Serum concentrations of oestrone,oestradiol and oestriol during various oestrogen treatments

Serum oestradiol/oestrone ratios were measured during various oestrogen treatments in castrated women. Oral oestriol succinate therapy (8 mg/day) caused little change in the pre-treatment oestradiol/oestrone ratio. During oestradiol valerianate therapy (2 mg/day) serum total oestrogens and the E₂/E₁ ratio were considerably increased. One day after the injection of 10 mg of oestradiol valerianate and 2.5 mg of oestradiol benzoate + 10 mg of oestradiol phenylpropionate the E₂/E₁ ratio was similar to the ratio in the middle of the normal ovulatory cycle. The change in serum oestriol was rather small after oral doses of 8 mg of oestriol succinate 15, 30 and 120 min after the application.     

Long-term post-menopausal hormone therapy and serum HDL-C, total cholesterol and triglycerides

Serum high-density lipoprotein cholesterol (HDL cholesterol), total cholesterol and triglyceride concentrations were determined in 158 post-menopausal women following long-term oral hormone replacement therapy. Oestradiol valerate (2 mg/day) was taken by 53 of the women and oestriol succinate (2 mg/day) by 42 others. The duration (means +/- SD) of the oestradiol valerate therapy was 6.4 (+/- 2.9) yr and of the oestriol succinate therapy 6.4 (+/- 2.3) yr. The remaining 63 women received oestradiol valerate (2 mg/day) combined sequentially with norgestrel (0.5 mg/day). The average duration of treatment with this combination was 3.3 (+/- 2.4) yr. The control group comprised 100 post-menopausal women who received no hormone therapy whatsoever. The HDL cholesterol levels in the women receiving oestradiol valerate were higher than those in the controls (P = 0.001) and in the women on oestradiol valerate plus norgestrel therapy (P less than 0.001). The HDL cholesterol levels in the oestriol succinate group did not differ significantly from those in the controls. The women receiving oestradiol valerate in combination with norgestrel had lower serum HDL cholesterol concentrations than the controls (P less than 0.05). Serum total cholesterol and triglyceride concentrations did not differ in either oestrogen group from those in the controls, but were lower in the oestradiol valerate-plus-norgestrel group than in the controls (P less than 0.001). There were no differences in serum total oestrogen, oestrone, oestradiol and oestriol levels between control subjects with normal HDL cholesterol concentrations and those with low concentrations.     

Serum oestrone, oestradiol and oestriol concentrations during oral oestradiol valerate and oestriol succinate therapy in ovariectomized women

Serum oestrone, oestradiol and oestriol concentrations were investigated during oral treatment with oestradiol valerate and oestriol succinate in ovariectomized women. The dosages used were 1 mg oestradiol valerate in the morning and 2 mg oestriol succinate in the evening of the first day and 2 mg oestradiol valerate in the morning of the second day of treatment. The other group of patients received the same therapy in reverse order. The variations in the serum oestrone and oestradiol concentrations with a daily dose of 1 or 2 mg of oestradiol valerate were considerable. 2 mg oestriol succinate caused a fairly small elevation of serum oestriol concentration. In both treatment groups the quotient E₃/(E₂ + E₁) was similar to that found at the 6–7th day and in the middle of the normal menstrual cycle, the quotient E₁/(E₂ + E₃) was somewhat higher than during normal cycle.     

Serum oestriol, oestrone and oestradiol concentrations during oral oestriol succinate treatment in ovariectomized women

Serum oestriol, oestrone and 17β-oestradiol concentrations during oral oestriol succinate treatment were investigated in ovariectomized women. Either a single dose of 8 mg or two doses of 4 mg were given daily. With the second divided dosage the serum oestriol levels remained uniform. The oestriol concentrations were clearly higher than in the beginning or in the middle of the normal menstrual cycle in the fertile woman. With both treatment schemes the ratio E₃/(E₂ + E₁) was clearly higher than before treatment and during the normal menstrual cycle. Oestriol succinate treatment lowered the ratio E₁/(E₂ + E₃), which was rather similar to the one during normal menstrual cycle.     

Bone loss during oestriol therapy in postmenopausal women

In contrast to all other oestrogens examined thus far oestriol hemisuccinate (12 mg/day) did not prevent bone loss in 28 postmenopausal women. The average bone loss, however, was somewhat less than expected from placebo studies, while the bone loss achieved by a group taking 4–6 mg/day was equal to that achieved by previous placebo groups. To be an effective agent for prevention of post-menopausal osteoporosis oestriol would have to be prescribed in daily doses considerably in excess of 12 mg.     

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.     

Intrauterine administration of levonorgestrel in two low doses in HRT. A randomized clinical trial during one year: effects on lipid and lipoprotein metabolism

Objective: To investigate the effects on lipid and lipoprotein metabolism of two doses (5- or 10 μg/24 h) of levonorgestrel released from an intrauterine device (IUD) in combination with orally administered estradiol (2 mg estradiol valerate) in perimenopausal women. Design: A 1-year prospective randomized single blind clinical trial. setting: Department of Obstetrics and Gynaecology, Östra Hospital, Göteborg, Sweden. Subjects: Fifty-one perimenopausal women with climacteric symptoms. Outcome measures: Cholesterol in serum and in lipoprotein fractions; high-density lipoprotein 9HDL), low-density lipoprotein (LDL). Triglycerides in serum and in very low-density lipoprotein. Results: In both treatment groups significant elevations in HDL-cholesterol of similar magnitude were observed after 1 month and these changes were maintained during the 12 month observation period. In both treatment groups an initial significant decrease of LDL-cholesterol was observed and the decrement was maintained after 12 months. Serum levels of cholesterol decreased significantly in both groups after 1 month and were maintained after 12 months in the levonorgestrel-IUD (LNG-IUD) 5 μg group. However, the initial reduction of serum cholesterol in the LNG-IUD 10 μg group did not differ from baseline after 12 months. Serum triglyceride levels fluctuated during the observation period. No significant changes occurred. Conclusion: continuous combined HRT with intrauterine administration of levonorgestrel, 5- or 10 μg/24 h, in perimenopausal women was observed to increase HDL-cholesterol and to decrease LDL-cholesterol compared with pretreatment values. the low doses of levonorgestrel did not reverse the beneficial effects on lipid metabolism usually seen after estradiol administration.     

Plasma oestriol following vaginal administration: morning versus evening insertion and influence of food

The aim of this trial was to study the vaginal absorption of oestriol and to investigate whether morning rather than evening oestriol administration would produce different plasma oestriol patterns. The influence of food intake on plasma oestriol levels was also investigated. Nine post-menopausal women were given 0.5 mg oestriol (ovula supplied by Leo AB, Sweden) intravaginally every evening for 16 days. Thereafter, 1 mg oestriol was given every evening for another 5 days, except on treatment days 18 and 19 when 1 mg oestriol was given in the morning instead. Venous blood samples were collected at frequent intervals on day 19 (morning administration) and a meal was allowed 4 h later. On the day 21 (evening administration), venous blood samples were taken at frequent intervals during the night and no meal was given until the next morning. Plasma concentrations of unconjugated oestriol were measured by means of a specific radioimmunoassay (RIA). A difference was seen in the plasma oestriol patterns when the results following morning and evening administration were compared. However, no significant difference as regards the total 24-h systemic availability of oestriol was observed. A minimal increase in plasma oestriol levels was seen after a meal in the case of both morning and evening intravaginal oestriol administration, possibly as a result of enterohepatic recirculation.     

Bioavailability of oestradiol and oestriol administered orally to oophorectomized women

A bioavailability study was performed on ten oophorectomized women in a randomized cross-over design. The absorption of tablets containing 2 mg of micronized oestradiol and 1 mg of micronized oestriol (Estrofem®) was compared to the absorption of the same micronized hormones administered in an aqueous suspension. Serum concentration values of oestradiol, oestriol and oestrone were measured by radioimmunoassay. The data obtained were analyzed both by univariate and multivariate analyses, and neither the serum concentrations at the various sample times, the maximum concentrations, the times for the maximum concentrations, nor the areas under the serum concentration curves disclosed any significant differences between the tablet and suspension administrations at the 5% level. The serum concentration values achieved by giving 2 mg of oestradiol and 1 mg of oestriol were of the same magnitude or higher than those of the normal menstrual cycle.     

Administration of dehydroepiandrosterone enanthate to oophorectomized women - effects on sex hormones and lipid metabolism

Eight bilaterally oophorectomized women were given a depot injection of 200 mg DHEA-enanthate to study the effect on endocrine and lipid metabolism.

A decrease in sex-hormone binding globulin (SHBG) and an increase in androstenedione was found 14 and 30 days after the injection. No changes could be detected in LH, FSH, oestrone, oestradiol or oestriol. Testosterone showed a tendency towards an increase. As compared to pre-treatment values, plasma lipids were unaltered after 30 days. A decrease in high density lipoproteins (HDL), cholesterol and in very low density lipoproteins (VLDL), free cholesterol, total cholesterol and phospholipids were seen in the lipid composition of the lipoproteins on day 30. These findings are in agreement with previous data reported after the administration of drugs with androgen-like effects. The relative fatty acid composition of plasma lecithin revealed only minor changes while the fatty acid composition of cholesterol esters indicated a decreased portion of essential fatty acids. These results suggest, in agreement with previous studies, an impaired endogenous cholesterol formation in the liver. The results from the analysis of the fatty acid composition of lecithin and cholesterol esters might indicate a decreased percentage of exogenous (dietary) cholesterol ester in plasma.     

Perimenopausal changes in serum lipids and lipoproteins: A 7-year longitudinal study

Although cross-sectional studies suggest considerable influence of menopause on serum lipids and lipoproteins in women, it is not exactly clear. During our 7-year longitudinal study, serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and low-density lipoprotein (LDL) cholesterol were measured in 16 healthy perimenopausal women (aged 47–56 years at menopause) who had undergone annual examinations 4 years before and 3 years after menopause under a health examination system in Osaka. Longitudinal design enabled us to study the natural course of serum lipids and lipoproteins. The results show that from 4 years before to 1 year after menopause, the serum concentration of total cholesterol and LDL cholesterol increased on average by 25 mg/dl (14%) and 20 mg/dl (19%), respectively. Serum concentrations of triglycerides and of HDL cholesterol remained virtually unchanged during the perimenopausal and postmenopausal periods. It was concluded that serum lipids and lipoproteins are thus significantly altered as a consequence of menopause, resulting in a more atherogenic profile in the postmenopausal period.     

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 μg/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 ± 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.     

Effects of oestradiol administration via different routes on the lipid profile in women with bilateral oophorectomy

To determine the influence of various oestrogenenic administrations on lipid response, 63 women with total abdominal hysterectomy and bilateral anexectomy were studied before and 6 and 12 months after receiving 17β-oestradiol by different means. The effect on the levels of lipids and lipoproteins of the 2 mg/24 h administration of oestradiol valerate was compared with 1.5 mg/day of percutaneous 17β-oestradiol and 0.05 mg/day of transdermic oestradiol. The treatments were given continuously over a year. The oestradiol valerate produced a statistically significant increase (P < 0.05) of the HDL-C levels both after 6 and 12 months (10.6% vs. 11.6%). A significant increase was also observed (P < 0.05) in the Apo Al levels during the treatment (18 and 25%). On the other hand, unfavorable side effects with oestradiol were not produced, either percutaneous or transdermic, on lipid plasmatic or lipoprotein levels. These data show the benefit of oral oestrogenic therapy and the maintenance of the lipid profile in percutaneous and transdermic therapies in oophorectomized women.     

Comparison of two HRT regimens with bimonthly and monthly progestin administration in postmenopause

OBJECTIVES: Here we report the results of a study in which natural estrogens were given transdermally cyclically and continuously for 1 year, and a progestin of the latest generation, namely nomegestrol acetate, was given for 10 days every month and for 15 days every 2 months. METHODS: The patients were a group of 34 post-menopausal women (51-56 years), 18 of whom (group A) were treated with continuous transdermal estradiol (50 micrograms/day) and cyclic oral nomegestrol at a dose of 5 mg/day for 15 days every 2 months for 1 year. The other 16 women (group B) were treated with cyclic transdermal estradiol for 3 weeks with oral nomegestrol for 10 days (12-21)/month. Endometrial thickness was evaluated by transvaginal ultrasonography before and after treatment. At the end of treatment, an endometrial biopsy was performed. Serum total cholesterol, HDL, LDL and triglycerides were assessed at baseline and every 4 months. The characteristics of the cycle were deduced from the diary cards recorded by the women. RESULTS: No significant differences were found in the mean interval between the last dose of nomegestrol and the start of bleeding or in the duration of bleeding. The total number of days of bleeding per year was significantly lower in group A than group B (27 +/- 12 vs. 52 +/- 18; P < 0.01). Total serum cholesterol and LDL significantly decreased after 1 year of treatment in both groups, HDL-cholesterol and triglycerides were found increased at most of the time points studied. CONCLUSIONS: The present protocol involving continuous transdermal administration of estrogen combined with oral progestin every 2 months gave good control of the menstrual cycle, did not increase the risk of endometrial pathology and met with good patient compliance.     

Nandrolone decanoate treatment of post-menopausal osteoporosis for 2 years and effects of withdrawal

This study investigated the effects of nandrolone decanoate (ND) therapy (50 mg i.m. every 3 or 4 wk) on bone mass and soft tissue body composition in post-menopausal women. Twenty-two (22) women were followed up over a period of 30 mth, during which they received ND therapy for 12–24 mth and were treatment-free for the other 6–18 mth. While they were receiving treatment forearm bone mineral content (BMC) and lean body mass (LBM) increased, whereas fat mass (FM) decreased. After withdrawal of ND therapy the BMC, LBM and FM values all tended to return to pretreatment levels.

Serum high-density-lipoprotein cholesterol showed a non-significant decrease, while serum lowdensity-lipoprotein cholesterol and serum total cholesterol remained unchanged during therapy. It was concluded that ND therapy can achieve an increase in BMC in post-menopausal women, but this is maintained only for as long as therapy is continued.     

Low-risk lipoprotein pattern in post-menopausal women on sequential oestrogen/progestogen treatment

Female hormones are known in influence serum lipoproteins. In post-menopausal women oestrogens decrease the concentration of low-density lipoprotein (LDL) and increase that of high-density lipoprotein (HDL), while progestogens may have the opposite effect. The risk of coronary heart disease (CHD) should consequently be decreased by oestrogens and increased by progestogens. We report here the changes observed in serum total cholesterol, triglycerides, and lipoproteins in post-menopausal women during sequential oestrogen/progestogen treatment. Oestriol and 17 beta-oestradiol were given alone for the first 12 days, in combination with norethisterone acetate (1 mg/day) for the next 10 days, and then in reduced amounts for the last 6 days of the 28-day cycle. Three different doses of the oestrogens were investigated (high, medium and low). A total of 177 normal post-menopausal women volunteered for random allocation to treatment or placebo groups. Blood samples were taken every 3 mth during the progestogen phase of the cycle. Serum total cholesterol was found to be 10-13% lower over a 3-yr period on the high oestrogen dose and 5 and 3% lower on the medium and low doses, respectively. No significant changes were seen in serum triglycerides. Determination of lipoprotein fractions showed that the reduction in total cholesterol was due to reduced LDL-cholesterol, the HDL-cholesterol levels remaining virtually unchanged.     

Influence of menopause on serum lipids and lipoproteins

The influence of the menopause on serum lipids and lipoproteins was examined longitudinally at 6-week intervals for 2–3 years in pre-menopausal women undergoing the menopause. Serum lipid and lipoprotein profiles were also examined cross-sectionally in 4 groups of pre-menopausal, perimenopausal and post-menopausal women, who were followed up longitudinally at 3-monthly examinations for 1–2 years. The results covering 1360 examinations and 270 woman-years are reported here.

Serum concentrations of total cholesterol (P = 0.001), low-density-lipoprotein (LDL) cholesterol (P = 0.001) and triglycerides (P < 0.05) increased significantly as a consequence of the menopause and all increases occurred within 6 months of cessation of menstrual periods. High-density-lipoprotein (HDL) cholesterol decreased significantly (P < 0.05) as a consequence of the menopause, but the decline occurred gradually over the 2 years preceding cessation of menses. In addition to the menopausal changes, serum concentrations of total cholesterol and LDL-cholesterol increased gradually in the pre-menopausal and post-menopausal years, but were significantly related to biological age only in the pre-menopausal groups (P < 0.05). Serum triglycerides and HDL-cholesterol levels remained virtually unchanged in the pre-menopausal as well as the post-menopausal groups and were only influenced by the actual menopause.

Serum lipids and lipoproteins are thus significantly altered as a consequence of the menopause. The result is a more atherogenic lipid profile which may partly explain the increased risk of cardiovascular disease observed in post-menopausal women.     

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 oestradiol valerate plus two different progestogens on serum lipids during post-menopausal replacement therapy.

A total of 27 post-menopausal women were treated with hormone replacement therapy over a period of 6 months for climacteric symptoms. Serum total cholesterol, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol and triglyceride concentrations were determined before therapy commenced and during the third and sixth treatment cycles. One group (13 women) was treated with 2 mg oestradiol valerate plus 7.5 mg megestrol acetate (EV + MA). The other group (14 women) received 2 mg EV plus 0.25 mg norgestrel (Cyclabil). The serum total cholesterol concentration decreased in both groups, the fall being more marked in that treated with Cyclabil. The serum LDL-cholesterol and triglyceride concentrations also decreased in both groups. The serum HDL-cholesterol concentration fell in the Cyclabil group but did not alter in the women treated with EV + MA. Our results suggest that the cyclic addition of megestrol acetate, a 17-alpha-hydroxyprogesterone derivative, to oestrogen therapy does not affect the serum HDL-cholesterol concentration, whereas norgestrel, which is a 19-nortestosterone derivative, causes it to decrease.     

Effect of isoflavones on lipids and bone turnover markers in menopausal women

OBJECTIVES: The purpose of this analysis was to compare the effects of two dietary supplements derived from red clover to placebo on lipids and bone turnover markers in symptomatic menopausal women. METHODS: The study was a 12-week randomized, double-blind, placebo-controlled trial. Two hundred and fifty-two menopausal women ages 45-60 years experiencing > or =35 hot flashes per week were randomly assigned to Promensil (82 mg total isoflavones), Rimostil (57.2 mg total isoflavones), or placebo. Primary outcome measures were mean absolute changes for HDL-cholesterol, serum osteocalcin, and urinary N-telopeptide. Secondary outcome measures were mean changes of total cholesterol, LDL-cholesterol, the ratio of HDL- to LDL-cholesterol, and triglycerides. RESULTS: Ninety-eight percent of participants completed the 12-week protocol. Women taking Rimostil or Promensil compared to those taking placebo had greater mean increases in HDL-cholesterol; however, this change was small in magnitude (<2 mg/dl) and did not reach significance. There was a significant decrease in triglyceride levels among women taking Rimostil (14.4 mg/dl, P = 0.02) or Promensil (10.9 mg/dl, P = 0.05) compared to those taking placebo. The decrease was primarily among women with elevated baseline triglyceride levels (P for interaction = 0.009). There were no differences in mean changes of total cholesterol, LDL-cholesterol, or the ratio of HDL- to LDL-cholesterol among treatment groups. There were no statistically significant differences among treatment groups for bone turnover markers. CONCLUSIONS: Compared with placebo, both of the supplements containing isoflavones decrease levels of triglycerides in symptomatic menopausal women; however, this effect is small in magnitude.