Dietary phytoestrogens and estrogen inhibit experimental atherosclerosis.

OBJECTIVE: The effect of phytoestrogen intake in combination with estrogen replacement therapy (ERT) on atherogenesis is largely unknown. The aim was thus to study the impact of phytoestrogens alone, or combined with oral estrogen, on experimental atherosclerosis in cholesterol-fed rabbits. METHODS: Two separate studies were performed in ovariectomized, cholesterol-fed female rabbits. In Study A, 45 rabbits were randomized to either a soy-free diet with or without oral 17 beta-estradiol (E2) 4 mg/day, or a soy-rich diet without any hormone for 14 weeks. In Study B, 100 rabbits were randomized into five groups (oral E2 0.5, 1, 2 or 4 mg/day, or no hormone) based on a soy-rich diet for 30 weeks. RESULTS: By the end of treatment in Study A, aortic cholesterol content was twice the amount in the group treated with the soy-free diet compared with the soy-rich group and with the soy-free plus E2 group (p < 0.001). In Study B, aortic cholesterol content showed no significant difference between the groups (ANOVA, p = 0.49), but a tendency towards a lower aortic cholesterol content in the E2-treated animals compared with placebo was observed. CONCLUSION: Dietary phytoestrogens significantly reduce aortic cholesterol content with a potency comparable to that of ERT, and seem to enhance (although mildly) the antiatherogenic effect of E2 in this model.

Raloxifene and estrogen reduces progression of advanced atherosclerosis--a study in ovariectomized, cholesterol-fed rabbits.

The present study investigated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on aortic atherosclerosis in 80 ovariectomized, cholesterol-fed rabbits with pre-induced atherosclerosis. The animals were fed an atherogenic diet containing 240 mg cholesterol/day for 15 weeks, after this period a baseline control group was sacrificed. Thereafter, oral treatment was initiated with either estradiol 4 mg/day (n=20), raloxifene (210 mg/day) or placebo (n=20). In the treatment period of 39 weeks, the dietary cholesterol content was reduced to 80 mg cholesterol/day. Postmortem evaluation showed a significantly increased uterine weight induced by estradiol treatment (10.3+/-1.2 g), whereas raloxifene intervention caused a decreased uterus weight (1.21+/-0.1 g) when compared to placebo (2.48+/-0.47 g). Throughout the study, serum lipids increased in all groups to levels seen in very high risk humans. After 58 weeks the cholesterol content in the aorta was 3.18+/-0.54 micromol/cm(2) (38% reduction) in the estradiol group, 3.66+/-0.52 micromol/cm(2) (29% reduction) in the raloxifene group and 5.12+/-0.60 micromol/cm(2) in the placebo group. Analyses of the aortic cholesterol content corrected for time-averaged serum cholesterol revealed that both estradiol and raloxifene therapy significantly reduced the progression of atherosclerosis (P<0.01 for both) as compared to placebo.

Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss.

OBJECTIVE: Our purpose was to study combinations of estradiol and gestodene for prevention of bone loss in early postmenopausal women. STUDY DESIGN: We randomly assigned 278 healthy, early postmenopausal women to receive either 2 mg 17beta-estradiol sequentially combined with 25 microg gestodene (group 2/25s), 2 mg estradiol sequentially combined with 50 microg gestodene (group 2/50s), 1 mg estradiol sequentially combined with 25 microg gestodene (group 1/25s), 1 mg estradiol continuously combined with 25 mg gestodene (group 1/25c), or placebo. RESULTS: After 3 years the changes in bone mineral density of the spine were as follows (mean +/- SEM): group 2/25s, 7. 41% +/- 0.72%; group 2/50s, 8.53% +/- 0.90%; group 1.25s, 6.67% +/- 0.88%; group 1/25c, 4.44% +/- 0.59%; and placebo group, -2.03% +/- 0. 64%. The changes in bone mineral density were mirrored in the biochemical bone markers. The average responses for the urinary C-terminal telopeptide fragments of type I collagen corrected for creatinine excretion were as follows (mean of baseline +/- SEM): group 2/25s, -68.8% +/- 0.03%; group 2/50s, -72.8% +/- 0.02%; group 1/25s, -60.7% +/- 0.03%; group 1/25c, -52.28% +/- 0.04%; and placebo group, 6.5% +/- 0.09%. Beneficial lipid effects were found in all active groups. The decreases in low-density lipoprotein were as follows (mean +/- SEM): group 2/25s, -13.7% +/- 3.0%; group 2/50s, -14.6% +/- 3.2%; group 1/25s, -9.28% +/- 2.2%; group 1/25c, -9.92% +/- 2.4%; and placebo group, 1.53% +/- 1.9%. CONCLUSION: These results demonstrate that estradiol therapy with 1 mg estradiol is fully protective against early postmenopausal bone loss.

Raloxifene reduces atherosclerosis: studies of optimized raloxifene doses in ovariectomized, cholesterol-fed rabbits.

OBJECTIVE: We have previously shown that raloxifene, a selective oestrogen receptor modulator, 35 mg/day inhibits atherosclerosis in ovariectomized, cholesterol-fed rabbits. This effect was only partial as compared to 17beta-oestradiol 4 mg/day; however, plasma raloxifene concentrations were low relative to those obtained in raloxifene-treated women. We therefore investigate the effects of raloxifene at higher doses. DESIGN: The study on atherosclerosis in ovariectomized, cholesterol-fed rabbits (n = 80) compared raloxifene 70 mg/day and 210 mg/day to 17beta-oestradiol 4 mg/day and placebo. RESULTS: After 48 weeks of therapy, the aortic cholesterol content in the 70 mg/day and 210 mg/day raloxifene treatment groups were 471 +/- 56 nmol/mg protein and 456 +/- 56 nmol/mg protein, respectively. This was significantly less than in the placebo group (654 +/- 69 nmol/mg protein; P < 0.05). In the oestrogen-treated group, the aortic cholesterol content was 357 +/- 62 nmol/mg protein (P < 0.01 as compared to placebo). Differences in serum lipids between the treatment groups could only partly explain the effect on aortic cholesterol content, indicating that additional anti-atherogenic mechanisms may contribute to the decrease in aortic atherosclerosis. This anti-atherosclerotic activity of raloxifene was observed at plasma concentrations comparable to those in postmenopausal women during raloxifene treatment. CONCLUSIONS: We conclude that clinically relevant raloxifene treatment inhibits aortic atherosclerosis in ovariectomized, cholesterol-fed rabbits.

Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits.

The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.

Regional body composition determined by dual-energy X-ray absorptiometry. Relation to training, sex hormones, and serum lipids in male long-distance runners.

This study investigated the regional distribution of fatty and lean tissue in long-distance runners, and the relation to training, sex hormones, and serum lipids. One hundred and twenty lean men (22 elite, 86 recreational runners and 12 non-running controls) aged 32 +/- 8.1 years (mean +/- SD) participated. Body composition (adipose and lean tissue) was measured by dual-energy x-ray absorptiometry in the total body and in the abdomen, the arms and the legs. Regional and total body fat correlated inversely with the performance at an incremental treadmill exercise test (-0.61 < r < -0.52, P < 0.0001), and the fat percentage in the abdomen and in the legs was 42% and 36% lower in the elite runners in comparison with the non-running controls. Sex hormonal status and serum lipids were unrelated to training. After multiple regression analysis the most significant determinant of the fat percentage in the legs was the weekly distance run (partial r = -0.40, P < 0.0001), whereas in the abdominal region the free testosterone index also contributed strongly (partial r = 0.39, P < 0.0001). In conclusion, long-distance runners had very low amounts of fatty tissue in the abdomen and in the extremities, and the fat percentages in the abdomen and in the legs were associated with both the training intensity and androgenic activity. Since the abdominal fatty tissue is a significant risk factor for cardiovascular disease, running may have a positive impact on the long-term risk.

Norethindrone acetate enhances the antiatherogenic effect of 17beta-estradiol: a secondary prevention study of aortic atherosclerosis in ovariectomized cholesterol-fed rabbits.

The influence of progestogens in combination with 17beta-estradiol (E2) on cardiovascular disease remains controversial. This study investigated the effect of norethindrone acetate (NETA) combined with E2 on aortic atherosclerosis. Eighty mature female rabbits were ovariectomized, then fed a cholesterol-rich diet (240 mg/d) for 14 weeks to induce aortic atherosclerosis. They were randomized to four equally large groups for the following 38-week intervention period. One group received placebo, another group oral E2 4 mg daily (E2), and the last two groups oral E2 4 mg daily combined with either NETA 1 mg (E2NETA1) or NETA 3 mg (E2NETA3). The cholesterol intake was reduced to a "maintenance" level of 80 mg/d during the intervention period. Total serum cholesterol and ultracentrifuged lipoproteins were analyzed enzymatically throughout the study. The cholesterol content in the aortic wall was 2.76+/-0.44 micromol/cm2 (mean+/-SEM) in the E2NETA1 group, 1.77+/-0.37 micromol/cm2 in the E2NETA3 group, 5.46+/-0.77 micromol/cm2 in the E2 group, and 7.20+/-0.94 micromol/cm2 in the placebo group (ANOVA P<0.0001). The difference (in the aortic cholesterol accumulation) between the E2 and each of the combined E2/NETA groups was statistically significant (P<0.01) but could only partly be explained by the differences in serum lipids and lipoproteins. In conclusion, NETA enhances the antiatherogenic effect of E2 in cholesterol-fed rabbits. This effect is only partially mediated through changes in serum lipids and lipoproteins.

Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits.

BACKGROUND: The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated. METHODS AND RESULTS: For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required. CONCLUSIONS: Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Impact of combined hormone replacement therapy on serum lipid metabolism: new aspects.

The objective of this study was to evaluate the impact of combined estrogen-progestogen therapy on low density lipoprotein (LDL) particle size (determined by the LDL cholesterol/apolipoprotein B ratio). The prospective study was carried out on 139 healthy Danish early postmenopausal women. The subjects were randomized to placebo or to 2 mg estradiol valerate equivalents, either sequentially combined with 75 micrograms levonorgestrel, 10 mg medroxyprogesterone acetate (MPA), or 150 micrograms desogestrel, or continuously combined with 1 mg cyproterone acetate. LDL particle size was calculated before treatment and at nine-well-defined times during the subsequent 84 days. LDL particle size was reduced by all four treatments. This change was statistically significant for estradiol valerate combined with levonorgestrel and MPA (6.2 +/- 2.7% and 5.6 +/- 2.1% (mean +/- SEM), respectively; p < 0.05 for both, placebo-corrected). Estradiol valerate combined with MPA induced cyclic (progestogen-minus estrogen-related values) decreases (-6.3 +/- 2.6%; p < 0.05), and with levonorgestrel there were cyclic increases (5.1 +/- 2.7%; p = 0.067) in LDL particle size (placebo-corrected). In conclusion, combined estrogen-progestogen therapy causes a decrease in LDL particle size. A cyclic variation in LDL cholesterol/apolipoprotein B ratio was observed during sequential treatment.

Tibolone: influence on markers of cardiovascular disease.

Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties relieves climacteric symptoms and prevents postmenopausal bone loss. The influence of tibolone treatment on coagulation, fibrinolysis, and lipid metabolism was investigated in 91 healthy late postmenopausal women. They were randomly assigned in a double-blind, placebo-controlled 2-year study to receive either tibolone 1.25 mg (n = 36, 29 completed) or 2.5 mg (n = 35, 28 completed) or placebo (n = 20, 13 completed). The biochemical markers of lipid metabolism, fibrinolysis, and coagulation were measured every 3 months. In both tibolone groups a similar (approximately 30%) decrease in high density lipoprotein cholesterol and a corresponding lowering of apolipoprotein A-1 (P < 0.001) was detected. Also serum total cholesterol and triglycerides were reduced (approximately 15%; P < 0.01), whereas low density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were unaffected by tibolone. The two dose levels of tibolone resulted in a similar, marked lowering (approximately 30%) of tissue plasminogen activator and plasminogen activator inhibitor activity as compared with placebo (P < 0.001). Plasminogen increased (approximately 15%; P < 0.001) in both groups. Fibrinogen was lowered (P < 0.01) in the low-dose group, and antithrombin III remained unchanged. The overall effect on hemostatic factors of the present doses of tibolone in healthy, late postmenopausal women tends towards increased fibrinolysis and unchanged coagulation. This may be beneficial and might theoretically counterbalance the potentially negative effect of the decrease in high density lipoprotein cholesterol.

The relationship of natural androgens to coronary heart disease in males: a review.

Published studies dealing with the relationship between circulating levels of testosterone and dehydroepiandrosterone (sulfate) (DHEA(S)) and coronary heart disease (CHD) in males, as well as corresponding experimental animal studies are reviewed. One randomized intervention study, eight prospective and 30 cross-sectional studies have evaluated this relationship. In the intervention study, testosterone undecanoate given orally significantly improved angina pectoris in 62 patients with CHD as compared to placebo. No significant association between serum testosterone and CHD was reported in the prospective studies, whereas those studies concerning DHEAS found either no or an inverse association with CHD. Of 30 cross-sectional studies, 18 reported reduced concentrations of testosterone (primarily), and/or DHEA(S) in CHD patients as compared to normals, 11 found similar circulating levels of these androgens in controls and patients with CHD, and one study found elevated levels of DHEA(S) in patients. Animal studies (six male rabbits and one in male chicks) suggest an anti-atherogenic effect of testosterone and DHEA. In conclusion, one intervention, eight cohort and several cross-sectional studies suggest either a neutral or a favourable effect of testosterone and DHEA(S) on CHD in males.

Tibolone: prevention of bone loss in late postmenopausal women.

The aim of the study was to assess the effects of 2 yr of treatment with two dose levels of tibolone on bone mineral density and bio-chemical markers of bone metabolism in late postmenopause. Ninety-one healthy women, more than 10 yr after menopause, entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36) or 2.5 mg/day (n = 35) Tibolone or placebo (n = 20). Densitometry and determinations of biochemical markers of bone metabolism in serum and urine were performed before randomization and every 3 months during the study. The results revealed a steady and equal increase in bone mineral density in both tibolone groups at the bone sites studied. Gains in BMD spine of 5.9 +/- 0.9% in the 1.25 mg group, 5.1 +/- 0.9% in the 2.5 mg group, and 0.4 +/- 1.1% in the placebo group were found. In the forearm, increases of 2.2 +/- 0.7% in the 1.25 mg group and 1.9 +/- 1.1% in the 2.5 mg group were detected, whereas the placebo group lost 2.1 +/- 1.0%. This was fully supported by changes in biochemical markers of bone resorption (urinary excretion of fragments from the osteoclastic degradation of the alpha 1-chain of the C telopeptides of type 1 collagen and hydroxyproline) and bone formation (serum osteocalcin), respectively. In conclusion, within 2 yr of treatment, tibolone increases bone mass in the spine and prevents bone loss in the forearm in late postmenopausal women determined by densitometry and several biochemical parameters of bone turnover. Tibolone at two doses (1.25 and 2.5 mg/day) had similar effects, indicating that even lower doses may be efficacious.

The impact of female sex hormones on secondary prevention of atherosclerosis in ovariectomized cholesterol-fed rabbits.

The present study investigated the effect of female sex hormones and diet on atherosclerotic arteries in rabbits. The animals were initially ovariectomized and then fed an atherogenic diet for 12 weeks (n = 60). They were thereafter randomized to 5 groups of which one immediately was killed. Three of the remaining groups received a moderate atherogenic diet plus oral 17 beta-estradiol, levonorgestrel or no hormones, whereas the last group was fed a diet without hormones or cholesterol. During the second phase of the study, the rabbits receiving the moderate atherogenic diet and no hormones had the highest serum concentration of cholesterol (48.0 +/- 3.4 mmol/l), whereas those having the cholesterol free diet had the lowest value (26.4 +/- 3.6 mmol/l) with the two hormone groups in between (mean +/- S.E.M., P < 0.05). The estradiol group had only approximately half of the aortic accumulation of cholesterol (854 +/- 155, nmol/mg) found in the levonorgestrel (1676 +/- 362) and moderate atherogenic diet (1829 +/- 361) groups (mean +/- S.E.M., P < 0.05). The estradiol group and the rabbits fed diet without hormones or cholesterol (1034 +/- 169) had a comparable degree of atherosclerosis. In conclusion, estradiol inhibits progression of atherosclerosis significantly. This beneficial effect is only partly explained by changes in serum lipids and lipoproteins.

Body composition and serum lipids in female runners: influence of exercise level and menstrual bleeding pattern.

The impact of running and menstrual disturbances on regional and total body fat distribution and serum lipids was investigated in 205 women. Body composition was measured by dual-energy X-ray absorptiometry. The total fat mass in the elite runners was approximately half of the normally active's (7.3 [0.48] kg vs. 14.3 [0.49] kg, P < 0.001) (mean [SEM]). The difference was most pronounced in the abdomen (fat percentage 9.7 [0.85]% vs. 22.0 [0.88]%, P < 0.001). The elite runners tended to have a more favourable lipid profile than the normally active (NS). A significant relation was found between lipoproteins and body fatness. In comparison with the regularly menstruating runners (n = 93), the 13 runners with amenorrhea tended to have less body fat and slightly less favourable lipid profiles (NS). In conclusion, regular exercise was associated with a low abdominal fat percentage, which may affect cardiovascular risk beneficially. Running-associated menstrual dysfunctions were not significantly related to a specific body composition or serum lipid profile.

[Bone metabolism in female runners. Menstruation disorders are frequent among long-distance runners, but the bone mass is not influenced, with the exception of runners with amenorrhea]. / Knoglemetabolisme hos kvindelige løbere. Langdistanceløbere har hyppigt menstruationsforstyrrelser, men knoglemassen er upåvirket, undtagen hos løbere med amenoré.

The purpose of the study was to investigate the prevalence of exercise-related menstrual and sex hormonal disturbances and the effect of exercise on bone mass and metabolism in female runners at various training levels. Two hundred and five premenopausal women (running 0-140 km a week) were recruited from a large population of female runners, who had responded to a questionnaire regarding exercise habits. Maximum oxygen uptake was determined by treadmill testing. Gynaecological status was assessed on entries in a menstrual calendar and by transvaginal ultrasonography; and sex hormonal status was measured three times with 10-day intervals. Bone mass was measured in the lumbar spine, proximal femurs and total body by dual energy x-ray absorptiometry, and in the forearm by single photon absorptiometry. Bone turnover was assessed by plasma osteocalcin, serum alkaline phosphatase, and urinary calcium and hydroxyproline. The results showed that sex hormonal disturbances were significantly related to training intensity. Compared with the normally active women, the baseline levels and fluctuations of oestradiol and progesterone in the elite runners were reduced by up to 25-44%, (0.01 < p < 0.05). The prevalence of amenorrhoea increased from 1% in the normally active to 11% in the elite runners. No statistically significant relation was found between running activity and bone mass or bone turnover. However, the group of amenorrhoeic runners had a 10% reduction in lumbar bone mass as compared to the normally menstruating runners (p < 0.05), but the bone turnover was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic permeability to LDL during estrogen therapy. A study in normocholesterolemic rabbits.

17 beta-Estradiol has recently been found to inhibit atherogenesis by mechanisms that are in part independent of the estrogenic action on plasma lipoprotein levels. Since aortic permeability to low-density lipoprotein (LDL) in normocholesterolemic rabbits is a strong predictor for subsequent atherosclerosis during hypercholesterolemia, the present study investigated a possible influence of 17 beta-estradiol on aortic permeability to LDL. Twenty rabbits were initially ovariectomized and then fed a nonatherogenic diet for 10 weeks. One group of rabbits (n = 10) received 4 mg of 17 beta-estradiol orally per day; the other group (n = 10) received placebo. Serum concentrations of very-low-density lipoprotein cholesterol and triglycerides increased significantly more in the placebo group than in the estrogen group (P < .03), whereas there were no statistically significant differences between groups in LDL, high-density lipoprotein, or total cholesterol. At the end of the experiment, 125I-LDL was injected intravenously into each rabbit. Aortas were removed 3 hours later, and the aortic permeability to LDL was calculated from the radioactivity in the plasma and the aortic intima/inner media. The aortic permeability to LDL was virtually identical in the 17 beta-estradiol (31.6 +/- 7.2 nL.cm-2.h-1) and the placebo (36.9 +/- 7.9 nL.cm-2.h-1) groups (mean +/- SEM). The aortic cholesterol content was also similar in the two groups. These data suggest that the plasma lipid-independent antiatherogenic effect of estradiol is not mediated through an effect on aortic permeability to LDL but rather is related to the metabolism of the lipoproteins after they have entered the arterial wall.

Low bone mass and high bone turnover in male long distance runners.

Running is a popular sport, but in some studies long distance running in women has been related to reduced bone mass and a potential risk of osteoporosis. To investigate the impact of running on bone mass in men, 120 healthy, physically active men (19-56 yr old; running 0-160 km/week) were studied. Bone mineral content was measured in the lumbar spine, total body, and proximal femurs by dual energy x-ray absorptiometry and in the forearm by single photon absorptiometry. Bone turnover was assessed by urinary pyridinium cross-links, plasma osteocalcin, and serum alkaline phosphatase. Lumbar bone mineral content was negatively correlated to the weekly distance run (r = -0.37; P < 0.0001), with a difference of 19 +/- 5% (mean +/- SEM) between controls and elite runners. A similar relation was found for all measurement sites. After adjustment for possible confounders, the correlations remained statistically significant in areas with a high proportion of trabecular bone. Bone turnover parameters were 20-30% higher in the elite runners, whereas sex hormone status was unrelated to running activity. We conclude that male long distance runners had reduced bone mass and increased bone turnover compared to controls, which suggests accelerated bone loss. The pathophysiological explanation was not clear, but sex hormones did not seem to play a key role.

Running induces menstrual disturbances but bone mass is unaffected, except in amenorrheic women.

PURPOSE: To investigate the prevalence of exercise-related menstrual and sex hormonal disturbances and the effect of exercise on bone mass and metabolism in female runners at various training levels. SUBJECTS AND METHODS: Two hundred five premenopausal women (running 0 to 140 km a week) were recruited from a large population of female runners who had responded to a questionnaire regarding exercise habits. Maximum oxygen uptake was determined by treadmill testing. Gynecologic status was assessed on entries in a menstrual calendar and by transvaginal ultrasonography; sex hormonal status was measured three times with 10-day intervals. Bone mass was measured in the lumbar spine, proximal femurs, and total body by dual-energy x-ray absorptiometry, and in the forearm by single-photon absorptiometry. Bone turnover was assessed by measurement of plasma osteocalcin, serum alkaline phosphatase, and urinary calcium and hydroxyproline. RESULTS: Sex hormonal disturbances were significantly related to training intensity. Compared with the normally active women, the baseline levels and fluctuations of estradiol and progesterone in the elite runners were reduced by up to 25% to 44% (0.01 < p < 0.05). The prevalence of amenorrhea increased from 1% in the normally active subjects to 11% in the elite runners. No statistically significant relation was found between running activity and bone mineral measurements or bone turnover. However, the group of amenorrheic runners had a 10% reduction in lumbar bone density as compared with the normally menstruating runners (p < 0.05), but the bone turnover was similar. CONCLUSION: In the large majority of the female runners, no skeletal affection was found despite significant sex hormonal and menstrual disturbances. Only the runners with amenorrhea might be at increased risk of osteoporosis.