Jytte Jensen

Cigarette Smoking, Serum Estrogens, and Bone Loss during Hormone-Replacement Therapy Early after Menopause

To elucidate the effect of smoking on estrogen metabolism, we examined 136 postmenopausal women treated for one year with one of three different doses of combined estrogen-progestogen or placebo. The women were grouped according to smoking status, and serum levels of estrone and estradiol were measured before and after treatment. The results showed reduced levels of both estrogens in smokers as compared with nonsmokers in all three dosage groups. This reduction was most pronounced in the high-dose group (4 mg of estradiol), in which the serum levels of estrone and estradiol in smokers were only 50 per cent of those in nonsmokers (P less than 0.001 and less than 0.05, respectively). In contrast, no significant changes could be demonstrated in the corresponding placebo groups. Moreover, it was possible to demonstrate significant inverse correlations between the number of cigarettes smoked daily and the changes in the levels of serum estrone and estradiol, respectively, (P less than 0.001). This study suggests that an increased hepatic metabolism of estrogens results in lower estrogen levels among postmenopausal smokers. This may contribute to the reported risk of osteoporosis among smokers.

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, peri-menopausal 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 less than 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 less than 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 less than 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.

Measurement of lean body mass and total body fat using dual photon absorptiometry

We describe a method for measuring the lean body mass (LBM) and total body fat (FAT) by dual photon absorptiometry (DPA). A total body rectilinear scan was employed with a radiation source of 1 Ci 153Gd. The reliability of estimating the lean percent was assessed in vitro using limb phantoms consisting of ox muscle, lard, and human bone. The precision and accuracy in vitro of the lean percent determination were 1.5% and 1.9%, respectively. The accuracy error in vivo of measuring the total mass of soft tissues (TMST) was approximately 1.4%, thus yielding an overall accuracy error of the LBM of about 2.5%. The precision in vivo of the lean percent and the LBM in kg of duplicate measurements on five healthy subjects was 2.5% and 2.2%, respectively. Other estimates of the LBM and FAT, ie, the calculation according to Boddy et al6 and the skinfold thickness measurement (triceps and subscapular), were compared to the DPA measurement in 100 healthy subjects. High correlations were found between the FAT or FAT% by DPA versus (1) the FAT or FAT% calculated according to the formulae of Boddy et al, and (2) the skinfold thickness. The correlations between the FAT and FAT% by Boddy et al and the skinfold thickness were, however, moderate. The correlation between LBM by DPA and LBM by Boddy et al was highly significant (r = 0.96, SEE = 4.4%). We conclude that LBM and FAT measurements using DPA have precision and accuracy errors that are commensurate with a reliable estimation of the gross body composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of smoking on serum lipoproteins and bone mineral content during postmenopausal hormone replacement therapy

We examined the effect of smoking on the treatment response in serum estrogens, serum lipids and lipoproteins, and bone mineral content in 110 postmenopausal women treated for 2 years with either percutaneous or orally administered combined hormones or placebo and followed up by examinations every 3 months. Serum estradiol and estrone levels during oral hormone administration were lower in smokers than in nonsmokers, whereas no differences related to smoking habits were observed during percutaneous hormone administration. Serum total and low-density lipoprotein cholesterol were significantly reduced in both smokers and nonsmokers receiving hormones, but the response in smokers was only half that observed in nonsmokers (not significant). When the impact of the route of hormone administration was examined in relation to smoking habits, the response in serum total and low-density lipoprotein cholesterol in smokers receiving oral hormones was significantly lower (p less than 0.05) than that observed in nonsmokers. No differences in serum lipids or lipoproteins were observed between smokers and nonsmokers receiving percutaneous hormones. The response in bone mineral content in smokers and nonsmokers receiving percutaneous hormones and placebo was not significantly different, although the overall response differed significantly in the two groups (p less than 0.001). In contrast, the response in smokers receiving oral hormones was significantly lower than that observed in the corresponding nonsmokers (p less than 0.01). We conclude that smoking greatly affects the response on circulating levels of estrogens in postmenopausal women treated with orally administered hormone replacement therapy and that the subsequent treatment response on serum lipids and lipoproteins and on bone mineral content is reduced accordingly. The study suggests that alternative routes of administration should be considered when postmenopausal estrogen therapy is instituted in women who smoke.

Cyclic changes in serum cholesterol and lipoproteins following different doses of combined postmenopausal hormone replacement therapy

Summary. Cyclic changes in lipoproteins after sequential oestrogen‐progestogen therapy were studied in a group of healthy postmenopausal women treated with three different hormone doses, and followed up for two consecutive cycles by twice weekly examinations (a total of 17 examinations). There was a significant rise in high density lipoprotein (HDL) cholesterol and a significant fall in low density lipoprotein (LDL) cholesterol closely related to the dose of the oestrogen component. Addition of the progestogen, 1 mg of norethisterone acetate, decreased the oestrogen‐induced rise in HDL, but HDL levels remained higher than initial values in the high‐dose (4 mg) and medium dose (2 mg) groups. The average increases in HDL cholesterol were 13%, 9% and 2% in the high‐dose, medium‐dose and low‐dose (1 mg) groups, respectively, and the corresponding mean decreases in LDL cholesterol were 18%, 15% and 10% respectively. We conclude that postmenopausal treatment with sequentially combined oestrogen‐progestogen has no adverse effects on the lipoprotein status.

CYPROTERONE ACETATE, AN ALTERNATIVE GESTAGEN IN POSTMENOPAUSAL OESTROGEN/GESTAGEN THERAPY

Seventy‐six healthy, early postmenopausal women (aged 45–54 years) were allocated to 2 years of treatment with a cyclic combination of 2 mg oestradiol valerate (21 d) and 1 mg cyproterone acetate (11 d) or placebo. Sixty‐five women (86%) completed the study. In the placebo group the bone mineral content in the forearms (measured by single photon absorptiometry) and the bone mineral content in the lumbar spine and total skeleton (measured by dual photon absorptiometry) decreased significantly and at the same magnitude (P < 0001), whereas all bone mass measurements remained unchanged in the hormone‐treated group. In the hormone‐treated group there was a significant decrease in biochemical estimates of bone turnover (serum alkaline phosphatase, serum phosphate, fasting urinary calcium and hydroxyproline), whereas these values were unchanged in the placebo treated group. We conclude that treatment with a cyclic combination of 2 mg oestradiol valerate and 1 mg cyproterone acetate is effective as prophylaxis of postmenopausal bone loss.

Continuous oestrogen-progestogen treatment and serum lipoproteins in postmenopausal women

Summary. Serum lipids and lipoproteins were examined in 44 healthy postmenopausal women every 3 months during 1 year of treatment with either continuous oestrogen‐norethisterone acetate or placebo. Total serum cholesterol and LDL‐cholesterol levels were reduced by approximately 15% and 20% (P<0.001), respectively in the hormone group but were unchanged in the placebo group. Serum triglycerides levels remained constant in both groups. HDL‐cholesterol levels were significantly reduced by approximately 10% in the hormone group but significant reductions of 5–10% also occurred in the placebo group so that differences between the two groups were only significant after 3 months of treatment. Vaginal bleedings were experienced during the first 3 months by eight of the 21 women receiving hormones, but in only one woman after 9 months of therapy. The addition of norethisterone acetate to postmenopausal oestrogen therapy in clinically relevant doses had no adverse effects on lipoproteins as previously reported, even though administered continuously. Moreover, the low frequency of bleeding with continuous oestrogen‐progestogen therapy would make this an appropriate alternative in postmenopausal replacement therapy.

Oestrogen-progestogen replacement therapy changes body composition in early post-menopausal women.

Changes in body composition were investigated in a group of 136 post-menopausal women treated for at least 1 yr with combined oestrogen-progestogen therapy at three different doses, or a placebo. The body composition changes were evaluated using the urinary creatinine excretion rate as an indicator of lean body mass, and the changes in daily creatinine excretion were related to the changes in serum oestradiol and oestrone. The urinary creatinine excretion rate was significantly increased (P less than 0.001) in the group receiving high-dose hormones, and the urinary creatinine/body weight ratio was significantly increased (P less than 0.05) in all treated groups as compared with the placebo-group. The body weight remained unchanged in all groups. The relationships between the changes in daily creatinine excretion and the changes in serum oestradiol and serum oestrone were both significant (P less than 0.05). The present study suggests that high-dose post-menopausal hormone therapy changes the body composition by increasing the muscle mass and that, since the body weight remains unchanged, a proportionate decrease in the fat mass seems to occur.

Cyproterone acetate, an alternative progestogen in postmenopausal hormone replacement therapy? Effects on serum lipids and lipoproteins

Summary. Serum lipids and lipoproteins were studied in 76 healthy postmenopausal women treated for 1 year with either oestradiol valerate sequentially combined with the anti‐androgenic progestogen cyproterone acetate (CPA) or placebo. The women were examined every 3 months between days 18 and 21 of the tablet cycle, where the progestogen had been added to the oestrogen for at least 6 days. Combined oestrogen‐CPA therapy resulted in significantly reduced levels of total serum cholesterol and LDL‐cholesterol at all examinations, but serum triglycerides and HDL‐cholesterol levels were similar in the two groups. Total serum cholesterol and LDL‐cholesterol were reduced by approximately 5% (P<0.01) and 8% (P<0.01), respectively, after 1 year of combined oestrogen‐CPA therapy in comparison with both the initial values and the placebo group but serum triglycerides and HDL‐cholesterol levels were unchanged in both groups.

Dose-response and withdrawal effects on climacteric symptoms after hormonal replacement therapy. A placebo-controlled therapeutic trial

Out of a sample of 162 early post-menopausal women, aged 45-54 yr, 131 completed a placebo-controlled study to investigate the effect of sex hormones on mild climacteric symptoms with special reference to the dose-response relationship and withdrawal effects. The women were followed up for 42 mth under four different study programmes. All the women were examined every 3 mth and a blind assessment made of the menopausal index estimated according to Kupperman et al. The data revealed a highly significant reduction in climacteric symptoms in the hormone-treated women as compared with the placebo group (P less than 0.001), a highly significant dose relationship between climacteric symptoms and treatment with 4, 2 and 1 mg oestradiol, respectively (P less than 0.001), a highly significant and dose-dependent rebound phenomenon after withdrawal of hormone treatment (P less than 0.001)--which levelled off after 6 mth following withdrawal--and complete relief of hot flushes with the two highest doses of oestradiol (4 and 2 mg oestradiol). It is concluded that sex hormones have a beneficial effect in post-menopausal women with even mild symptoms.