The effect of oral hormone replacement therapy on lipoprotein profile, resistance of LDL to oxidation and LDL particle size

Objectives: To disclose if oral estradiol (E₂), alone or in combination with natural progesterone (P) or medroxyprogesterone acetate (MPA), may modify the oxidizability of low density lipoprotein (LDL), and if the effect is achieved at physiological dosages. LDL oxidizability was assessed by the resistance to oxidation by copper and by the particle size profile, since small particles have increased oxidation susceptibility. Methods: Thirty-three women received two consecutive, two-month length doses of 1 and 2 mg/day of oral E₂. They were then randomly assigned to a fourteen-day treatment of 2 mg/day E₂ plus either 300 mg/day P or 5 mg/day MPA. A parallel group of experiments was performed on a pool of baseline plasma, where hormones were added at the desired concentration. Lipoprotein levels, resistance of LDL to oxidation, and LDL particle diameter, were measured at baseline and after each treatment. Results: Estradiol reduced LDL levels and increased high density lipoprotein (HDL) and triglycerides. P abolished these changes, whereas MPA only reversed the increase of HDL. Estradiol protected LDL from oxidation in a dose-dependent manner, although only at pharmacological concentrations (1 μM or higher). Both P and MPA were inert at either physiological or pharmacological concentrations. The size of the LDL particles remained unaffected except under MPA, in which it was reduced. Conclusions: Estradiol has a protective effect against LDL oxidation, although only at pharmacological dosages. P and MPA did not limit the E₂ action. The size of the LDL particles remained unaltered after each E₂ dose, but MPA, and not P, was associated with a diminution.     

Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.     

Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use

Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms. Treatment was with either 2 mg 17β-oestradiol with I mg norethisterone acetate [E₂ + NEta]; 2 mg oestradiol valerate with 75 μg levonorgestrel [E₂V + Lng]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E₂V + Mpa]; or 1.5 mg 17β-oestradiol with 150 βg desogestrel [E₂ + DG]. A placebo-controlled study lasting 12–24 months was completed by 143 healthy early postmenopausal women. Bleeding lengths were not substantially different; in all regimens the majority of women were bleeding for 3–6 days. Bleeding onset showed differences when related to the 11th day of progestogen addition; in the regimen with E₂V + LNG, 21% of the women were bleeding before the 11th day of progestogen addition 26% on, and 53% after that day. In the regimen with E₂V + MPA, 56% of the women were bleeding before the 11th day, 28% on, and 17% after that day, whereas in the regimen with E₂ + DG, 15% of the women were bleeding before the 11th day, 5% on, and 80% after that day. All regimens reduced climacteric symptoms to the same extent. Breast tenderness occurred in all the regimens, except in the E₂ + DG. Conclusively, the differences between the responses to treatment were not conspicuous. However, our data indicate that one regimen (E₂ + DG) resulted in optimal bleeding control, optimal effect on climacteric symptoms, and no production of breast tenderness.     

Endometrial morphology after 12 months of vaginal oestriol therapy in post-menopausal women

The endometrial effect of long-term vaginal oestriol (E₃) therapy for urogenital atrophy was assessed in 23 post-menopausal women. Hysteroscopic and histological examinations were performed in each patient to assess endometrial atrophy before treatment and after 6 and 12 months of therapy (0.5 mg vaginal E₃ for 21 days, then 0.5 mg twice weekly). The primary atrophie picture was confirmed at the end of the 6th month in all but one of the patients. In one case, the histology showed an abnormal stromal reaction with no epithelial alterations. Treatment was continued and after the 12th month complete atrophy was confirmed both hysteroscopicaliy and histologically in all patients. Efficacy as regards vaginal and urogenital complaints was good. Our results demonstrate that in women with endometrial atrophy effective and well-tolerated treatment with vaginal E₃ can be safely continued for up to 12 months.     

Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen on serum lipid profile in early menopausal women

Objective: We investigated the long-term effects of oral estriol (E₃) on serum levels of total cholesterol (t-Cho), high-density lipoprotein cholesterol (HDL-Cho), low-density lipoprotein cholesterol (LDL-Cho), and triglycerides in early menopausal women. Methods: We studied 67 healthy early menopausal women who were treated for 48 months with 2.0 mg of E₃ plus 2.5 mg of medroxyprogesterone acetate daily (E₃ group, n=21), 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily (CE group, n=19), or 1.0 μg of 1-hydroxyvitamin D₃ daily or 1.8 g of calcium lactate containing 250 mg of elemental calcium daily (control group, n=27). The serum levels of t-Cho, HDL-Cho, LDL-Cho, and triglycerides were evaluated at baseline and every 6 months. Results: After 48 months of treatment, the t-Cho decreased significantly by 4.3±2.1% (mean±SE) from baseline in the E₃ group, did not change in the CE group (−1.9±2.1%), and significantly increased (5.4±3.4%) in the control group. The HDL-Cho significantly increased in the CE group (10.7±2.4%), but not in the E₃ group (3.8±3.3%) or in the control group (−3.6±3.0%). The LDL-Cho significantly decreased in the CE group (−11.4±4.0%), did not change in the E₃ group (−5.2±3.6%), and significantly increased in the control group (11.8±6.3%). The triglyceride level decreased significantly in the E₃ group (−6.7±4.9%), whereas it significantly increased in the CE group (17.6±11.4%), and did not change in the control group (6.1±6.4%). Conclusions: Oral E₃ prevented a postmenopausal rise in the t-Cho. Oral estriol did not induce the hypertriglyceridemia that was seen after treatment with conjugated estrogen. Oral E₃ may be a useful alternative therapy in women with hypertriglyceridemia and in women who are reluctant to continue conventional hormone replacement therapy because of uterine bleeding.     

Apolipoprotein A1 levels in oophorectomized women treated with Org OD 14, oestradiol valerate and a placebo

Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium.

The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E₂V) and a placebo.

Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E₂V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period.

There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E₂V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease.

Long-term treatment with OD 14 might therefore be hazardous in this respect.     

Endocrinological and clinical investigations in post-menopausal women following administration of vaginal cream containing oestriol

The maturation value (MV), cervical mucus paråmeters (ferning, Spinnbarkeit), oestrone (E₁), oestradiol (E₂), oestriol (E₃), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyrotropin (TSH), growth hormone (GH), sex hormone binding globulin (SHBG), cortico-steroid binding globulin (CBG) and thyroxin-binding globulin (TBG) were determined in 11 post-menopausal women presenting with vaginal atrophy prior to, and following, treatment with Ovestin® vaginal cream containing 0.5 mg/day of E₃ for 8 wk. In 6 of the patients E₃ was measured during frequent plasma sampling on days 1, 21 and 56; in the same patients and on the same days TRH-stimulated PRL, TSH and GH levels were estimated.

While the therapy induced a sharp rise in the MV, there was a moderate effect on ferning/Spinnbarkeit. Baseline E₃ rose from undetectable levels to a mean value of 86.8 pmol/1 at day 21. E₃ levels achieved during frequent plasma sampling were higher on day 1 than on days 21 and 56 - a decline of the areas under the response curves being significant (P₂-sided = 0.03). There was a slight supression of FSH and LH. No changes in the circulating levels of E₁, E₂, SHBG, CBG, TBG, PRL, TSH and GH were seen. TRH-stimulated PRL, TSH and GH levels remained unaffected. Clinical effect was excellent and no untoward effects were reported.     

Endometrium and plasma hormone profile in the peri-menopause and post-menopause

Endometrial histology and plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E₂), oestrone (E₁) and progesterone (P) were studied in 483 women over a period of 13 yr (6 yr before and 7 yr after the start of definitive amenorrhoea, defined as the last menstrual bleeding). The patterns for these parameters were established on the basis of the results of 1227 gonadotrophin and steroid determinations and 721 endometrial biopsies.

Three periods were identified. During the first, from year −6 to year−3, gonadotrophin levels increased gradually, while those of E₂ remained normal, with peaks in some cases. Mean plasma P levels were within the normal range until year −3, but they then decreased progressively. Endometrial histology was similar to that observed during reproductive life.

In the second period, from year −3 to year +1, there was a concomitant rise in gonadotrophins as the E₂ and P levels decreased. However, at the start of definitive amenorrhoea, the mean E₂ and P levels fluctuated between 60 and 100 pg/ml and between 2 and 3 ng/ml, respectively. The endometrium reflected this decrease in E₂ and P production. It was not atrophic but proliferative when definitive amenorrhoea commenced.

During the last period, from year +1 to year +7, gonadotrophins reached a plateau at high levels, while those of E₂ continued to fall, reaching very low values at year +4, after which they reached a plateau. P levels were at the detection limit of the technique.

The correlations between all plasma steroid levels and endometrial histology demonstrated discrepancies in 30% of cases: prliferative or hyperplastic endometria were seen at E₂ levels of under 60 mg/ml, atrophic endometric at E₂ levels of over 60 pg/ml and secretory endometria at very low P levels.     

The treatment of postmenopausal vaginal atrophy with Ovestin vaginal cream or suppositories: clinical, endocrinological and safety aspects

Seventy-four postmenopausal women presenting with vaginal atrophy were treated with either Ovestin® vaginal cream (Group A, 23 women: 1 mg/day E₃; Group B, 30 women: 0.5 mg/day E₃) or vaginal suppositories (Group C, 21 women: 0.5 mg/day E₃), applied daily for 3 wk (A and B) or 2 wk (C) before retiring. Ten women from A and 10 from B applied a maintenance dose (1 application twice weekly) during wk 4–16. Effects on vaginal cytology, cervical mucus and clinical and colposcopic findings were studied. Endometrial biopsies were done in 16 patients (A) before and after 3 wk of treatment, and, in 8 of the cases, at 16 wk. A routine laboratory screening program was performed before and after 16 wk of treatment in 10 patients (A). Plasma samples for hormone level determinations were obtained in 32 patients.

Clinical and colposcopic findings showed a beneficial effect of treatments, confirmed by vaginal smears, and persisting during maintenance therapy. Effect on cervical mucus was slight to moderate. No side effects occurred and tolerance was very good. Endometrium remained atrophic under treatment. Screening program revealed no abnormalities. Treatments induced a sharp rise in plasma E₃, followed by a gradual decline. Gonadotropins were slightly suppressed. E₁, E₂, PRL and SHBG capacity remained unchanged.     

Developmental, Neuro and Immunotoxic Effects of Perinatal Diazepam Treatment in Rats

In utero exposure of rats to low dosages of diazepam (1.0—2.0 mg/kg) has been found to result in depression of the cellular and humoral immune responses during adulthood. Behavioral dyshnctions were also reported in infants from mothers with high benzodiazepine (BDZ) intake during pregnancy. The present experiment was undertaken to reconsider the potential action of diazepam during ontogeny in order to obtain hrther information about developmental processes using a refined methodology. Time-pregnant rats were treated subcutaneously with diazepam (2.0 mg/kg/day: group E₁) or with diazepam vehicle (group C) from gestational day 14 to 20. Other dams (group E₂) received the same BDZ dose from the 1^st to the 21^st day of lactation (weaning) or were not treated, remaining undisturbed in their home cages (group C₂). The following results were obtained for animals perinatally treated with diazepam compared to groups C1 and C₂: 1- increased time for testis descent and decreased time for vaginal opening (group E₂); 2- no changes in the dates for ear end eye opening, or incisor tooth eruption (groups E₁ and E₂); 3- increased locomotor activity in the open-field (group E₂) and/or in the plus maze (groups E₁ and E₂); 4- decreased levels of anxiety measured in the plus maze (goups E₁ and E₂); 5- decreased macrophage spreading and phagocytosis (groups E₁ and E₂). These results, which occurred in the absence of overt signs of maternal or fetal toxicity, demonstrate developmental, neuro- and immunotoxic effects of perinatal diazepam treatment in rats.     

Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in post-menopausal women

The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE₁S, 2.5 mg/day) and oestradiol valerate (E₂V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 μg/day) were compared in 8 post-menopausal women, using a randomized cross-over design.

The end points measured in peripheral plasma included oestrone (E₁), oestradiol (E₂), oestriol (E₃), oestrone sulphate (E₁S), oestradiol sulphate (E₂S) and oestriol sulphate (E₃S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed.

The plasma levels of E₃ were invariably below the detection limit (220 pmol/1). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E₃S following PE₁S administration than those recorded after E₂V ingestion.

The terminal half-lives of the circulating oestrogens measured after PE₁S administration did not differ from those found after E₂V administration.

After 21 days of PE₁S administration (in combination with LNG for the the last 10 days), the maximum levels of all the oestrogens (except those of E₂) were significantly higher than those seen after the first dose. No such difference was observed after E₂V administration.

There was no difference between the effects of the two treatment regimens with regard to the E₁/ E₂ ratios, but the E₁/E₁S ratios were significantly lower after PE₁S treatment than after E₂V administration.

It is concluded that, compared with an equivalent dose of PE₁S, daily repeated oral administration of E₂V yields consistently lower peripheral plasma levels of E₂ and its principal metabolites. However, in contrast to PE₁S therapy, prolonged administration of E₂V does not result in an accumulation of the circulating oestrogens measured.     

Comparison of pharmacokinetic profiles of a 17β-estradiol gel 0.6 mg/g (Gelestra) with a transdermal delivery system (Estraderm TTS 50) in postmenopausal women at steady state

Objectives: to compare the patterns of a 17β-estradiol (E₂) gel containing 0.6 mg/g (1.5 mg E₂ per day, Gelestra); with the transdermal delivery system (Estraderm TTS 50) applied every 3 days over a 14-day period to women in spontaneous or surgical menopause. Methods: a single centre, open, randomised, parallel-group study was conducted. A total number of 33 postmenopausal women were enrolled. In 23 of them the menopause occurred spontaneously, while 10 women were bilaterally ovariectomized. Randomly, the subjects were treated with Estraderm TTS 50 (no. 8) or with Gelestra (no. 14). The pharmacokinetic study of the drugs was performed at the seventh, ninth and 14th day in Gelestra treated women and at the first, third and second day in Estraderm TTS 50 treated women. In fact, the seventh, ninth and 14th day of percutaneous treatment corresponds to the first, third and second day of application of the transdermal system application. Blood samples were taken by each subject at baseline and 1, 2, 3, 4, 8, 12 and 24 h after the gel or transdermal system application. In almost all samples the level of E₂ and estrone (E₁) were evaluated. Statistical analysis was performed by comparing the two groups of treatment. The following parameters were assessed: mean E₂ and E₁ concentrations, E₂ peak serum concentration within interval from 0 to 72 h (C_max), E₂ trough concentration within interval from 0 to 72 h (C_min), area under the E₂ time concentration curve in the interval from 0 to 72 h (AUC_(0–72)), the average E₂ concentration during the measurement interval, calculated by dividing AUC_(0–72) by 72 h (C_av), E₁/E₂ ratio, and percentage fluctuation (%Fluct) which is equal to 100 (C_max−C_min/C_max). Results: there was no significant difference in E₂ C_av between the two treatments. However, significant differences in favour to the gel on the first day (first h) and on third day (72nd h) and in favour to the patch at the second day (48th h) were detected. C_max, E₁/E₂ ratio and AUC_(0–72) were not statistically different, while a significantly higher C_min for the gel was observed. Furthermore, the 90% confidence interval for AUC_(0–72) ratio (0.83–1.10) was within the commonly applied bioequivalence acceptance range (0.80–1.25). The %Fluct was significantly lower for Gelestra than for Estraderm TTS 50. Conclusions: although the mean E₂ and E₁concentrations, C_max, E₁/E₂ ratio and the AUC_(0–72) did not differ between the two E₂ treatments, the Gelestra treatment showed a lower day-to-day variation over the three day application, than the Estraderm TTS 50.     

Effects of intravaginal oestrogen treatment upon the vaginal absorption of conjugated equine oestrogens

Conjugated equine oestrogens (0.625 mg) were administered daily and intravaginally to 7 post-menopausal women (aged 70–93 yr) for 14 days. Blood samples were taken at days 1 and 14 immediately before and 2, 4 and 6 h after oestrogen application and at days 4, 6, 8, 11 and 13, 4 h after application. Serum samples were analyzed with respect to total oestrone (E₁), unconjugated 17β-oestradiol (E₂), FSH and LH. Serum total E₁ and E₂ increased rapidly at day 1 to luteal and follicular phase levels respectively. After that total E₁ levels decreased to a plateau corresponding to follicular phase values and remained at that level throughout the treatment period. Serum E₂ remained at the follicular phase level during the entire period of treatment. No increase in serum oestrogens could be detected after oestrogen application at day 14. Serum gonadotrophins were already suppressed at day 4 and further decreased to premenopausal values during the latter half of the treatment period. It is speculated that the effects of oestrogens upon a post-menopausal vaginal mucosa involves a diminished resorption of conjugated oestrogens. This effect is, however, not sufficient to avoid systemic effects at the dosage used.     

Changes in normal lipid profile of menopausal women with combined hormone replacement therapy. Comparative clinical trial of two hormonal combinations (conjugated estrogens/medroxyprogesterone acetate versus estradiol valerate/cyproterone acetate).

OBJECTIVES: To compare the effect on plasma lipids of conjugated estrogens/medroxyprogesterone acetate (CE/MPA) and estradiol valerate/cyproterone acetate (EV/CPA) in healthy peri and postmenopausal women during 1 year. METHODS: Multicentric, controlled, single blinded Phase III clinical trial. Women were randomized to two treatment groups: Group A (n = 49 women): CE 0.625 mg/day for 21 days and MPA 5 mg from day 12 to 21. Group B (n = 55 women): EV 2 mg/day for 21 days and CPA 1 mg from day 12 to 21. Total cholesterol (TC), high density cholesterol (HDL-C), low density cholesterol (LDL-C), triglycerides, aminotransferases and alkaline phosphatase were measured before starting therapy, and after 3, 6, 9 and 12 months of hormone replacement therapy (HRT). TC/HDL-C and LDL-C/HDL-C ratios were determined. RESULTS: There were no changes in TC levels. HDL-C increased and LDL-C decreased significantly, with no differences between groups but within each group. Triglycerides increased significantly but remained within normal values, with no differences between groups. TC/HDL-C ratio showed a slight and steady decrease in both groups. LDL-C/HDL-C ratio decreased in both treatment groups. CONCLUSION: Both cyclic sequential preparations used in HRT showed a favorable effect on plasma lipids in healthy peri and postmenopausal women, with an increase in HDL-C and a decrease in LDL-C levels, as well as in the LDL-C/HDL-C and TC/HDL-C ratios. Our study confirms the positive effect of estrogens on lipids, which does not seem to be adversely affected by the addition of progestogens derived from pregnanes.     

Long-term effects of percutaneous estradiol on bone loss and bone metabolism in postmenopausal hysterectomized women

Objective: To determine whether percutaneous estradiol (pE₂) (1.5 mg/day) is able to counteract the postmenopausal bone loss in postmenopausal hysterectomized women, in a double-blind study versus oral estriol (E₃) (2 mg/day). Methods: The bone mineral density of the lumbar spine (LS) and of the proximal femur (PF) was measured every 3 months by dual energy X-ray absorptiometry for 2 years in 43 hysterectomized postmenopausal women (21 in the E₂ group and 22 in the E₃ control group), and in a subset of patients for a 3rd year. The statistical analyses were performed on Macintosh using StatView II^TM. Results: A significant bone loss of 1.2 (0.4)% and of 1.3 (0.3)% per year was observed in the control group, respectively at LS and at PF, versus a significant gain of 1.2 (0.5)% per year in the treated group at the LS. No significant change at PF occurred in the treated group. In the 20 patients followed up for a 3rd year on pE₂, an increase of 1.2 (0.9) and 2.5 (1.4)% at LS in the 12 former active group patients and the eight formerly control patients, respectively was seen. The same trend was observed at the proximal femur. Conclusion: pE₂ (1.5 mg E₂) is able to counteract the postmenopausal bone loss in hysterectomized women, whereas E₃ (2 mg/day administered orally) is unable to maintain bone mass.     

Hormone levels in healthy post-menopausal women and in women with post-menopausal bleeding with or without endometrial carcinoma

FSH, oestrone (E₁), 17β-oestradiol (E₂) and androstenedione (A) were determined in 250 healthy pre- and post-menopausal women, with ages ranging from 40 to 78 yr. These hormone levels were not found to have changed significantly in women of this stable, post-menopausal phase after the age of 54. The results found in this group of women (n = 107), who now range between the ages of 55 and 78, were compared with results from two groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma. The second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma.

FSH was determined by double-antibody radioimmunoassay. E_l, E₂ and A were fractionated chromatographically after extraction with ether and determined radioimmunologically. The data were analysed using the Kruskal—Wallis test and the Wilcoxon test.

When comparing the measurement of hormone levels in the healthy group of women with that of women with post-menopausal bleeding without endometrial carcinoma, no differences were found. However, in the group of women with post-menopausal bleeding and endometrial carcinoma, lower levels of FSH and E₂ and increases in the E₁/E₂ ratio were found; both changes were statistically significant. The slight increase in E₁ and A found in these women was not significant. Any changes which occur in the hormone levels of women with endometrial carcinoma may indicate a correlation between hormones and the onset of endometrial carcinoma.     

Hormone replacement therapy: lipid responses to continuous combined oestrogen and progestogen versus oestrogen monotherapy.

Fifty-five postmenopausal women with climacteric complaints were randomly assigned to treatment with either 2 mg oestradiol valerate (E2V) (cyclic regimen: 21 days of treatment followed by a 7-day treatment-free interval), or 2 mg E2V combined with 1 mg cyproterone acetate (E2V+CPA) daily, over a 6-month period. Treatment was by the oral route in both cases. The aim was to compare the influence of these two hormone replacement therapy regimens on lipid metabolism. Blood samples were obtained before and after 1 and 6 months of treatment. Serum was analyzed for total cholesterol (TC), high-density lipoproteins (HDL), apolipoproteins A1 and B and triglycerides. The low-density lipoprotein (LDL) concentrations were derived by calculation. All parameters were evaluated in terms of mean +/- S.D. There was no significant difference in the response of the blood lipids to the two treatments, as assessed by analysis of variance (P greater than 0.05). Serum levels of TC were found to have fallen after month 1 and 6 by 5.3 and 5.6%, respectively, during E2V treatment and by 2.4 and 0.2% during E2V+CPA treatment. Serum HDL levels had increased after months 1 and 6 by 9.7 and 5.2%, respectively, in the E2V group and by 6.9 and 2% in the E2V+CPA group, which was also confirmed by the increase in apolipoprotein A1 levels. There was, however, a borderline increase in LDL and apolipoprotein B in the E2V+CPA group. Serum triglycerides were reduced and serum levels of SHBG increased during treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of vaginally-administered oestriol on post-menopausal urogenital disorders: a cytohormonal study

Forty post-menopausal women with urogenital disorders who were inpatients in the same geriatric hospital were treated with oestriol (E₃) for 6 weeks. For the first 2 weeks 0.5 mg E₃ (Leo AB, Sweden) was administered intravaginally every day. Over the following 4 weeks the patients received the same quantity either once or twice weekly as a maintenance dose. Oestrogen influence on the vaginal and urethral epithelium was assessed by means of the karyopyknotic index (KPI), while the degree of maturation of the vaginal epithelium was estimated visually. Urinary bacteria were cultivated. A pronounced and progressive rise in KPI was seen in both the vaginal and the urethral epithelium following daily E₃ treatment. However, neither of the two maintenance dosages was sufficient to sustain the initial maturation of the vaginal and urethral epithelium induced by E₃, since the KPI returned to pretreatment values within 4 weeks. The effect of E₃ administration on the vaginal epithelium was overestimated by the visual assessment method. No changes were seen in urinary bacteria. Medroxyprogesterone acetate was given before and after E₃ treatment. None of the women suffered from withdrawal bleeding.     

Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17β-oestradiol and progesterone in the pre- and post-menopause

Serum concentrations of 17β-oestradiol (E₂), unconjugated oestrone (E₁), total oestrone (tE₁), progesterone (P), follicle-stimulating hormone (FSH) and sex-hormone-binding globulin (SHBG) were measured before and after daily intravaginal administration of 250 μg micronized E₂ and 10 mg micronized P for 14 days to 12 post-menopausal and for 1 day only (during cycle days 5–8) to 11 pre-menopausal women. In the post-menopausal women the levels of all steroids increased to maximum values on day 1, 8–10 h after administration and fell thereafter. In the pre-menopausal women the steroid concentrations rose slowly to a plateau level 10–15 h after administration. Significantly higher absorption of E₂ and E₁ (area under the curve increments) was noted in the post-menopausal than in the pre-menopausal women.

In the post-menopausal women the steroid levels measured on days 7 and 14 corresponded to those observed in the very early or late luteal phase. Area under the curve increments were usually smaller on days 7 and 14 than on day 1 and the absorption kinetics altered to a ‘pre-menopausal’ pattern. FSH levels were significantly reduced as from 12 h after administration on day 1 and onwards. A slight (10%) but significant increase in SHBG levels was noted on day 14. It was concluded that the combined E₂ and P treatment used in this investigation brings about a physiological response with only minimal side effects on the liver as judged from changes in SHBG concentrations.     

A group-comparative study of effects of Ovestin cream versus premarin cream in post-menopausal women with vaginal atrophy

Fourteen post-menopausal women with vaginal atrophy applied, intravaginally, Ovestin® cream (0.5 mg oestradiol/day; 7 patients) or Premarin® cream (1.25 mg conjugated oestrogens/day; 7 patients) for 3 wk. Effects on plasma E₁, E₂, E3, FSH, LH, PRL, TRH-stimulated PRL release, SHBG, and on maturation value (MV), ferning (F) and spinnbarkeit (S) were studied. Endometrial biopsies at pre-treatment and at 2 wk were obtained from 2 patients from each group.

Premarin induced a significant and progressive rise in E₁ and E₂ levels and in SHBG, whereas Ovestin induced no changes. Both creams increased E₃ slightly and suppressed FSH and LH, Premarin suppression of FSH and LH being significantly greater. No significant changes in PRL or TRH-stimulated PRL release occurred with either cream. A similar, marked rise in the MV occurred, but the effect of Premarin on F and S was significantly greater. Endometrium remained atrophic in the 2 Ovestin-treated patients, but moderate proliferation occurred in the 2 Premarin-treated patients. The data showed Ovestin cream to be superior to Premarin cream because of the absence of undesirable effects on E₁ and E₂ levels and the subsequent changes in SHBG and endometrium.