help explain some of the beneficial effects of estrogen on arterial disease risk.

The genetic epidemiology of ovarian cancer has been investigated by complex segregation analysis of 462 pedigrees ascertained through a normal consultant. The observed pattern of ovarian cancer is compatible with an autosomal dominant gene. The gene frequency of the abnormal allele is 0.0015-0.0026 with a lifetime penetrance of 0.74-0.79. The gene frequency accounts for a significant proportion of ovarian cancer in young women. By age 70 the majority of affected women are phenocopies. The results from this analysis should enable the risks of ovarian cancer to be more accurately estimated than by empiric methods for relatives of affected women, and can maximize the usefulness of screening programmes and future linkage studies.

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.

Objective: To provide information on endometrial stimulation after discontinuation of treatment with oestradiol implants., Design: Long term follow up of withdrawal bleeding patterns in women taking progestogens cyclically every month after oestradiol implant treatment was ended., Setting: Specialist menopause clinic., Subjects: 10 Postmenopausal patients (at least 12 months' amenorrhoea after the last spontaneous period) who were treated with oestradiol implants for typical symptoms of oestrogen deficiency. The oestradiol dose was 50 mg, reimplantation occurring roughly every six months. Patients subsequently either needed to discontinue the hormone treatment for medical reasons or expressed a desire to stop treatment., Main Outcome Measure: Duration of endometrial stimulation--defined as the presence of withdrawal bleeding in response to progestogen given cyclically--after insertion of the last oestradiol implant., Results: Four patients eventually stopped bleeding, their mean duration of bleeding being 35 months (range 27-43 months). One patient required hysterectomy 26 months after the last implantation because of persistent irregular bleeding despite treatment with high doses of progestogen. Three patients bled for 22, 30, and 36 months and then restarted oestrogen treatment because symptoms returned. The last two patients subsequently continued to bleed 12 and 21 months after the last implantation., Conclusions: The duration of endometrial stimulation after implantation can be prolonged, up to 43 months. Insertion of oestradiol implants can carry a long term commitment to the cyclical administration of progestogen and regular withdrawal bleeding if endometrial hyperplasia and carcinoma are to be avoided.

Objective: To assess whether changes in the intraovarian vasculature or blood flow impedance can be used to identify potentially malignant masses., Design: Open, non-comparative prospective study., Setting: Ovarian screening clinics at King's College Hospital and the Hallam Medical Centre., Subjects: 50 Women selected on the basis of their medical history and the result of a previous transvaginal ultrasound scan. Thirty women (10 premenopausal (scan taken on days 1 to 8 of the menstrual cycle) and 20 postmenopausal) had normal ovaries, and 20 had at least one ovary with an abnormal morphology or volume, or both., Interventions: Women with a positive result on screening were referred for laparotomy., Main Outcome Measures: Presence or absence of coloured areas (neovascularisation) and the pulsatility index within each ovary. The pulsatility index is a measure of the impedance to blood flow, a low value indicating decreased impedance and a high value increased impedance to blood flow., Results: Two women with a positive result on screening had hydrosalpinges, 10 a benign tumour or a tumour-like condition, and eight primary ovarian cancers. No areas of neovascularisation were seen in the 30 women with morphologically normal ovaries and the two patients with hydrosalpinges; the pulsatility index ranged from 3.1 to 9.4. Similarly, nine patients (10 affected ovaries) with a non-malignant mass had no signs of neovascularisation and the pulsatility index varied from 3.2 to 7.0. One patient with bilateral dermoid cysts containing nests of thyroid-like cells had vascular changes and pulsatility index values of 0.4 and 0.8. Seven patients (eight ovaries) with primary ovarian cancer (one stage IV, four stage II, and two stage Ia) showed clear evidence of neovascularisation and pulsatility index values were from 0.3 to 1.0. One patient with an intraepithelial serous cystadenocarcinoma in a small ovary (less than 5 ml volume) had no signs of any vascular change and the pulsatility index was 5.5., Conclusion: Transvaginal colour flow imaging may be used to identify potentially malignant ovarian masses and help elucidate the early stages of tumorigenesis. The routine application of this technique may reduce the rate of false positive results of an ultrasonography based screening procedure.

Oral progesterone 100, 200, or 300 mg daily was given for the first 10 days of each calendar month to postmenopausal women also receiving conjugated oestrogens 1.25 mg daily continuously. Endometrial biopsy specimens were taken on the sixth day of the third or subsequent cycle of combined treatment for histological, ultrastructural, and biochemical evaluation. Secretory histological changes were induced within the endometrium in a dose dependent manner, as were progesterone sensitive ultrastructural features such as nucleolar channel systems, giant mitochondria, and subnuclear accumulations of glycogen. Dose response relations were also observed for suppression of DNA synthesis and nuclear oestrogen receptor, and for induction of the activities of oestradiol and isocitric dehydrogenases. Progesterone administered by mouth clearly provokes an end organ response within the endometrium. Suboptimal effects were observed with the lower doses but progesterone 300 mg daily achieved responses approaching and within the physiological range. This dose may therefore be effective as an alternative to synthetic progestogens for therapeutic purposes.

Nuclear oestrogen-receptor and soluble progesterone-receptor have been measured in postmenopausal endometria from women receiving either Premarin or Premarin plus norethisterone. Oestradiol dehydrogenase has been measured in some samples. It is concluded that the doses of Premarin currently in use have a potent oestrogenic effect on the endometrium. Norethisterone does not affect the amount of oestrogen entering the nucleus but it may temporarily suppress the biological activity of the oestrogen.

Cyclical regimes of unopposed oestrogens are associated with the development of both cystic glandular and atypical hyperplasia, and the incidence of hyperplasia is related to the dose of oestrogen prescribed. Atypical hyperplasia develops later than, and perhaps from, cystic glandular hyperplasia. With sequential oestrogen/progestogen therapy the incidence of this condition was greatly reduced, and therefore, progestogens appear to protect against the development of this condition. In all cases but one, sequential regimes also reversed both spontaneously-arising and oestrogen-induced hyperplasia to a normal endometrium. Cyclical high-dose unopposed oestrogen therapy may not be capable of reversing spontaneously-arising hyperplasia, and this condition may progress to endometrial adenocarcinoma. Spontaneously-arising hyperplasia can be present before therapy commences, but may be unsuspected, as it can occur in the absence of abnormal vaginal bleeding. Therefore, cyclical oestrogen therapy should not be prescribed unless pre-treatment curettage has been performed and spontaneously-arising hyperplasia has been excluded; and unless subsequent monitoring of the endometrial response is being performed by serial biopsy.

In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.

Endometria of normal histology from postmenopausal women receiving either estrogen or estrogen plus a progestin have been analyzed for nuclear estradiol receptor, epithelial DNA synthesis, isocitric dehydrogenase, and estradiol dehydrogenase activities. Epithelial DNA synthesis correlated positively with nuclear estradiol receptor and negatively with both the dehydrogenases; this result was obtained regardless of whether the enzyme activity was related to the protein or DNA content of the samples. Thus, either of the dehydrogenases might provide an index of progestin effects on proliferative activity in endometrial carcinomata. Provera administered in vivo had no effect on either dehydrogenase activity in soluble estradiol receptor-poor carcinomata, whereas both dehydrogenase activities were high in some but not all soluble estradiol receptor-rich tumors. The enzyme activities in Provera-treated tumors have been compared with those in normal epithelium and endometrium from postmenopausal women taking estrogen plus progestin. The activities of both dehydrogenases were lower in soluble estradiol receptor-rich carcinomata than in either endometrium or epithelium from estrogen plus progestin-primed, normal postmenopausal women. This may indicate suboptimal progestin effects in the patients with carcinoma, and potential reasons for this are discussed.

Endocrine changes during early pregnancy have been studied in 12 patients between days 35 and 91 from the last menstrual period. Ovulation had occurred spontaneously in five patients and was induced with clomiphene citrate (CC) in the remaining seven women. All the patients collected daily samples of early morning urine throughout the period of study; on each sample, human chorionic gonadotropin (hCG), pregnanediol-3-alpha-glucuronide (PGDG) and estrone-3-glucuronide (E1G) were measured by chemiluminescence immunoassay. No significant difference was observed between the two groups of patients with respect to the concentrations of hCG and PGDG. The excretion of E1G, however, was significantly higher in patients treated with CC. These data suggest that the induction of ovulation with CC may affect estrogen production in early pregnancy.

Objective: To assess the incidence and severity of physical and psychosexual symptoms in young women due to ovarian failure caused by total body irradiation for leukaemia and the women's response to hormone treatment., Design: Postal questionnaire and interview., Setting: Leukaemia unit of oncology hospital., Patients: Consecutive series of 46 English speaking women who had developed ovarian failure after total body irradiation and bone marrow transplantation as treatment for leukaemia., Results: Of the 36 responders, 33 reported some symptoms, vaginal dryness being the most common (29). This profoundly affected sexual function. Although 22 women had had sexual intercourse within six months after treatment, 16 were less interested in and 18 experienced difficulties with sexual intercourse. Anxieties about sterility, femininity, and appearance were common and reduced self confidence. Almost half reported that they had changed their social habits and restricted their social activities. Treatment seemed effective in abolishing symptoms in 24 women, but vaginal dryness remained a problem in three. Two women failed to respond and intercourse remained impossible., Conclusions: Such patients are vulnerable and access to gynaecologists and endocrinologists soon after treatment would be valuable. The optimal treatment regimen and the long term benefits of treatment have yet to be established.

The use of calcium supplements to prevent postmenopausal bone loss and hence osteoporosis is widespread, but the evidence for their efficacy, either alone or in combination with other treatments, is contradictory. Skeletal measurements and dietary intake of calcium were determined in 59 healthy postmenopausal women, most of whom were within five years of the menopause. No correlation was found between current intake of calcium and either total calcium in the body or the density of trabecular or cortical bone in the forearm or vertebral trabecular bone. Dietary intake of calcium did not influence the rate of postmenopausal bone loss in the 54 women who completed 12 months of active or placebo treatment. Even when extremes of calcium intake were examined no difference was found in bone measurements between the women with the highest and lowest intakes. The results of this study suggest that the bone density of women in the early menopause is not influenced by current dietary intake of calcium.

The absorption, metabolism, and clearance of progesterone from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg daily for five consecutive days. Maximal plasma concentrations of progesterone were observed within four hours after ingestion of the last dose, when the range (22.11-34.18 nmol/l; 696-1077 ng/100 ml) was comparable with that observed during the mid-luteal phase of the ovarian cycle. The surge in values lasted six hours, and progesterone concentrations remained raised for at least 96 hours. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment, the peak values ranging from 1097 nmol/l (54.9 microgram/100 ml) to over 2000 nmol/l (100 microgram/100 ml), which was the upper limit of the assay used. Concentrations of 17-hydroxyprogesterone were least raised, and the peak values ranged from 4.32 to 9.68 nmol/l (143-319 ng/100 ml). The plasma profile of 20 alpha-dihydroprogesterone most closely approximated that of progesterone, although the range of maximal values was lower (7.11-16.06 nmol/l; 228-514 ng/100 ml). Plasma concentrations of oestradiol were unchanged by giving progesterone. It is concluded that the increases in circulating concentrations of progesterone and the biologically active metabolite 20 alpha-dihydroprogesterone, and the duration of these increases, were sufficient to modulate the biochemistry of responsive tissues. Oral progesterone may thus have a therapeutic role, and this route of administration merits further investigation.

The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.

Calcitonin gene related peptide is an extremely potent vasoactive peptide that causes profound vasodilatation in man. Its distribution in perivascular nerves suggests that one of its functions may be the regulation of peripheral vascular tone. Pregnancy is a physiological condition in which there are major haemodynamic changes. An increase in plasma volume of about 40% necessitates changes in peripheral vascular tone. In a cross sectional study plasma concentrations of immunoreactive calcitonin gene related peptide were measured throughout normal pregnancy and at five to seven days post partum. Calcitonin gene related peptide concentrations were significantly increased throughout pregnancy but fell after delivery. Calcitonin gene related peptide may participate in the physiological regulation of vasomotor tone in man.

Objective: To assess the value of ultrasonography in a screening procedure for early ovarian cancer., Design: Prospective study of at least 5000 self referred women without symptoms of ovarian cancer. Each woman was scheduled to undergo three annual screenings (consisting of one or more scans) to detect grossly abnormal ovaries or non-regressing masses., Setting: The ovarian screening clinic at King's College Hospital, London., Subjects: 5479 Self referred women without symptoms (aged 18-78, mean age 52)., Interventions: Women with a positive result on screening were referred for laparoscopy or laparotomy, or both., Main Outcome Measures: Findings at surgery and from histology of abnormal ovaries., Results: A total of 14,594 screenings (15,977 scans) were performed. A positive result was obtained at 338 screens (2.3%) comprising 326 subjects (5.9%). Five patients with primary ovarian cancer (four stage Ia, one stage Ib; two at first screening three at second) were identified (prevalence 0.09%). An additional four patients had metastatic ovarian cancer (three at first screening, one at second). The apparent detection rate was 100%. It was not possible to differentiate between the ultrasonic appearance of early malignant and benign tumours. The rate of false positive results for primary ovarian cancer was 3.5% at the first screening, 1.8% at the second, and 1.2% at the third. Overall the rate of false positive results was 2.3%; the specificity was 97.7% and the predictive value of a positive result on screening was 1.5%. The odds that a positive result on screening indicated the presence of an ovarian tumour, any ovarian cancer, or primary ovarian cancer were about one to two, one to 37, and one to 67 respectively., Conclusion: Ultrasonography can be used to screen women without symptoms for persistent ovarian masses that will include early ovarian cancer.

Exogenous oestrogens prescribed for the relief of menopausal symptoms are being given in pharmacological doses and the term 'hormone replacement therapy' is inappropriate. The frequent development of endometrial hyperplasia during unopposed cyclical oestrogen therapy is therefore to be expected, but no single pattern of vaginal bleeding accurately reflected the histology of the endometrium. As such doses of oestrogens are required for effective relief of symptoms, progestogens must be given to protect against endometrial hyperstimulation. Patient acceptability of sequential oestrogen/progestogen therapy is high (90%) and with such therapy breakthrough bleeding may subsequently be shown to be a reliable indicator of underlying endometrial pathology.

In a dose-ranging study, medroxyprogesterone acetate, 2.5, 5, or 10 mg daily, was given for 12 days of each calendar month to postmenopausal women also receiving conjugated estrogens, 0.625 mg daily, continuously. Endometrial biopsy specimens were taken on the sixth day of combined therapy for histologic, ultrastructural and biochemical evaluation. Medroxyprogesterone acetate induced secretory and ultrastructural changes within the endometrium, but the responses were variable and inconsistent. Suppression of epithelial deoxyribonucleic acid synthesis appeared dose-dependent. The levels of nuclear estradiol receptor, although reduced to within the secretory phase range, were not significantly lower than the values observed during the estrogen-only phase of treatment. Induction of both estradiol and isocitrate dehydrogenase activities was to within the secretory phase ranges, but the magnitude of these responses appeared less than those observed previously with other progestogens. Both morphologically and biochemically, medroxyprogesterone acetate, even at high dosage, produced suboptimal responses. Further studies are required to establish whether this is a dose-related effect.

The effects of at least three doses of each of five orally administered progestins on estrogen-primed, postmenopausal endometrial biochemistry and morphologic features were analyzed. The progestins tested were norethindrone, medroxyprogesterone acetate (MPA), norgestrel, dydrogesterone, and progesterone. The dose required to elicit responses similar to those seen in premenopausal, secretory endometria was assessed for each of the parameters measured, and the relative potencies were calculated. Potencies, relative to a value of 1 for norethindrone, are L norgestrel 8 (D/L norgestrel 4), MPA 0.1, dydrogesterone 0.02, and progesterone 0.002. The dose of norethindrone required to elicit secretory phase activity was about 0.35 mg/day. These values agree with published data obtained with the use of different methods (delay of menstruation in premenopausal women, endometrial histologic features of estrogen-primed, ovariectomized women).