Jorma Heikkinen

HRT and exercise: effects on bone density, muscle strength and lipid metabolism. A placebo controlled 2-year prospective trial on two estrogen-progestin regimens in healthy postmenopausal women

OBJECTIVES To evaluate the effect of 1- or 3-monthly sequential combinations of estradiol valerate (E2V) and medroxyprogesterone acetate (MPA) on menopausal symptoms, bone density, muscle strength and lipid metabolism in postmenopausal women. METHODS Changes in bone mineral density (BMD), isometric muscle strength, serum lipids and climacteric symptoms were evaluated in 78 women, 49-55 years of age, with a spontaneous menopause 0.5-3 years earlier. Treatment group I received 2 mg E2V tablets for 11 days, followed by 2 mg E2V + 10 mg MPA for 10 days and placebo for an additional 7 days; treatment group II received 2 mg E2V for 70 days, 2 mg E2V + 20 mg MPA for 14 days, and placebo for 7 days. The placebo group received placebo continuously for 24 months. Each group was further randomised to exercise and non-exercise subgroups. RESULTS Both hormone regimens significantly reduced menopausal symptoms, and prevented equally well the decrease of BMD both in the lumbar spine and proximal femur. A positive effect of exercise on BMD was observed in the placebo group. No synergistic effect of exercise and estrogen on BMD could be shown. Both hormone regimens increased the isometric strength of back extensor muscles. Serum total and LDL cholesterol decreased during the first year with both estrogen regimens. CONCLUSIONS Estrogen-progestin regimens were equally effective in the control of menopausal symptoms and preventing bone loss, increasing muscle strength and lowering serum cholesterol.

CHANGES IN SERUM BILE ACID CONCENTRATIONS DURING NORMAL PREGNANCY, IN PATIENTS WITH INTRAHEPATIC CHOLESTASIS OF PREGNANCY AND IN PREGNANT WOMEN WITH ITCHING

Two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), and one secondary bile acid, deoxycholic acid (DCA), were measured by radioimmuno‐assay in pregnancy serum from 30 healthy women, 49 women with itching and 45 with intrahepatic cholestasis of pregnancy. All subjects were studied serially from between 16 and 20 weeks gestation until 35–60 days post partum. In healthy pregnant women, serum CA and DCA levels did not change significantly at any time. The mean CDCA level rose significantly towards term. In women with intrahepatic cholestasis, serum levels of CA and CDCA were increased ten‐ and five‐fold, respectively, at the time of appearance of clinical Symptoms and the CA/CDCA ratio rose from l/l to 2/1; there was also a moderate increase in the serum concentration of DCA. In 4 of 8 women studied prospectively an increase in serum bile acid levels preceded the appearance of Symptoms or other laboratory evidence of intrahepatic cholestasis. Nine of the women with itching with normal routine liver function test results had increases in serum CA and CDCA concen‐trations suggesting mild cholestasis.

Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2–4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.

Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine

Nineteen patients suffering from the intrahepatic cholestasis (IHC) of pregnancy were studied. Twelve of them were treated with phenobarbital (100 mg/day) and seven with cholestyramine (18 g/day). The overnight fasting levels of serum cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) were measured by radioimmunoassay. The activities of serum transaminases, gamma-glutamyltranspeptidase, alkaline phosphatase and total and conjugated bilirubins were also analyzed. It was found that there was no correlation between the itching symptom and the serum bile acid levels. During phenobarbital treatment serum bile acid concentrations did not change. Also, the other measured parameters as well as the CA/CDCA ratio did not change significantly. Transaminases had, however, a slight tendency to decrease. The therapy successfully relieved itching in half of the cases. There was no relationship between the relief of the itching and the change in the bile acid concentrations. Cholestyramine treatment did not decrease the CA level significantly, but that of the CDCA decreased (P less than 0.05) and the ratio of CA/CDCA increased (P less than 0.05). In the other analyzed liver function test results, an increase (P less than 0.05) occurred only in the concentrations of conjugated bilirubin. The itching was relieved in five of the seven cases during the first week of treatment, but after that the symptom tended to reappear. There was a slight correlation between the decrease in the CDCA level and in the relief of the itching. The two drugs did not cause any particular side effects.

Long-term Outcomes of Exercise: Follow-up of a Randomized Trial in Older Women With Osteopenia

BACKGROUND Long-term evidence from randomized trials of the effectiveness of exercise in preventing disability and fall-related fractures in elderly people has been lacking. METHODS We performed extended follow-up of 160 women (aged 70-73 years at baseline) with osteopenia in a population-based, randomized, controlled exercise trial. The trial was conducted from April 1 through April 30, 2001. Follow-up was conducted from May 1, 2001, through December 31, 2005. Mean total time in observation was 7.1 years. Primary outcome measures were femoral neck bone mineral density, postural sway, and leg strength. Secondary outcome measures were hospital-treated fractures and functional ability measures. Outcomes were measured annually using masked assessors. RESULTS There was a significant difference between groups in favor of exercise in terms of postural sway (group × time interaction, P = .005), walking speed (group × time interaction, P < .001), and Frenchay Activities Index score (group x time interaction, P = .001). The bone mineral density decreased similarly across time in both groups. The incidence rate of fractures during the total follow-up among women in the exercise group vs women in the control group was 0.05 vs 0.08 per 1000 person-years (Poisson incidence rate ratio, 0.68; 95% confidence interval, 0.34-1.32). There were no hip fractures in the exercise group, whereas 5 hip fractures occurred in the control group. One woman in the exercise group and 8 women in the control group died (Poisson incidence rate ratio, 0.11; 95% confidence interval, 0.01-0.85). CONCLUSION Mainly home-based exercises followed by voluntary home training seem to have a long-term effect on balance and gait and may even protect high-risk elderly women from hip fractures. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00655577.

Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels

Low levels of insulin-like growth factor binding protein-1 (IGFBP-1) have recently been associated with several risk factors for cardiovascular disease. The effects of estrogen replacement therapy (ERT) on plasma IGFBP-1 levels are, however, unclear. A double-blind, placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women randomized into two groups: oral estradiol (E2) valerate, 2 mg/day (n = 35) and transdermal E2 gel, 1 mg/day (n=38). Plasma IGFBP-1, insulin-like growth factor-I (IGF-I) and lipoprotein(a) (Lp(a)) were determined at baseline, 3 and 6 months. The groups were similar for age and BMI. The baseline levels of estrone (E1), E2, IGFBP-1, IGF-I and Lp(a) did not differ between the groups. During treatment, serum estradiol concentrations increased in both groups. During oral ERT, IGFBP-1 levels increased by 104% (P<0.001), whereas IGF-I levels decreased by 13% (mean, P<0.05). IGF-I and IGFBP-1 levels remained unchanged in the transdermal group. Lp(a) levels decreased by 23% (median, P<0.001) in the oral group, but were unaffected by transdermal therapy. The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a) (r = -0.40, P<0.05, Spearman correlation). In conclusion, oral ERT seems to enhance plasma levels of IGFBP-1, which may be one reason for the reduced Lp(a) levels.

Can progestin be limited to every third month only in postmenopausal women taking estrogen

We evaluated whether a progestin, added for 14 days every 3 months to estrogen replacement therapy, is capable of preventing the development of endometrial hyperplasia in postmenopausal women during a treatment period of 2 years. Postmenopausal women (263) in 10 hospitals and medical centers in Finland participated in this non-randomized prospective multicenter trial. The women received estradiol valerate 2 mg daily for 84 days and 20 mg of medroxyprogesterone acetate daily for days 71-84 followed by seven drug-free tablets. This regimen was repeated four times per year. The first year of treatment was completed by 227 (86%) women and the second year by 143 out of 146 women. The incidence of unscheduled and heavy bleedings was higher in women who were postmenopausal for less than 3 years. Endometrial biopsies demonstrated progestational response in 64% at 12 and 24 months, respectively. The 3 month regimen prevented development of endometrial hyperplasia but was not able to restore a hyperplastic endometrium to normal.

Effects of estrogen replacement therapy on natriuretic peptides and blood pressure.

OBJECTIVE Estrogen replacement therapy (ERT) has been reported to affect blood pressure. Since natriuretic peptides have natriuretic and vasodilatory activity and also inhibit the renin-angiotensin-aldosterone system and lower blood pressure, it was hypothesized that the changes in blood pressure effected by ERT might be mediated via changes in natriuretic peptides. METHODS Fifty-eight postmenopausal hysterectomized women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate 2 mg/day or transdermal estradiol gel containing 1 mg estradiol/day for 6 months. Blood pressure was measured by using an automatic, oscillometric device. Plasma atrial natriuretic peptide (ANP), N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP), aldosterone, and renin were determined by radioimmunoassay. RESULTS The mean decrease in diastolic blood pressure was -6 mmHg both in the peroral group (n = 26) (P = 0.002) and in the gel group (n = 27) (P = 0.001), and the corresponding decreases in systolic blood pressure were -4 mmHg (P = 0.070) and -7 mmHg (P = 0.028) in the sitting position. Plasma NT-proANP rose from 212 to 264 pmol/l (P = 0.001) on peroral ERT and from 240 to 292 pmol/l (P = 0.008) on transdermal ERT. No significant changes were observed in the plasma ANP, BNP, aldosterone, and renin levels. CONCLUSIONS Both peroral and transdermal ERT result in elevated plasma levels of NT-proANP, indicating an activation of the natriuretic peptide system. This could explain, at least in part, the lowering of blood pressure during ERT.

Mechanisms Regulating LDL Metabolism in Subjects on Peroral and Transdermal Estrogen Replacement Therapy

To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized postmenopausal women aged 48 to 62 years were randomized in a double-blind double-dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4. 19+/-0.83 (mean+/-SD) to 3.39+/-0.78 mmol/L (P<0.001) in the peroral group and from 4.11+/-0.86 to 3.72+/-0.78 mmol/L (P<0.001) in the transdermal estrogen group. Peroral estrogen did, but transdermal treatment did not, enhance the fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB). However, the decrease of LDL cholesterol was related to an increase in FCR for LDL apoB on both peroral and transdermal ERT (r=-0.645, P<0.001 and r=-0.627, P<0.001, respectively). These changes were associated with changes in the serum estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to 10% (P<0.05). The effects of estrogen were not modified by the polymorphisms of apoE and apoB or cholesterol 7alpha-hydroxylase. In conclusion, the ERT-induced LDL cholesterol-lowering effect is related to changes in estrogen level, which presumably enhance LDL receptor activity, which is manifested as an increase in FCR for LDL apoB. The small decrease in the absorption efficiency of dietary cholesterol does not seem to contribute largely to the cholesterol lowering on either transdermal or peroral ERT.

Estrogen replacement therapy decreases plasma adiponectin but not resistin in postmenopausal women

The effects of estrogen replacement therapy (ERT) to cardiovascular disease risk are still unclear. Low adiponectin and high resistin plasma concentrations are reported to be associated with atherosclerosis. However, it is not known how ERT affects plasma adiponectin and resistin concentrations. Seventy-three hysterectomized, nondiabetic, postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate or transdermal 17beta-estradiol gel for 6 months. Biochemical measurements were determined from samples taken before and after the therapy. Peroral estradiol valerate therapy decreased adiponectin concentrations from 13.6 to 11.6 mg/L (P = .008), whereas transdermal 17beta-estradiol gel had no effect (12.7 vs 12.2 mg/L). Neither treatment changed the resistin concentrations significantly. Plasma concentrations of estradiol and estrone did not correlate with adiponectin or resistin concentrations before or after therapy. The change in adiponectin concentration correlated significantly with the changes in waist-hip ratio, very low-density lipoprotein triglycerides, and insulin-like growth factor 1 in the peroral estradiol valerate group. The changes in these variables and the change in estradiol concentration explained 43.1% (P = .001) of the variability in the change of plasma adiponectin, the change in very low-density lipoprotein triglycerides being the strongest determinant (beta = -.407, P = .011). The results show that peroral ERT can decrease plasma adiponectin levels. However, ERT does not seem to influence plasma resistin concentrations.