Transvaginal ultrasonography and endometrial histology in peri- and postmenopausal women on hormone replacement therapy.

OBJECTIVE: To determine the association between endometrial thickness and endometrial histology in a large sample of women using HRT. DESIGN: Results from three multi-centre studies were combined. PARTICIPANTS: Five hundred and sixty-four climacteric women were treated with either sequential, continuous combined or long-cycle therapy. MAIN OUTCOME MEASURES: The women underwent 717 examinations with both transvaginal ultrasonography and histological examination of the endometrium. Endometrial thickness was measured and associated with the histological findings. RESULTS: Eight cases of endometrial hyperplasia were diagnosed. All the hyperplasias were simple without atypia. Two cases had an endometrial thickness < 4 mm and two a thickness > 8 mm. The > 4 mm threshold for abnormal endometrium had a sensitivity of 75%, a specificity of 47%, a positive predictive value of 2% and a negative predictive value of 99%. CONCLUSION: No association could be found between the endometrial thickness measured by transvaginal ultrasonography and endometrial pathology. In six out of eight women with simple hyperplasia the endometrium measured > 4 mm.

Seventeen year follow-up study of bone mass in patients with mild asymptomatic hyperparathyroidism some of whom were operated on.

OBJECTIVE: To compare the effect of operation and observation on bone mineral mass in patients with mild asymptomatic hyperparathyroidism (HPT). DESIGN: A randomised 17-year follow-up study. SETTING: University hospital, Sweden. SUBJECTS: 48 women who had been diagnosed as having asymptomatic HPT during a health screening survey in Stockholm, Sweden during 1971-73. INTERVENTIONS: 26 patients were operated on and 22 were observed. 46 normocalcaemic women served as a reference population. 17 years later, operated on (n = 12), not operated on (n = 8) and control subjects (n = 16) were followed up. MAIN OUTCOME MEASURES: Bone mineral content (BMC) of distal non-dominant forearm, and serum concentrations of calcium and creatinine. RESULTS: On entering the study in 1971-73, the BMC of the distal forearm was 14% lower in the patients with HPT than in age, body mass, and postmenopausal age-matched controls (mean (SD) 1.01 (0.23) compared with 1.18 (0.30) g/cm; p < 0.05). During the first 3 years after operation bone mass increased significantly in the group operated on (n = 26) to 106% of the initial values (95% confidence interval (CI) 100% to 111%), remained unchanged (mean 101%; (97% to 106%)) in the unoperated group (n = 22), and decreased significantly to 94% (92% to 97%) of the initial values in the reference group (n = 46). At follow up 17 years later BMC of distal radius in the operated group (n = 12) and patients treated conservatively (n = 8) showed similar values; that were not significantly lower than those of the controls (difference: -12 (18)%). CONCLUSIONS: Our results suggest that patients with mild asymptomatic HPT have already experienced their major bone loss when diagnosed. Parathyroidectomy had an initial positive effect on bone mineralisation, but we could find no long-term advantage in operative treatments. During the 17 year follow-up period HPT patients who were not operated on showed an improvement in bone mass compared with healthy control subjects.

Denser trabecular bone in women with endometrial carcinoma.

Bone mineral density (BMD) was measured in the distal radius of patients with endometrial carcinoma (EC). The patients were classified into two subgroups depending on whether earlier hormonal replacement therapy (HRT) was given. Two groups of women were recruited as controls: patients with post-menopausal bleeding for non-malignant reasons (hospital controls) and healthy women, free of gyn-ecologic symptoms (non-hospital controls). The BMD was significantly higher in the cancer patients and also in the hospital controls than in the non-hospital controls. When several possible confounding factors were checked for in a multivariate analysis, BMD still differed between the groups. This could lend support to the hypothesis that patients with EC may have an altered endogenous endocrine status which eventually affects their bone mass. The results also stress the importance of using strictly defined, healthy women as controls.

Is there an altered steroid profile in patients with endometrial carcinoma?

BACKGROUND: Besides the well-known association between endometrial carcinoma (EC) and unopposed estrogen, androgens also may play a role in this respect; however, previous studies on endogenous estrogens and androgens in patients with EC and control subjects have yielded mostly divergent results, probably because of the use of poorly defined control groups. METHODS: Circulating steroid and pituitary hormones and sex hormone-binding globulin were measured in patients with EC and matched control groups of either patients with nonmalignant postmenopausal bleeding (hospital control subjects) and healthy, symptom-free women (nonhospital control subjects). RESULTS: Patients with EC had higher serum levels of adrenal C21 and C19 steroids, estrogens, and biologically active testosterone than nonhospital control subjects, whereas the hospital control subjects constituted an intermediate group in this respect. CONCLUSIONS: The results clearly indicate an altered steroid homeostasis, probably reflecting an increased "adrenal drive" in patients with EC. The results also stress the necessity of using strictly defined, healthy, symptom-free control subjects instead of the frequently used hospital control subjects when studying more subtile endocrine aberrations.

Reduced risk of hip fracture in women with endometrial cancer.

The effect of excessive endogenous oestrogens on the risk of hip fracture was investigated in a population-based cohort of 2111 women with endometrial carcinoma who were followed up from age 50 years regarding the occurrence of a first hip fracture. Overall, 77 cases of hip fracture were observed, as against 120.8 expected, which meant a significantly reduced relative risk, standardized incidence ratio (SIR) = 0.6, 95% confidence interval (CI): 0.5-0.8. This possible protective effect was significant for cervical fractures, SIR = 0.6 (95% CI: 0.4-0.8), but not for trochanteric, SIR = 0.8 (95% CI: 0.5-1.1). Age at endometrial cancer diagnosis was not a determinant of the risk of hip fracture. A lowered relative risk was present regardless of age at diagnosis and persisted during the entire follow-up period and into advanced ages. A case-control analysis within the cohort, and based on medical record data, indicated that a higher weight might be associated with a greater protective effect, as compared with a lower weight. Exposure to exogenous oestrogens was infrequent and could not have explained the present results. We conclude that persistent influence of oestrogens, notably of endogenous origin, can reduce the risk of hip fractures, and that this protective effect may be long-lasting and extend to advanced ages.

Dehydroepiandrosterone sulfate in postmenopausal women: lack of influence of parity.

Serum concentrations of dehydroepiandrosterone sulfate (DHAS) were analyzed in 251 healthy, medicine-free postmenopausal women 46-65 years of age. Twentyfour of the women were nulliparous and 227 parous (1- to 7-parous). There was no association, whatsoever, between parity and DHAS levels. The data are at variance with previous findings in menstruating women of higher DHAS levels in nulliparous than in parous women. This difference between menstruating and postmenopausal women may reflect an influence of age per se on DHAS metabolism. It may also reflect the exclusion in this study of women with i.e. endometrial hyperplasia/cancer, diseases often associated with elevated DHAS levels and increased risk for nulliparous women.

Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: differences related to age and sex.

Serum concentrations of dehydroepiandrosterone sulphate (DHAS) were determined in 590 healthy women aged 20-87 yr. Simultaneous assays of dehydroepiandrosterone (DHA) were performed in 417 of the women. DHA and DHAS levels correlated negatively with age while the DHA/DHAS ratio proved to be unrelated to age. When values for 60 healthy men in the age range 20-84 yr were compared with those obtained in 60 randomly-selected healthy women who were exactly age-matched, the DHAS levels were found to be significantly lower and the DHA/DHAS ratios significantly higher in the women. These results might be of use in establishing normal clinical ranges for serum DHA, DHAS and the DHA/DHAS ratio in women.

Dehydroepiandrosterone sulfate in saliva.

Concentrations of dehydroepiandrosterone sulfate (DHAS) in saliva and serum were determined in 11 healthy men aged 23-40 yrs, 55 healthy, non-medicated women aged 20-81 yrs and 13 healthy women aged 20-30 yrs, all taking combined oral contraceptives (OC). Serum DHAS was higher in men than in women of corresponding age and was negatively correlated to age in OC-free women. These sex- and age-related differences were not found for salivary DHAS. Salivary and serum DHAS values were poorly correlated and the ratios between salivary and serum DHAS were variable, with a tendency to higher values in older subjects. Low saliva/serum DHAS ratios were found in OC users. The lack of a uniform, unequivocal relation between DHAS concentrations in saliva and serum renders salivary DHAS assays unsuitable for clinical purposes.

Adrenal steroids in post-menopausal women: relation to obesity and to bone mineral content.

Basal levels and ACTH-induced increments of serum 17 alpha-hydroxyprogesterone (170HP), cortisol, 4-androstene-3,17-dione (A-4), dehydroepiandrosterone (DHA), and dehydroepiandrosterone sulphate (DHAS) were related to the degree of obesity and to trabecular bone mineral density in 29 postmenopausal women. The ACTH-induced increment of 170HP (delta 170HP) was negatively correlated to basal DHA and delta DHA. Positive correlations were found between obesity, expressed as Broca's index, and delta DHA and the delta DHA/delta 170HP ratio. Bone mineral density was positively correlated to basal DHAS, delta DHA, delta DHAS and the delta DHA/delta 170HP ratio, and negatively correlated to delta 170HP. DHA and 170HP represent a crossroad in adrenocortical steroid biosynthesis, leading to delta 5-androgens and glucocorticoids as main products. Besides age, obesity may also influence the intra-adrenal distribution between these two main steroidogenic pathways. The results suggest that differences at a very early stage of the adrenal steroidogenesis may influence calcium homeostasis in the post-menopausal woman.

Serum sex hormone binding globulin (SHBG), testosterone/SHBG index, endometrial pathology and bone mineral density in postmenopausal women.

Serum levels of sex hormone binding globulin (SHBG) and testosterone (T) and bone mineral density (BMC) in the non-dominant forearm were determined in 28 postmenopausal women aged 44-62 years. Significant correlations (Spearman's rank correlation test) were found between BMC and SHBG (negative) and between BMC and the T/SHBG index on biologically active androgen (positive). Significant correlations were also found between endometrial pathology (Kruskal-Wallis test; 0 = atrophic, 1 = hyperplasia, 2 = cancer) and SHBG (negative) and the T/SHBG index (positive). It is suggested that SHBG may act as one common denominator in the pathogenesis of postmenopausal osteoporosis and endometrial disease by regulating the levels of unbound, biologically active androgens and estrogens.

Clinical experience with a low-dose combination of estradiol valerate and levonorgestrel. Double-blind comparative study between SH D 386 F and Cyclabil. Effects on symptoms, lipids and endometrial condition.

In a double blind study of the effects of hormone replacement therapy in climacteric women, two different dosages of estradiol--17 beta valerate and levonorgestrel, with the same ratio between the amounts of the two steroids (Cyclabil and the trial preparation having the code number SH D 386 F respectively), were compared. The differences in effects on symptoms, certain humoral parameters including serum lipids, and endometrial histology before and after 12 months of therapy were evaluated. The study population consisted of 120 healthy women in the age range 41-63 years, many of whom had undergone previous estrogen treatment. All had typical climacteric symptoms and were peri- or postmenopausal. There were no significant differences between the two preparations as regards the effects on symptoms--except for episodes of hot flushes and depression (loss of confidence), which were more frequent during treatment with the higher dosage. One of the main objects of the study was to determine whether the lower dosage would be sufficient to prevent the development of endometrial hyperplasia. To this end, endometrial samples were collected before and after 12 months of treatment, using "Mi-markTM" disposable equipment for endometrial cytology/histology. No significant endometrial hyperplasia was found in either of the groups during the period of investigation. The serum lipid pattern was evidently more influenced in the group treated with Cyclabil. The drop-out rate was 20%, most of them being due to side effects of mild to moderate severity such as undesirable withdrawal bleedings or unsatisfactory relief of symptoms, which sometimes resulted in a wish to return to earlier treatment regimens.

Relative fatty acid composition of lecithin during postmenopausal replacement therapy--a comparison between ethinyl estradiol and estradiol valerate.

The relative fatty acid composition of serum lecithin was followed in groups of women during postmenopausal replacement therapy. The effects of estradiol valerate and ethinyl estradiol in two different doses, and the modulating influence of various progestogens and antiestrogens were compared. Unopposed estrogen treatment enhanced liver lecithin synthesis along pathway I, i.e. reduced the amount of stearic acid and increased the amount of palmitic acid. The effect was clearly dose-dependent and even the low dose of 10 micrograms of ethinyl estradiol was more potent than 2 mg of estradiol valerate. No qualitative difference between the two estrogens was recorded. The sequential addition of the antiestrogen tamoxifen significantly reduced the influence of ethinyl estradiol. Liver lecithin synthesis along pathway I may be stimulated by all estrogens and not only by 17C-alkylated compounds. The prostaglandin precursors, dihomogammalinolenic and arachidonic acid, showed a seemingly dose-dependent increase during estrogen treatment. The comparatively weaker effects of estradiol valerate on lipid metabolism should make this non-alkylated estrogen the first choice in clinical practice.

Peripheral hormone levels and the endometrial condition in postmenopausal women.

Thirteen postmenopausal women with benign endometrial changes including proliferative, secretory and polypous endometrium, endometrial hyperplasia and atypia (group I) and 13 randomly selected age-matched controls with normal atrophic endometrium (group II) were studied with respect to serum levels of dehydroepiandrosterone (DHA) and its sulfate (DHAS), testosterone, total estrone, estradiol-17 beta, progesterone, FSH and prolactin. Serum levels of DHA, DHAS, testosterone and total estrone were significantly higher in group I than in group II; otherwise no significant differences were found. Mean values for body weight and for Broca's index, respectively, were almost identical in the two groups. It is speculated that the adrenal androgens may affect the endometrium in two ways, viz. via peripheral conversion to estrogens and/or via direct interaction with endometrial steroid receptors. The results give further support to the hypothesis of an association between adrenocortical hyperactivity and endometrial abnormalities including endometrial carcinoma.

Serum levels of 4-androstene-3,17-dione in menstruating and postmenopausal women. Evaluation of a radioimmunoassay and correlation with bone mineral content and endometrial pathology.

A radioimmunoassay for serum 4-androstene-3,17-dione (A-4) using anti-4-androstene-3, 17-dione-11 alpha-hemisuccinate bovine serum albumin was applied to serum samples from 16 healthy, normally menstruating women in different phases of the menstrual cycle, from 36 healthy postmenopausal women and from 23 postmenopausal women with various bone mineral contents and endometrial conditions, undergoing an acute ACTH stimulation test. The values obtained in the normal subjects were consistent with those found in the literature. A-4 levels were significantly higher at midcycle than in the follicular phase and were significantly lower in postmenopausal than in menstruating women. ACTH increased the levels of A-4 significantly. However, no significant correlation was found between basal levels or the ACTH-induced increments of A-4 on the one hand and bone mineral content, endometrial condition and the patients' weight, age, or Broca's index on the other. This is in contrast to our previous finding of significant correlations between basal dehydroepiandrosterone sulfate and ACTH-induced increments in dehydroepiandrosterone on the one hand and bone mineral content on the other in the same clinical material. We discuss whether the differences in correlations to bone mineral content between the two adrenocortical androgens may be due to a rather more complex origin of the steroid moiety of A-4.

Adrenocortical steroids, bone mineral content and endometrial condition in post-menopausal women.

In 23 post-menopausal women, serum levels of cortisol, unconjugated dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), testosterone, unconjugated and total oestrone and prolactin were measured before and during an ACTH test. Significant positive correlations were found between basal levels of DHA and DHAS; DHA and unconjugated oestrone; DHA and total oestrone; testosterone and total oestrone and between unconjugated and total oestrone. ACTH significantly raised the levels of the steroids but not of prolactin. Significant positive correlations were found between basal levels and ACTH induced increments in DHA; between basal DHAS and increments in DHA and between increments in DHA and DHAS. A significant negative correlation was found between basal levels and increments in cortisol. No significant correlations were found between other combinations of hormone basal levels and/or increments. Significant positive correlations were found between basal levels of DHAS and the DHA response to ACTH respectively, and trabecular bone mineral content of the distal forearm. A significant correlation was also found between bone mineral content and pre-cancerous/cancerous state of the uterine epithelium. The results are a further support to the concept of a link between adrenal androgens and bone mineral density, and do also indicate a relation to endometrial pathology. The lack of correlation between cortisol and other steroids indicate different regulatory mechanisms. Prolactin does not seem to be involved in the regulation of the adrenal androgen synthesis.

Treatment with oral estrone sulphate in the female climacteric. II. Hormonal aspects.

Of forty-three perimenopausal women aged 40.1-56.5 years with climacteric complaints 25 were treated with sodium piperazine estrone sulphate 2.5 mg daily and 18 were given methyl scopolamine. All subject had initial serum FSH levels in the postmenopausal range (20 U/l). The serum levels of FSH, LH, unconjugated immunoreactive estrogens, total estrone, total dehydroepiandrosterone (DHAS), and the urinary low polar estrogens were followed during 18 months of treatment. In the estrogen treated group serum unconjugated immunoreactive estrogens and total estrone as well as urinary low polar estrogens increased significantly during treatment. The serum levels of FSH decreased significantly during the whole test period; LH only at three months. No effects could be seen on serum DHAS. In the group given methyl scopolamine the only changes found were a decrease in FSH at three months and a positive trend for LH (during the whole treatment period). In the total material, positive correlations were found between pretreatment values of unconjugated immunoreactive estrogens and total estrone and between total estrone and DHAS. A negative correlation was found between unconjugated immunoreactive estrogens and FSH. It is concluded that the effects of estrogens on the endocrine system in peri- and postmenopausal women are influenced by chemical structure, dosage and mode of administration of the estrogen as well as by the endogenous hormone profile.

Treatment with oral estrone sulphate in the female climacteric. I. Influence on lipids.

Twenty women in the perimenopause were studied for 12 months during which sodium-piperazine-estrone-sulphate 2.5 mg/day was given for 3 weeks out of 4 as a hormone replacement therapy. Blood samples were drawn at the start of therapy, then after 3, 6 and 12 months and analyzed for serum triglyceride, total cholesterol, cholesterol content of high density lipoprotein (HDL) fraction and the relative fatty acid composition of serum lecithin. Triglyceride levels were increased after 3 months (p less than 0.01). After that there was a gradual decline to almost pretreatment levels. Total cholesterol decreased during the latter period of treatment and became virtually normal; significantly lower levels (p less than 0.01) were found at 12 months. The HDL-cholesterol, which constitutes most of the high density lipoprotein fraction, showed a continuous increase and reached statistical significance at 12 months (p less than 0.01). This type of lipoprotein pattern is associated with a reduced risk of ischemic cardiovascular disease. After 3 and 6 months of treatment an increase in the relative content of palmitic acid in serum lecithin was seen, an increase that might indicate an altered liver lecithin synthesis, usually seen in cholestasis. However, after 12 months the palmitic acid level declined and was not significantly altered from the pretreatment value, indicating that the change was transitory.

Treatment with oral estrone sulphate in the female climacteric. III. Effects on bone density and on certain biochemical parameters.

Thirty-eight women were treated with estrone sulphate over a period of 30 months for climacteric problems. A random control group of 29 women were given methyl scopolamine. Bone mineral assays were performed by means of dual photon absorptiometry before the start of treatment and after 6, 12, 18, and 30 months. There was a difference in the mineral loss of trabecular bone between the two groups after 30 months of treatment, that the control group being significantly higher (p less than 0.001). In the estrogen-treated group there was a decrease in serum phosphorus (p less than 0.01), alkaline phosphatase activity (p less than 0.001), and albumin (p less than 0.001). In the control group, serum albumin showed the same decrease, while the other factors either showed no differences or even increased. The urinary excretion of calcium was not significantly reduced in the estrogen group, whereas there was an increase in the control group (p less than 0.01). There was an increase in hematocrit in both groups. Positive correlation was found between parity and loss of trabecular bone mineral (p less than 0.01).U

Adrenal steroids, bone mineral content and endometrial pathology in postmenopausal women.

In 19 postmenopausal women, basal serum levels of cortisol, unconjugated dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), testosterone and unconjugated and total estrone were measured both before and during an ACTH test. A positive correlation was found both between basal levels of DHAS and the DHA response to ACTH, respectively, and trabecular bone mineral content of the distal forearm. A significant correlation was also observed between bone mineral content and precancerous/cancerous states of the uterine epithelium.