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The effects of an oestrogen/progestagen transdermal therapeutic system (TTS) were evaluated in sixteen oestrogen-deficient women. The patients applied conventional oestradiol-TTS for 14 days, then two combined norethisterone acetate/oestradiol patches for a further 14 days. The treatment was repeated for five cycles. Ten patients then underwent metabolic studies. One patient had amenorrhoea, but the rest experienced regular withdrawal bleeding which was seldom heavy. Fourteen endometrial biopsy samples were taken during the fifth treatment cycle; none showed proliferative or hyperplastic features. The effects of transdermal norethisterone acetate on symptoms, lipid metabolism, and psychological status were determined by comparing features in the oestrogen-only phase and in the combined phase; the effects were very mild. These preliminary findings show that transdermal progestagen can be successfully administered in hormone replacement therapy to prevent endometrial proliferation while minimising the adverse effects that may be seen with oral administration.

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 man, the major function of calcitonin appears to be prevention of excessive or unwanted bone resorption. There is a striking sex difference in circulating levels, with a relative deficiency in women. Calcitonin secretion in young adults is increased by oestrogens and therefore long periods of oestrogen lack, such as after the menopause, may be associated with a more pronounced calcitonin deficiency. This exaggerated deficiency could be an important factor in the pathogenesis of postmenopausal bone loss, especially since the latter may be due to excessive bone resorption. In a study of the effects of oestrogen treatment on circulating levels of calcitonin, parathyroid hormone, and vitamin-D metabolites in postmenopausal women, the most striking change was a sharp rise in plasma-calcitonin. Oestrogens prevent postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss. Its place in the treatment of postmenopausal osteoporosis warrants further evaluation.

Intracellular oestrogen metabolism has been investigated in endometrial tissue from postmenopausal women receiving oestrogen therapy either alone or in combination with a progestogen. During oestrogen therapy alone, there was a 3.2 fold predominance of oestradiol over oestrone within the endometrial cell nucleus and the mean nuclear oestrogen receptor content was 1.40 pmol/mg DNA. The addition of norethisterone decreased the nuclear oestradiol/oestrone ratio to 1.4:1 by lowering the oestradiol mass. A concurrent reduction in the mean level of the nuclear oestrogen receptor to 0.58 pmol/mg DNA indicated a decrease in oestrogenic stimulation. The activity of oestradiol-17 beta dehydrogenase was significantly increased. There was a plasma excess of oestrone over oestradiol during oestrogen therapy alone and oestrone/oestradiol ratio was not significantly altered following norethisterone administration. The ability of the endometrium to incorporate oestradiol selectively into the nucleus is discussed in relation to the risk of endometrial hyperplasia with unopposed oestrogen therapy. The profound biochemical changes induced by norethisterone help elucidate mechanisms whereby progestogens lower oestrogenic potency and thereby protect the endometrium against excessive stimulation.

Progestogens are added to the oestrogen treatment for 10-12 days each cycle in order to prevent endometrial abnormalities. However, concern has been expressed about the safety of certain of the currently available progestogens because of the potential adverse metabolic effects. We have evaluated the effects of nomegestrol acetate - non-androgenic progestogen - for administration to post-menopausal oestrogen users. Thirty-six (36) women receiving 50 mg oestradiol implants at regular intervals also took nomegestrol acetate for 12 days each calendar month at doses of 0.5 mg, 1.0 mg and 2.5 mg daily. Allocation to one of the dose regimens was random. Physical and psychological side-effects were recorded and all vaginal bleeding was noted: an endometrial biopsy was performed on the sixth day of progestogen addition for histological, ultrastructural and biochemical evaluation. Adverse side-effects were responsible for a dose-dependent drop out rates of 17%. All patients experienced a regular, progestogen-induced withdrawal bleed each month; and histological, ultrastructural and biochemical changes were induced within the endometrium by all 3 doses. Nomegestrol acetate is a potent progestogen and further studies are required to determine its lowest effective dose.

In a double-blind study naproxen sodium (550 mg), or placebo was administered 1 h before Vabra curettage and pain associated with the procedure was assessed immediately after operation and 30, 60 and 120 min later by visual analogue and verbal rating scales, and the McGill pain questionnaire. The pre-curettage anxiety of the patients was assessed by the Spielberger state anxiety inventory. Of the 58 patients, 51 (87.9%) reported pain during the procedure; there was no relation between the level of pain experienced and the pre-curettage anxiety score. Compared with the placebo group, the pain experienced by the naproxen group was significantly less as measured by the McGill pain questionnaire immediately after curettage, and by visual analogue scales 30 and 60 min after the procedure. The verbal rating scales showed that naproxen significantly reduced backache 30 min after curettage, and cramp immediately after the procedure and 30 and 60 min later but did not reduce the severity of the pain associated with the procedure.

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.

This chapter has stressed the urgent need for a screening test for the early detection of ovarian cancer. Real-time, mechanical sector ultrasonography is non-invasive, rapid, painless and has no harmful effects. It can be used to determine ovarian morphology and measure ovarian volume quickly in 99.4 per cent of post-menopausal women. Used correctly, with a precise knowledge of the pelvic anatomy and with proper training in methodology, the risk of false positive diagnoses of ovarian enlargement is small. The incidence of ovarian abnormality diagnosed by ultrasound in this series was 3 per cent. The ovarian neoplasms included clear-cell carcinoma, and serous and mucinous cystadenomas. However, ultrasound appearances of ovarian neoplasms bore little, if any, correlation with the histological diagnosis. Thus, we believe that real-time mechanical sector ultrasonography is reliable in the detection of ovarian neoplasms but the diagnosis can be made only by histological examination. The potential of this technique as a screening test for the early detection of ovarian cancer warrants further evaluation.

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.

In prospective studies, we have determined the endometrial histologic characteristics and patterns of vaginal bleeding in 12 perimenopausal or postmenopausal women during administration of transdermal estradiol, 0.05 mg daily, given either alone or in combination with a progestogen. In the first study, we administered transdermal estradiol in cyclical fashion for 3 months. Outpatient curettage at pretreatment produced no endometrial sample or tissue too scant for assessment from 10 of the 12 patients (83%). At the end of therapy, proliferative or nonsecretory endometrium was diagnosed in nine patients (75%). Eight patients experienced treatment-related vaginal bleeding but no regular pattern, and seven patients reported breakthrough bleeding. Eight patients participated in the second study in which transdermal estradiol was administered continuously and norethindrone, 0.35 mg, was added for 12 days of each calendar month. A further curettage was performed at the end of treatment, and proliferative endometrium was the most common finding. No endometrial hyperplasia was observed. Only one patient experienced breakthrough bleeding. There were no consistent changes with time in the number of patients bleeding each month or in the duration or heaviness of the bleeding.

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.

Progesterone was assayed in samples of saliva collected daily throughout the menstrual cycle and correlated with corresponding daily concentrations of pregnanediol-3 alpha-glucuronide in early morning urine. Ovarian follicular growth was monitored on a daily basis with a real-time sector scanner. The concentrations of salivary progesterone shows a specific pattern with a mid-cycle rise and a peak in the luteal phase. The mean concentration in the follicular phase, as determined, was 40.4 pmol/l (range 15.3-110.7 pmol/l). It increased in the peri-ovulatory period to a peak of 201.1 pmol/l (range 46.4-289.8 pmol/l) 6 days following follicular rupture.

Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.

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.

Plasma-calcitonin levels, measured with an established and reliable extraction radioimmunoassay technique, were significantly higher throughout normal pregnancy and lactation than in normal non-pregnant women, and were not immediately influenced by the acute stimulation of breast-feeding. Thus, more calcitonin circulates at times of physiologically increased calcium need. It is suggested that an important function of calcitonin is the protection of the healthy maternal skeleton from excessive resorption by opposing the resorptive action of 1,25-dihydroxycholecalciferol on bone.

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.

Although progestogens protect the endometrium against excessive oestrogen-induced stimulation, they can cause adverse symptomatic and psychological effects and may have undesirable metabolic consequences. Thus, the minimum progestogen dose which results in consistent endometrial transformation should be prescribed. To define this dose for norethisterone and dl-norgestrel, 197 endometrial samples obtained from postmenopausal women receiving conjugated equine oestrogens (0.625 mg or 1.25 mg daily) with one of six doses of norethisterone (or the acetate), or one of three doses of dl-norgestrel added for the first 12 days of each calendar month were examined with the light microscope; 109 samples were also assessed by transmission electron microscopy. There was an inverse relation between the percentage of samples showing proliferative features and the progestogen dose. However, proliferative endometrium was observed in 6% of samples with the highest dose of dl-norgestrel (500 micrograms) and in 3% of samples with 2.5 mg norethisterone. Conversely, complete secretory transformation was observed in 25% of samples with the lowest dose of norethisterone (0.1 mg) and in 40% of samples with 75 micrograms dl-norgestrel. Mild atypical hyperplasia was diagnosed in four samples. There was a wide inter-patient variation in response and none of the nine progestogen dose regimens induced secretory change in every patient.

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.

Systemic side effects that result from oral administration of estrogens to postmenopausal women may be minimized by use of the transdermal route. We administered transdermal estradiol, 0.05 mg/day, cyclically for 3 months to 12 postmenopausal and perimenopausal women to study the efficacy, acceptability, and metabolic effects of this dosage form. The results showed that transdermal estradiol significantly increased plasma levels of estradiol and estrone and urinary concentrations of estradiol conjugates, and produced significant improvement in menopausal symptoms and vaginal cytologic findings. The patches were well tolerated and no systemic side effects were reported. No clinically significant adverse biochemical changes were observed. Plasma renin substrate and renin activity were unchanged during therapy.

In a prospective, double-blind, randomized, cross-over trial, the effects of oral oestradiol, 2 mg daily, on the endometrial histology, frequency and severity of vaginal bleeding, and the symptomatic and psychological status of postmenopausal women were compared with those of oral oestradiol, 2 mg daily, plus oestriol, 1 mg daily. Both therapies were prescribed for 3 months on a cyclical basis. The addition of oestriol to oestradiol did not modify the endometrial response. The prevalence of proliferative/hyperplastic endometrium (64%: 9 of 14 biopsies) was similar after both treatments and there were no significant differences in either the frequency or heaviness of vaginal bleeding. Both therapies significantly reduced hot flushes, night sweats and vaginal dryness: no significant differences in effect on the symptomatic and psychological status were recorded. The addition of 1 mg of oestriol to 2 mg of oestradiol did not confer any benefit and the value of such an addition is challenged.

Persistent ovarian masses have been found in a substantial proportion of 5479 self-selected asymptomatic women who were screened for early ovarian neoplasia. Each woman was scheduled to undergo three ultrasound screens (consisting of 1-12 scans) to detect regressing and non-regressing masses. A total of 14,594 screens (15,977 scans) was performed. The average interval between successive screens was 595 days (range 214-1134 days). Overall, 650 screens (4.4%; 10.1% of women) produced a positive result which became negative with successive scans (four times more frequently in pre- than naturally postmenopausal women), and 338 screens (2.3%; 5.9% of women) had a final positive result (at least one ovary that was grossly abnormal or contained a persistent mass). Biopsies were taken from 336 ovaries (89% of total, 271 women). Overall, 134 tumour-like conditions and 119 benign tumours were identified. The detection rate of tumour-like conditions was 1.5 times higher in premenopausal than naturally postmenopausal women, whereas the proportion of tumours to normal ovaries was similar in both groups. Overall, 51% of tumour-like conditions and 70% of all tumours were detected at screen 1. Four women had metastatic ovarian cancer (three at screen 1, one at screen 2; two were bilateral). Five women (0.1%) had a primary malignant tumour (two at screen 1, three at screen 2; four were stage 1a and one was stage 1b). All women are being monitored to obtain additional information about the significance of the findings.

Ovarian volumes have been determined by pelvic ultrasonography in 2246 apparently healthy postmenopausal women of whom 2221 were included in the statistical analysis. Factors associated with gonadal size have been identified, and reference ranges for derived indices have been determined for use (in association with criteria for abnormal morphology) in a screening programme for ovarian carcinoma. The right ovary was present in 98.9% of subjects and the left in 99.1%. The mean (SD; range) of right and left ovarian volumes were 3.58 (1.40; 1.00-14.01) and 3.57 (1.37; 0.88-10.9) ml respectively. Significant predictors of ovarian volume were years since the menopause, weight, parity, age at menopause, a history of hormone replacement therapy, and previously diagnosed breast cancer. Abnormal ovarian volumes were assessed from a score equal to the (observed mean log volume (MLV) minus the predicted MLV)/0.327. A simplified nomogram has been prepared for routine clinical use. The relative abnormality of one ovary was assessed from a ratio score equal to loge (larger ovarian volume/smaller ovarian volume)/0.211 compared with the 99th centile for the Gaussian distribution.

The major function of calcitonin in man appears to be the prevention of excessive or unwanted bone resorption. There is a marked sex difference in circulating levels, with a relative deficiency in women. As calcitonin secretion in young women is known to be increased by estrogens, long periods of estrogen lack - such as the postmenopause - are possibly associated with a more pronounced calcitonin deficiency. This exaggerated deficiency could be an important factor in the pathogenesis of postmenopausal bone loss, especially as the latter is believed to be due to excessive bone resorption. We have studied the effects of three exogenous estrogens on the circulating levels in postmenopausal women of calcitonin, parathyroid hormone, the vitamin D metabolites 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D, and calcium and phosphate. The most striking finding was a sharp rise in the plasma levels of calcitonin. Estrogens are known to prevent postmenopausal bone loss but the mechanism of action remains obscure. We suggest that the beneficial effects of estrogens could be mediated, at least in part, through control of calcitonin secretion. Thus calcitonin may prove effective in the prevention of postmenopausal bone loss and its role in the treatment of established osteoporosis warrants further evaluation.

Postmenopausal women receiving conjugated oestrogens 1.25 mg daily continuously were also given dydrogesterone either 5, 10 or 20 mg daily for the first 12 days of each calendar month. Endometrial tissue obtained on the sixth day of combined therapy in the third or subsequent treatment cycle was subjected to histological, ultrastructural and biochemical assessments. Dydrogesterone provoked secretory histological and ultrastructural changes within the endometrium in a dose-dependent manner. A daily dose of 5 mg produced sub-optimal responses but 10 and 20 mg daily produced effects similar to those observed in the secretory phase of the ovulatory cycle. Dydrogesterone 10 mg and 20 mg daily reduced epithelial DNA synthesis and nuclear oestradiol receptor levels to values within the secretory phase range. A dose-response relation was seen in the induction of oestradiol-17 beta and isocitrate dehydrogenase activities; hyperphysiological values were observed with 20 mg of dydrogesterone daily. This study has demonstrated that dydrogesterone exerts potent anti-oestrogenic and progestational effects on the human endometrium which are dose-related. The 10 and 20 mg doses induced responses equal to or greater than those observed in the secretory phase of the ovulatory cycle and both dosages can be recommended for use in combination with exogenous oestrogens in postmenopausal women: and they may also have a role in the management of anovulatory dysfunctional uterine bleeding.

To study the effects of exogenous estrogens on the postmenopausal endometrium, and to determine the time course and minimum dosage of added progestins necessary to oppose estrogen stimulation, we obtained endometrial specimens from symptomatic postmenopausal women being treated with various preparations of estrogens and progestins. Morphologic changes were assessed with light and electron microscopy, and biochemical effects through measurement of DNA synthesis, estradiol and progesterone receptors, and isocitric and estradiol dehydrogenase activity. For comparison, identical studies were carried out on specimens from premenopausal women in the proliferative and secretory phases of their cycle. All the estrogens exerted stimulatory effects in the postmenopausal specimens that were comparable to those observed in the premenopausal proliferative-phase specimens. Estropipate, subcutaneous estradiol, and conjugated estrogens had some hyperphysiologic effects. Maximal progestational effects occurred in the postmenopausal specimens only after norethindrone was administered for six days, and a constant level of activity equal to that in premenopausal secretory-phase specimens was then observed until the 10th day of exposure. Similar maximal effects occurred after six days of treatment with D/L-norgestrel (150 and 5 mg daily [10 mg daily produced less complete changes]). We conclude that many estrogen preparations subject the endometrium to a potent stimulus. Norethindrone and norgestrel are protective because they counteract the proliferative effects of estrogens, but the currently recommended daily dosages of these progestins can be greatly reduced without loss of response.

The major hazard of postmenopausal cyclic estrogen therapy is endometrial hyperstimulation. The incidence of hyperplasia is dose dependent; the incidence of carcinoma is both dose and duration dependent. The risk of carcinoma is small. Invasive procedures such as endometrial biopsy to detect those patients with hyperplasia and carcinoma are unlikely to be cost-effective and have other disadvantages. With cyclic estrogens, biopsies should be performed at regular intervals irrespective of the bleeding pattern. The possible alterations to cyclic treatments to reduce the risk of endometrial hyperstimulation have been reviewed; only progestogen addition has been shown to be effective. Maximal effects are obtained when progestogens are added for 12 to 13 days each calendar month. To reduce the risk of side effects, the minimum dose of progestogen should be prescribed, and with the nor-testosterone derivatives, a small dose of norethindrone, approximately 1 mg daily, is as effective as 5 mg daily. The smaller doses cause minimal lipid changes. Interpatient variation in response to the 17-hydroxyprogesterone derivatives can occur, and at high doses, adverse lipid effects have been reported. With sequential estrogen/progestogen therapies, the endometrial histology appears to correlate with the bleeding pattern, thereby, perhaps, obviating the need for biopsy. The development of regimens to induce endometrial atrophy and amenorrhea is suboptimal, and further research is required.

A major function of calcitonin in humans appears to be maintenance of the skeleton. There is a marked sex difference in circulating calcitonin levels: women have much lower levels. This has led to speculation that calcitonin lack may be one factor involved in the pathogenesis of postmenopausal bone loss. We have measured levels of calcitonin and the other major calcium-regulating hormones in healthy women during the early menopause, and studied the effects of reversing their oestrogen deficiency with natural and synthetic oestrogen. The major findings were that calcitonin levels were increased by oestrogen administration (P less than 0.02-less than 0.001) and that the levels of the bone-resorbing hormones, parathyroid hormone and 1,25 dihydroxyvitamin D, were not higher in postmenopausal than in premenopausal women. We suggest that loss of oestrogen at the menopause accelerates the natural age-related decline of calcitonin secretion, thus further decreasing the calcitonin levels. This leads to increased sensitivity of the skeleton to the actions of the bone-resorbing hormones. It seems likely that the well-known effect of oestrogen in preventing postmenopausal bone loss is achieved, at least in part, by enhancement of calcitonin secretion.