Skeletal effects of oral oestrogen compared with subcutaneous oestrogen and testosterone in postmenopausal women.

STUDY OBJECTIVE--To compare oral and implanted oestrogens for their effects in preventing postmenopausal osteoporosis. DESIGN--Non-randomised cohort study of postmenopausal women treated with oral or depot oestrogens and postmenopausal controls. SETTING--Gynaecological endocrine clinic in tertiary referral centre. PATIENTS--Oral treatment group of 37 postmenopausal women (mean age 57.5 years, median 8.75 years from last menstrual period), compared with 41 women given oestrogen implants (mean age 56.2 years, median 9.5 years from last menstrual period) and 36 controls (mean age 51.8 years, median 2.0 years from last menstrual period). Weight was not significantly different among the groups. INTERVENTIONS--Oral treatment group was given continuous treatment with cyclic oestrogen and progesterone preparations (Prempak C or Cycloprogynova) for a median of 8.0 years. Implant group was given subcutaneous implants of oestradiol 50 mg combined with testosterone 100 mg, on average six monthly for a median of 8.5 years. Controls were not treated. END POINT--Significant increase in bone density. MEASUREMENTS AND MAIN RESULTS--Bone density measured by dual beam photon absorptiometry was 1.02 (SD 0.13) g hydroxyapatite/cm2 in implant group versus 0.89 (0.11) in oral group (p less than 0.01) and 0.87 (0.14) in controls (p less than 0.01). Serum oestradiol concentration in implant group was (median) 725 pmol/l versus 170 pmol/l in oral group (p less than 0.01) and 99 pmol/l in controls (p less than 0.01). Serum follicular stimulating hormone was median 1 IU/l (range 1-11) in implant group (equivalent to premenopausal values) versus 43 (4-94) IU/l in oral group (p less than 0.01) and 72 (28-99) IU/l in controls (p less than 0.01). CONCLUSIONS--Subcutaneous oestrogen is more effective than oral oestrogen in preventing osteoporosis, probably owing to the more physiological (premenopausal) serum oestradiol concentrations achieved. It also avoids problems of compliance that occur with oral treatment.     

Increased risk of atherosclerosis in women after the menopause.

An increase in the incidence of cardiovascular disease has generally been observed in postmenopausal women, but there have been few studies of the association between menopausal state and atherosclerosis. In this study 294 premenopausal and 319 postmenopausal women aged 45 to 55 were examined radiographically for calcified deposits in the abdominal aorta, which have been shown to represent intimal atherosclerosis. Aortic atherosclerosis was present in eight (3%) of the premenopausal women and in 38 (12%) of the postmenopausal women. After adjustments for age and other indicators of cardiovascular risk women with a natural menopause had a 3.4 times greater risk of atherosclerosis than premenopausal women (95% confidence interval 1.2 to 9.7; p less than 0.05); women who had had a bilateral oophorectomy had a 5.5 times greater risk (1.9 to 15.8; p less than 0.005). No excess risk of atherosclerosis was observed among women who had had a hysterectomy without removal of both ovaries. These results suggest that when oestrogen production stops, either naturally or after surgery, the risk of atherosclerosis is increased.     

Oestrogen receptor content of normal breast cells and breast carcinomas throughout the menstrual cycle

To examine the presence and distribution of oestrogen receptors in the normal breast during the menstrual cycle cytological samples obtained by fine needle aspiration from 69 premenopausal women with normal breasts were analysed immunocyto-chemically with a monoclonal antibody to oestrogen receptor; samples from 15 postmenopausal women were also analysed. The receptor content of breast cancers from 83 premenopausal women was also determined in relation to when during the menstrual cycle excision was performed. In the normal premenopausal women oestrogen receptors were detected in the nuclei of epithelial cells in 21 out of 68 (31%) assessable samples. All 21 of these samples were obtained from the 35 women who were studied during the first half of their menstrual cycle (days 28 to 14). None of the 33 samples obtained during the second half of the cycle contained oestrogen receptors. Samples were assessable in eight of the postmenopausal women, six giving a positive result for oestrogen receptor. Fifty one of the 83 carcinomas were positive for oestrogen receptor, 24 having been excised during the first half of the cycle and 27 during the second half.Production of oestrogen receptor protein is suppressed at the time of ovulation in the normal breast epithelium of premenopausal women. In contrast, breast carcinoma cells either synthesise this protein continuously throughout the cycle or fail to express it despite fluctuations of serum hormone concentrations.     

Postmenopausal oestrogen treatment and stroke: a prospective study.

STUDY OBJECTIVE--To determine whether post-menopausal oestrogen use affects the risk of dying from stroke. DESIGN--Postal questionnaire survey to elicit details of oestrogen replacement therapy and potential risk modifiers. SETTING--Californian retirement community. PARTICIPANTS--All 22,781 residents of community (white, affluent, well educated) contacted by mail and phone; 13,986 (61%, median age 73) responded, including 8882 women. These formed cohort for mortality follow up, using health department death certification. Only 13 lost to follow up, apparently not deceased, but 34 excluded because no information on oestrogen use. INTERVENTIONS--None. END POINT--Mortality rate from stroke compared in women who did and did not receive oestrogen replacement treatment. MEASUREMENTS AND MAIN RESULTS--Age adjusted mortality rates were computed using internal standard and four age groups. By January 1987 there had been 1019 deaths in the cohort. Twenty out of 4962 women who used oestrogen replacement treatment died from stroke compared with 43 out of 3845 women who did not use oestrogen replacement treatment: relative risk 0.53, 95% confidence interval 0.31 to 0.91. Protection was found in all age groups except the youngest and was unaffected by adjustment for possible confounding factors (hypertension, smoking, alcohol, body mass index, exercise). CONCLUSIONS--Oestrogen replacement treatment protects against death due to stroke.     

Oestrogen receptors and survival in early breast cancer.

Oestrogen receptor status was related to survival in 414 patients with primary breast cancer. Women with oestrogen receptors in their tumours survived significantly longer than those without receptors; this was true for both premenopausal and postmenopausal women and also when the patients were subdivided into those with and without axillary metastases. Patients with axillary metastases and no oestrogen receptors in their tumours had the worst prognosis, while women with axillary metastases and oestrogen receptors had a death rate similar to that of women with no axillary metastases and no receptors. Patients without oestrogen receptors and with no axillary metastases were identified as a high-risk group, and it would seem appropriate to include such patients in future trials for adjuvant therapy in early breast cancer.     

The relationship of the oestrogen and progestin receptors in the abnormal uterus of the adult anovulatory rat. Effects of neonatal treatment with testosterone propionate or clomiphene citrate.

The neonatal administration of testosterone propionate to Wistar rats resulted in anovulatory adults in persistent vaginal oestrus. Clomiphene citrate had a similar effect. In both groups of adults, hyperplasia of the uterine epithelium and occasional metaplasia was observed. The uterine nuclear and cytosol oestrogen and progestin receptors of these anovulatory rats were found to have affinities for their respective ligands similar to those of normal females. The nuclear oestrogen receptor comprised occupied and unoccupied components, as in normal females. The content of the nuclear oestrogen receptor was comparable with that of females in the late dioestrous or pro-oestrous phase. This content was higher in the clomiphene-treated group. Despite the relatively high nuclear oestrogen receptor content the content of progestin receptors, a putative index of the oestrogenic response, was lower in the treated rats than in normal adult females throughout the cycle. Administration of oestradiol to both treatment groups resulted in depletion of cytosol oestrogen receptor content 1 h later, which, however, was not reflected by an increase in the content of nuclear oestrogen receptors. There was no measurable increase in progesterone receptor content in treated rats after daily administration of oestrogen (5 microgram/rat) for 3 days. These changes in sex-hormone-receptor interactions involving an impairment of the normal oestrogenic response may be associated with the abnormal differentiation of the uterus in these sterile, anovulatory animals.     

Effect of raloxifene on vascular endothelial growth factor expression in breast carcinomas of postmenopausal women

Objective:  This study aimed to evaluate the effect of raloxifene on vascular endothelial growth factor (VEGF) expression in breast carcinomas of postmenopausal women.
Materials and methods:  Sixteen postmenopausal patients with operable stage II, oestrogen receptor-positive, infiltrating ductal breast carcinoma were treated with raloxifene at a dose of 60 mg/day, for a period of 28 days prior to definitive surgery. Tumour size varied from 3 to 5 cm (mean 3.7 cm) and mean age of patients was 61.8 years (range 49–72 years). Tumour samples were obtained by incisional biopsy at the time of diagnosis and again at the time of surgery. Immunohistochemical evaluation of VEGF expression was assessed semiquantitatively based on fraction of stained tumour cells and on intensity of staining. McNemar's test of symmetry was used to evaluate agreement between positive or negative classification of VEGF expression prior to and following raloxifene treatment ( P  < 0.05).
Results:  Fourteen of the 16 patients (88%) were classified as positive for VEGF expression prior to raloxifene treatment, while only 5 (31%) were classified as positive following treatment ( P  < 0.007).
Conclusion:  Raloxifene significantly reduced VEGF expression in these oestrogen receptor-positive breast carcinomas of postmenopausal women.     

Effect of Hormonal Therapy on Plasma Testosterone Levels in Prostatic Carcinoma

Plasma concentrations of testosterone were estimated in normal men, in patients before treatment for prostatic cancer, and in patients who had had various forms of endocrine treatment for prostatic carcinoma. There was no decline in plasma testosterone levels with age. Patients with non-metastatic disease had levels similar to those of normal controls, but in advanced metastatic disease the levels were low. After orchidectomy the plasma testosterone level fell to that found in normal women. In every patient stilboestrol in doses as small as 1 mg three times a day suppressed plasma testosterone at first to negligible amounts, irrespective of the clinical response. Subsequently a small but significant rise in the concentration was always observed over a period of six months'' oestrogen therapy. Pituitary ablation with yttrium-90 lowered the plasma testosterone concentration again to negligible amounts in patients who had been on stilboestrol. In advanced metastatic disease this was often associated with relief of pain. Preliminary studies with aminoglutethimide indicate that it can produce biochemical and clinical effects similar to those of pituitary ablation.     

Effect of long term hormone replacement on plasma prolactin concentrations in women after oophorectomy.

Plasma prolactin concentrations were studied in 88 oophorectomised women who had been receiving mestranol or placebo for three to 11 years. Thirty one of them were also studied under basal conditions and by tests with thyrotrophin releasing hormone. Under basal conditions the mean prolactin concentration was higher in the oestrogen treated group but under non-rested, clinic conditions the difference was lost because of a rise in prolactin value in the placebo group only. Hence the groups showed a different prolactin response to the mild stress of clinic attendance but the same proportionate responsiveness to thyrotrophin releasing hormone. The data suggest that long term hormone replacement has no significant effect on circulating prolactin concentrations under non-rested, everyday conditions and that the prolactin stimulating effects of minor stress and oestrogen may share a similar mechanism.     

Oestrogen replacement therapy after hysterectomy.

OBJECTIVE--To identify those women who might benefit from oestrogen replacement after hysterectomy. DESIGN--Targeted health screening. SETTING--Large group practice. SUBJECTS--All women aged under 50 who had had a hysterectomy. MAIN OUTCOME MEASURES--Concentration of follicle stimulating hormone, symptom profile, uptake of oestrogen replacement therapy. RESULTS--145 of 1953 women aged 32-49 had had a hysterectomy. 35 of the 41 with bilateral oophorectomy and 27 of 104 with one or more ovaries conserved were taking oestrogen replacement. 62 of the 68 who had ovaries conserved and were not taking oestrogen replacement attended for review, of whom 14 had a follicle stimulating hormone concentration > or = 20 IU/l. 16 of the 19 women identified as potentially able to benefit from oestrogen replacement started treatment and were still on treatment at six months of follow up. CONCLUSION--Systematic review of women who had had a hysterectomy identified an important group who would potentially benefit from oestrogen replacement therapy.     

The response to oestrogen deprivation of the cartilage collagen degradation marker, CTX-II, is unique compared with other markers of collagen turnover

Introduction  

The urinary level of the type II collagen degradation marker CTX-II is increased in postmenopausal women and in ovariectomised rats, suggesting that oestrogen deprivation induces cartilage breakdown. Here we investigate whether this response to oestrogen is also true for other type II collagen turnover markers known to be affected in osteoarthritis, and whether it relates to its presence in specific areas of cartilage tissue.     

Comparative trial of nafoxidine and ethinyloestradiol in advanced breast cancer: an E.O.R.T.C. study.

A randomized clinical trial of nafoxidine, a non-steroidal oestrogen antagonist, and ethinyloestradiol in postmenopausal patients with advanced breast cancer produced objective remissions in 31% of 49 women receiving nafoxidine and in 14% of 49 receiving ethinyloestradiol. The differences in remission rates was almost significant (0.05 less than P less than 0.10). Life-threatening complications were more frequent with ethinyloestradiol than with nafoxidine but the latter produced specific toxic reactions on skin and hair that may limit its practical usefulness. Synthetic oestrogen antagonists may occupy a privileged place in the treatment of breast cancer, and other representatives of this new class of compounds should be accurately assessed in randomized clinical trials.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Reduced serum free thyroxine concentration in postmenopausal women receiving oestrogen treatment.

Thyroid hormone state was assessed in a group of postmenopausal women who had received long term treatment with oestrogen. Serum concentrations of total thyroxine, triiodothyronine, and thyroxine binding globulin were raised compared with those in a control group given placebo; serum concentrations of thyroid stimulating hormone did not differ between the groups. Oestrogen treatment resulted in a significant decrease in the serum free thyroxine concentration and in the ratio of thyroxine to thyroxine binding globulin, which supports the view that oestrogen is the causative factor of the physiological reduction in free thyroid hormone during pregnancy.     

Endometrial disease after treatment with oestrogens and progestogens in the climacteric.

A prospective study of 745 women receiving different regimens of hormone treatment for the climacteric for a total of 21 736 months was performed. There was a lower incidence of endometrial hyperplasia in biopsy specimens in the women receiving cyclical low-dose oestrogen by mouth than in those receiving cyclical high-dose oestrogen by mouth. The incidence of abnormalities in the women receiving sequential oestrogen and progestogen was lower than in either of these two groups. Among the women receiving subcutaneous oestrogen implants the incidence was higher still, but over half of the abnormal specimens were from women who had not taken their progestogen. The incidence of hyperplasia fell with longer courses of progestogen, and no hyperplasia was found in patients taking progestogen for over 10 days each month. The incidence of adenomatous and atypical hyperplasia is significantly reduced by a progestogen when taken for 10 or more days monthly. The absence of vaginal bleeding or of a regular bleeding response does not guarantee histologically normal endometrium in patients taking oestrogens without progestogen.     

Longitudinal associations of the endocrine environment on fat partitioning in postmenopausal women

Among postmenopausal women, declining estrogen may facilitate fat partitioning from the periphery to the intra-abdominal space. Furthermore, it has been suggested that excess androgens contribute to a central fat distribution pattern in women. The objective of this longitudinal study was to identify independent associations of the hormone milieu with fat distribution in postmenopausal women. Fifty-three healthy postmenopausal women, either using or not using hormone replacement therapy (HRT) were evaluated at baseline and 2 years. The main outcomes were intra-abdominal adipose tissue (IAAT), subcutaneous abdominal adipose tissue, and total thigh fat analyzed by computed tomography scanning and leg fat and total body fat mass measured by dual-energy X-ray absorptiometry. Serum estradiol, estrone, estrone sulfate, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate), sex hormone-binding globulin (SHBG), and cortisol were assessed. On average, in all women combined, IAAT increased by 10% (10.5 cm(2)) over 2 years (P < 0.05). Among HRT users, estradiol was inversely associated with, and estrone was positively associated with, 2-year gain in IAAT. Among HRT nonusers, free testosterone was inversely associated with, and SHBG was positively associated with, 2-year gain in IAAT. These results suggest that in postmenopausal women using HRT, greater circulating estradiol may play an integral role in limiting lipid deposition to the intra-abdominal cavity, a depot associated with metabolically detrimental attributes. However, a high proportion of weak estrogens may promote fat partitioning to the intra-abdominal cavity over time. Furthermore, among postmenopausal women not using HRT, greater circulating free testosterone may limit IAAT accrual.     

Whole body vibration exercise improves body balance and walking velocity in postmenopausal osteoporotic women treated with alendronate: Galileo and Alendronate Intervention Trail (GAIT)

A randomized controlled trial was conducted to determine the effect of 6 months of whole body vibration (WBV) exercise on physical function in postmenopausal osteoporotic women treated with alendronate. Fifty-two ambulatory postmenopausal women with osteoporosis (mean age: 74.2 years, range: 51-91 years) were randomly divided into two groups: an exercise group and a control group. A four-minute WBV exercise was performed two days per week only in the exercise group. No exercise was performed in the control group. All the women were treated with alendronate. After 6 months of the WBV exercise, the indices for flexibility, body balance, and walking velocity were significantly improved in the exercise group compared with the control group. The exercise was safe and well tolerated. The reductions in serum alkaline phosphatase and urinary cross-linked N-terminal telopeptides of type I collagen during the 6-month period were comparable between the two groups. The present study showed the benefit and safety of WBV exercise for improving physical function in postmenopausal osteoporotic women treated with alendronate.     

Future uses for aromatase inhibitors in breast cancer

Over recent years highly potent, well-tolerated aromatase inhibitors have been developed, which essentially obliterate peripheral aromatase activity in postmenopausal women. Their role as the optimal second-line agents (post-tamoxifen) for the treatment of advanced breast cancer has recently been established in large comparative clinical trials. Their testing as adjuvant therapy is warranted, but their eventual application in this (or the prophylactic) setting will be dependent on the currently unknown effects of profound oestrogen deprivation on the physiology of postmenopausal women as well as on its efficacy. It is also possible that these new compounds could suppress oestrogen synthesis in premenopausal women, but the consequences on ovarian folliculogenesis might prevent their widespread use in this group of patients.     

Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study.

OBJECTIVE--To examine the role of peak bone mass and subsequent postmenopausal bone loss in the development of osteoporosis and the reliability of identifying women at risk from one bone mass measurement and one biochemical assessment of the future bone loss. DESIGN--Population based study. SETTING--Outpatient clinic for research into osteoporosis. SUBJECTS--178 healthy early postmenopausal women who had participated in a two year study in 1977. 154 of the women underwent follow up examination in 1989, of whom 33 were excluded because of diseases or taking drugs known to affect calcium metabolism. MAIN OUTCOME MEASURES--Bone mineral content of the forearm and values of biochemical markers of bone turnover. RESULTS--The average reduction in bone mineral content during 1977-89 was 20%, but the fast losers had lost 10.0% more than had the slow loser group (mean loss 26.6% in fast losers and 16.6% in slow losers; p less than 0.001). Prediction of future bone mineral content using baseline bone mineral content and estimated rate of loss gave results almost identical with the actual bone mineral content measured in 1989. Seven women had had a Colles'' fracture and 20 a spinal compression fracture. The group with Colles'' fracture had low baseline bone mineral content (34.7 (95% confidence interval 31.3 to 38.1) units v 39.4 (38.1 to 40.8) units in women with no fracture) whereas the group with spinal fracture had a normal baseline bone mineral content (38.1 (35.0 to 41.1) units) but an increased rate of loss (-2.4 (-3.5 to -1.3)%/year v -1.8 (-2.1 to -1.5)%/year in women with no fracture). CONCLUSIONS--One baseline measurement of bone mass combined with a single estimation of the rate of bone loss can reliably identify the women at menopause who are at highest risk of developing osteoporosis later in life. The rate of loss may have an independent role in likelihood of vertebral fracture.     

Relations between bleeding pattern,endometrial histology,and oestrogen treatment in menopausal women

Vacuum curettage was performed on 348 women who had received various regimens of oestrogen treatment for an average of 9·7 months for climacteric symptoms. In 62 cases (18%) the specimens were unsatisfactory for histological assessment; among the remainder, however, they showed a normal endometrium in 257 cases (90%), cystic hyperplasia in 21 (7%), adenomatous hyperplasia in 7 (2%), and endometrial adenocarcinoma in one. Cyclical unopposed oral oestrogen treatment (98 cases) was associated with a 12% incidence of endometrial hyperplasia, but among those given an additional five-day course of progestogen in each cycle (37 cases) the incidence was only 8%. No case of hyperplasia occurred among 102 women taking regimens including 10 or 13 days of progestogen. Among women treated with subcutaneous oestradiol implants and monthly five-day courses of oral progestogen (50 cases) there was a 28% incidence of hyperplasia including the one case of carcinoma, though some of those with hyperplasia may not have taken the full course of progestogen. Regular withdrawal bleeding during treatment was associated with a lower incidence of endometrial hyperplasia (6%) than unscheduled breakthrough bleeding (28%), but the one patient with carcinoma had experienced regular bleeding only.The risk of developing endometrial carcinoma from oestrogen treatment may be reduced by avoiding the use of unopposed oestrogen regimens, the addition of more than five days'' treatment with a progestogen, and recognising that a regular bleeding response to oestrogen is no guarantee of a healthy endometrium.