Transdermal estradiol reduces plasma myeloperoxidase levels without affecting the LDL resistance to oxidation or the LDL particle size

OBJECTIVE: This study was designed to investigate the effects of different therapeutic range doses of transdermal estradiol (E(2)), alone or in combination with progesterone (P) or medroxyprogesterone acetate (MPA), on plasma lipoprotein levels and on three parameters related with LDL oxidizability, the resistance of LDL to oxidation by copper, the LDL particle size, and the myeloperoxidase levels. DESIGN: Thirty-five healthy postmenopausal women who had been amenorrheic for at least 1 year received two consecutive, 2-month doses of transdermal estrogen (25-microg and 50-microg E(2) patch). Thereafter, they were randomly assigned to receive a 2-month treatment of either a 100-microg E(2) patch or a 50-microg E(2) patch combined with P (300 mg/day) or MPA (5 mg/day) during the last 14 days. RESULTS: Neither transdermal E(2) alone nor transdermal E(2) plus progestogen modified the lipoprotein profile, the LDL resistance to oxidation, or the LDL particle size. However, all treatments similarly reduced the myeloperoxidase protein levels. CONCLUSIONS: Different dosages of transdermal E(2) within the therapeutic range were equally effective in reducing myeloperoxidase protein levels. The effect remained after addition of P or MPA in a sequential regime.     

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.     

Benefits and risks of different hormonal replacement therapies in post-menopausal women

A total of 113 women who presented with climacteric symptoms participated in the study. They were randomly allocated to seven groups of 10–27 subjects, who received for 6 mth the following therapies, respectively: (1) conjugated oestrogens (CE) 0.625 mg/day for 21 days + norethisterone (NET) 5 mg/day from day 12 to day 21; (2) CE + cyproterone acetate (CPA) 12.5 mg/day from day 1 to day 10; (3) oestradiol valerate (EV) 2 mg/day for 21 days + NET; (4) EV + CPA; (5) oestriol (E₃) 2–4 mg/day; (6) tibolone (ORG OD14) 2.5 mg/day; and (7) placebo, one tablet/day.

Hot flushes decreased significantly over the treatment period in all seven groups. However, E₃ was less effective at the dose used than CE, EV or ORG OD 14. At the end of the 6 month treatment period histological examination revealed no changes in endometrial morphology in any of the patients treated. Indeed, the addition of a progestogen even induced regression of endometrial hyperplasia in 8 cases.

No significant variation in the plasma levels of tryglycerides, total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) was observed after the second and sixth months of treatment with E₃ or ORG OD 14. After 6 months, treatment with CE/EV + CPA produced a significant increase in HDL, while treatment with CE/EV + NET brought about a reduction in total cholesterol and HDL and an increase in LDL.     

Effects of estrogen on susceptibility to oxidation of low-density and high-density lipoprotein in postmenopausal women

Objective: To investigate the effects of estrogen on the susceptibility to oxidation of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in postmenopausal women. Methods: A total of 23 postmenopausal women were treated with 0.625 mg of conjugated equine estrogen daily for 3 months. Blood samples were obtained before and after therapy. Plasma levels of total cholesterol and triglyceride and the concentrations of cholesterol, triglyceride, phospholipid in LDL and HDL were determined enzymatically and the levels of apolipoprotein A-I, A-II in HDL and apolipoprotein B in LDL were measured by turbidimetric immunoassay. The isolated LDL and HDL were incubated at 37°C for 24 h with CuSO₄ 5 μmol/l and the lipid peroxide concentration of LDL and HDL was measured. Results: Estrogen significantly reduced the plasma level of total cholesterol and significantly increased the plasma level of triglyceride. The LDL concentrations of cholesterol, phospholipid and apolipoprotein B were significantly decreased following estrogen therapy. The triglyceride level of LDL did not change significantly. The HDL concentrations of cholesterol, triglyceride, phospholipid and apolipoprotein A-I and A-II were all significantly elevated after estrogen therapy. Estrogen significantly inhibited the peroxidation of LDL at 50–2000 μg of LDL protein (14.17±4.17–11.49±1.42 nmol/200 μg of LDL protein, P<0.001) and of HDL (4.49±1.74–3.37±1.24 nmol/200 μg of HDL protein, P<0.03) induced by their incubation in the presence of CuSO₄. Conclusions: Estrogen inhibited the susceptibility of LDL and HDL to oxidative modification and favorably affected lipid metabolism by reducing the number of LDL particles and increasing the number of HDL particles in plasma that were resistant to oxidation.     

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.     

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.     

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.     

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.     

Effects in post-menopausal women of transdermal estrogen associated with progestin upon the removal from the plasma of a microemulsion that resembles low-density lipoprotein (LDL)

Objective: To evaluate the effects of transdermal estradiol and medroxyprogesterone acetate (MPA) treatment on the removal from the plasma of a cholesterol-rich microemulsion (LDE) that roughly resembles low-density lipoprotein (LDL) structure and that binds to LDL receptors. Methods: Ten healthy post-menopausal women were studied before and after 3-month treatment with transdermal estradiol in the following dosages administered every 3.5 days: 25, 50, 50, 100, 100, 50, 50 and 25 μg. From the 15th to the 21st day and from the 22nd to the 28th day of estrogen treatment, respectively, 10 and 5 mg q.d. MPA per oral were associated to the transdermal estrogen. The emulsion labeled with ¹⁴C-cholesteryl oleate was injected after 12 h fasting and its fractional catabolic rate (FCR) was calculated from the plasma decaying curves of the isotope. Results: Treatment reduced LDL-cholesterol levels by 8% only (149.0 ± 36.0 mg/dl, 138.0 ± 27.0 mg/dl; P = 0.046), but the FCR of LDE expressed in medians (25%; 75%) increased from 0.0054 (0.003; 0.052) h⁻¹ to 0.021 (0.009; 0.10) h⁻¹, P = 0.002. Conclusion: The association used in this study so as to mimic the increasing–decreasing pattern of the hormonal ovarian production reduced modestly LDL-cholesterol levels but pronouncedly increased the lipoprotein removal as tested by LDE FCR.     

Comparative metabolic study of percutaneous versus oral micronized 17β-oestradiol in replacement therapy

The aim of this study was to compare the metabolic effects of two presentations of 17β-oestradiol (E₂) which are of recognized effectiveness in the prevention of post-menopausal bone loss, one being administered via the oral and the other via the percutaneous route. During this prospective, randomized study, 32 patients were treated for 2 mth with either 2 mg/day of oral micronized E₂ (n = 16) or 3–5 mg/day of percutaneous E₂ (n = 16). Both regimens proved efficacious, since significant increases in oestrone (E₁) and E₂ concentrations ranging up to mid-follicular values were observed.

In the percutaneous-treatment group we noted a significant decrease in triglycerides (TG), without any significant changes in high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). In the oral-treatment group, we saw no significant increase in HDL-C, although significant increases were observed in body weight, TG, plasma renin substrate (PRS) and sexhormone-binding globulin (SHBG) as well as significant decreases in antithrombin III (AT III) activity and antigen. All of these metabolic variations led us to the conclusion that oral E₂ at the dose established as effective in preventing post-menopausal osteoporosis may, even when micronized, alter certain metabolic and haemostatic parameters in a population characterized by increases in cardiovascular risk factors and morbidity. Oral oestrogen replacement therapy should therefore continue to be used only in carefully selected patients and be strictly followed up by systematic checks on a series of metabolic criteria.     

Effect of menopause on low-density lipoprotein oxidation: is oestrogen an important determinant?

Objectives: Significantly increased risk for developing cardiovascular disease in post-menopausal women is linked with the fall of oestrogen. Although supraphysiological levels of oestrogen may inhibit oxygen free radical mediated low-density lipoprotein (LDL) oxidation, the effect of physiological level of oestrogen on LDL oxidation is unknown. Methods: The present study compared oxidizability of LDL in healthy pre- and post-menopausal women by using a commonly employed copper ion-dependent method. Results: Pre-menopausal women (n=20, mean age 27) had significantly higher serum oestradiol level (576±109 pmol/l) in comparison to post-menopausal women (n=23, mean age 51, oestradiol 64±18 pmol/l, P<0.001). The oxidation of LDL in two groups was not different by measuring either the lag phase of conjugated dienes formation (54±12 vs. 55±14 min, P>0.05) or the generation of thiobarbituric acid reactive substances over 4 h of oxidation. The major lipid soluble antioxidant in LDL, vitamin E (determined as -tocopherol) is similar in two groups (2.34±0.48 vs. 2.40±0.56 nmol/mg LDL, pre- and post-menopausal subjects, respectively, P>0.05). Linear regression analysis found a weak but significant correlation between LDL vitamin E level and oxidizability of LDL in both groups but did not show effect of serum oestradiol levels. Conclusion: The results suggest that physiological levels of oestrogen may not be able to affect in vitro LDL oxidation.     

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.     

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.     

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.     

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.     

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.     

Effects of tibolone on lipoprotein(a) and HDL subfractions

Objective: To determine the effects of tibolone, a synthetic steroid used to alleviate climacteric symptoms and prevent osteoporosis, on lipoprotein metabolism, with particular reference to lipoprotein(a) levels and HDL subfraction profiles.Design: Thirty nine postmenopausal women were treated with tibolone (Livial) 2.5 mg/day for 6 months and fasting serum lipoprotein levels were estimated at 0, 2, 4 and 6 months. Results: Lipoprotein(a) levels were reduced significantly over the 6 months from a median level of 245 (range <60–780) mg/I to 152 (range <60–530) mg/l, a reduction of 39% in the median level. A decrease was observed in approximately two thirds of the women. Reductions were noted in all 6 subjects whose pretreatment levels were high, although concentrations remained at a level associated with increased risk in all but one. There were significant decreases in triglycerides and VLDL cholesterol and no significant change in LDL cholesterol. There was a significant reduction of 18% in HDL cholesterol and a 26% reduction in the HDL₂:HDL₃ ratio. Conclusion: The reduction in lipoprotein(a) levels may have a beneficial effect on cardiovascular risk, which could go some way towards balancing the potentially adverse effect on the cardiovascular system caused by the reduction in HDL cholesterol.     

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.     

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.     

Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone

Doses of 100 mg of micronized progesterone (P) and of 0.5 mg of micronized estradiol (E₂) were administered vaginally and orally, respectively, in the early follicular phase of the menstrual cycle in six premenopausal women. In the second cycle, the same doses were administered in the same subjects, orally for P and vaginally for E₂. Serial blood samples were collected and the following steroids were assayed by highly reliable techniques: P, E₂, estrone (E₁), deoxycorticosterone (DOC), 5- and 5β-pregnanolone and the sulfates of E_l, E₂, and DOC. Circulating P and E₂ levels were higher after vaginal than after oral administration, while those of E₁ were similar after either route. Metabolites of P (DOC, DOCS and pregnanolone) were higher after oral administration. Concerning estrogen sulfates, E₁S concentrations were similar whichever the route, while those of E₂S were lower after oral than after vaginal administration. This study has confirmed that metabolism of ingested P and E₂ occurs mainly in the intestine. Moreover, P was predominantly metabolized to 5-reduced derivatives, whatever the route of administration. In view of the metabolic pathways which are operative and of the peripheral plasma levels which were found, the vaginal route appears to be more adequate than the oral one for hormone replacement therapy.