Estradiol and dydrogesterone. A review of their combined use as hormone replacement therapy in postmenopausal women

The focus of this review is hormone replacement therapy (HRT) with continuous oral 17 beta-estradiol (herein referred to as estradiol) 2 mg/day plus sequential oral dydrogesterone 10 or 20 mg/day for 14 days of each 28-day cycle. According to data from nonblind trials, this regimen relieves climacteric symptoms, preserves bone mineral density (BMD) and improves the cardiovascular risk profile in postmenopausal women. Increases in mean BMD in the lumbar spine of 2.4 to 6.4% have been reported after 2 years' treatment. The effect on BMD of oral estradiol plus sequential dydrogesterone was similar to that achieved with transdermal estradiol plus sequential oral dydrogesterone or with oral tibolone. Good protection against endometrial hyperplasia and cancer is provided by the dydrogesterone component. Cyclical vaginal bleeding occurs in most treatment cycles, but is generally light to moderate and the time of onset is highly predictable. Noncyclical bleeding occurs in < 10% of cycles. Mean serum high density lipoprotein-cholesterol levels are increased and low density lipoprotein-cholesterol levels are decreased during treatment with oral estradiol plus sequential dydrogesterone. Insulin resistance appears to be improved. Blood pressure and bodyweight are not generally affected to any clinically important extent. Serum homocysteine levels were reported to decrease in postmenopausal women with high pretreatment levels. No data are available on the general tolerability profile of this regimen. However, the adverse events that most commonly led to discontinuation of treatment in clinical trials were typical of those associated with HRT, including vaginal bleeding headache, bloating and breast tenderness. Although the risk of breast cancer has not been specifically assessed for this regimen, it is unlikely to carry a greater risk than that of other HRT regimens. In summary available data indicate that treatment with continuous oral estradiol plus sequential dydrogesterone is effective in relieving climacteric symptoms and preserving BMD in postmenopausal women. The dydrogesterone component provides good endometrial protection and cycle control without negating the cardiovascular benefits of estradiol. Comparisons with other standard HRT regimens and long term data (including clinical end-points) are needed. In the meantime, this regimen can be regarded as an acceptable HRT option.     

Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group

BACKGROUND: Prospective studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine. OBJECTIVES: To determine the effects of unopposed esterified estrogens on bone mineral density, lipid levels, and endometrial tissue structure, and to relate these effects to changes in plasma estradiol levels. METHODS: Four hundred six postmenopausal women were given calcium, 1000 mg/d, and randomly assigned to receive continuous esterified estrogens (0.3, 0.625, or 1.25 mg/d) or placebo for 24 months. Bone mineral density measurements and endometrial and laboratory assessments were conducted every 6 months; plasma estradiol concentrations were measured after 12, 18, and 24 months. RESULTS: All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6, 12, 18, and 24 months. Mean plasma estradiol levels increased with esterified estrogens dose, and individual subject bone mineral density changes appeared related to plasma estradiol concentrations. Clinically relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily. Lipid changes were dose related and apparent in all groups. CONCLUSIONS: Esterified estrogens at doses from 0.3 to 1.25 mg/d, administered unopposed by progestin, produce a continuum of positive changes on bone and lipids. Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities. The 0.3-mg dose resulted in positive bone and lipid changes without inducing endometrial hyperplasia.     

Effects of estrogen replacement therapy on the lipoprotein profile in postmenopausal women with ESRD

BACKGROUND: Patients with ESRD have excessive cardiovascular morbidity and mortality. In postmenopausal women with normal renal function, estrogen replacement therapy decreases cardiovascular mortality by 50%, in part because of their beneficial effects on the lipoprotein profile. Because of similarities in the lipoprotein profile between healthy, postmenopausal women, and women with ESRD, we examined the effects of estrogen replacement on lipoproteins in 11 postmenopausal women with ESRD. METHODS: In a randomized, placebo-controlled crossover study (8 week treatment arms) using 2 mg daily of oral, micronized estradiol, 11 postmenopausal women with ESRD were treated. Neither baseline lipid nor lipoprotein abnormalities were used as entry criteria for study participation. RESULTS: Blood estradiol levels were 19 +/- 4 with placebo and 194 +/- 67 pg/ml (P = 0.024) with estradiol treatment. Total HDL cholesterol concentrations increased from 52 +/- 19 mg/dl to 61 +/- 20 mg/dl (16%), with placebo and estradiol treatments, respectively (P = 0.002). Apolipoprotein A1 increased by 24.6% (P = 0.0002) with estradiol intervention. HDL2 concentrations were 19 +/- 13 with placebo and 24 +/- 16 with estradiol treatment (P = 0.046). There were no differences in total or LDL cholesterol, other lipoprotein fractions including Lp(a), and triglycerides with 2 mg daily estradiol treatment. No significant side effects were observed. CONCLUSIONS: Therefore, using standard dosage regimens for estrogen replacement therapy in postmenopausal women with ESRD, HDL cholesterol is increased to an extent that would be expected to improve their cardiovascular risk profile. Further studies are needed to assess whether estrogen replacement therapy decreases the incidence or severity of cardiovascular disease in ESRD patients to a similar degree compared with other women.     

Transdermal estradiol. A potentially improved method of hormone replacement

Estrogen replacement is usually administered as an oral preparation. Concerns have been expressed about the impact these oral preparations have on hepatic function. This paper reviews studies of one nonoral preparation that delivers estradiol into the systemic circulation by use of a transdermal system. Support for this delivery system for treating menopausal symptoms and, potentially, for avoiding side effects is presented.     

Unusual presentation of nephroblastomatosis]

OBJECTIVE: Little is known about the association between free IGF-I levels and bone mineral density (BMD). DESIGN: A cross-sectional study of 218 healthy subjects (103 men, 115 women, age 55-80 years) was carried out. METHODS: Fasting serum free IGF-I, total IGF-I, estradiol and sex hormone-binding globulin (SHBG) levels were measured. The ratio of estradiol to SHBG was used as an index of free estradiol. BMD measurements were performed by dual-energy X-ray absorptiometry of the lumbar spine and the proximal femur. RESULTS: In multivariate analyses with BMD of the lumbar spine as the dependent variable and serum free IGF-I, age, body mass index (BMI) and the free estradiol index as independent variables, the free IGF-I was positively related to the BMD of the lumbar spine in men (P = 0.02) but not in women. When the same analyses for the lumbar BMD were performed with total serum IGF-I the association was also only statistically significant in men (P = 0.05). In multivariate analyses with the trochanter BMD as the dependent variable and serum free IGF-I, total IGF-I, age, BMI and the free estradiol index as independent variables, the associations between (free and total) IGF-I and the trochanter BMD in men was of borderline significance. CONCLUSIONS: In elderly men free and total IGF-I were positively related to lumbar BMD, while (free and total) IGF-I was borderline positively related to trochanter BMD. As these relationships were not observed in elderly women, we suggest a weak gender-specific anabolic effect of IGF-I on BMD on trabecular bone.     

Advanced colorectal carcinoma: redefining the role of oral ftorafur

The therapeutic performance, effect on quality of life and cost effectiveness of an orally administered medication in a home care setting were examined prospectively in a group of 61 patients presenting with advanced colorectal carcinoma. A regimen of daily ftorafur capsules (370 mg/m2) and leucovorin tablets (20 mg/m2) was offered to 35 symptomatic patients with poor performance status; the standard in-hospital i.v. protocol of 5-fluouracil and leucovorin was given to the remaining 26 patients. Follow-up and survival analysis indicated that there was no compromise in survival associated with home care and oral chemotherapy. There were statistically significant advantages in terms of reduced toxicity and improved Karnofsky performance status in this group. Home care was approximately 70% less expensive. A home treatment program based on oral ftorafur may be the most desirable option for all patients with advanced colorectal carcinoma.     

Platelet antibodies in patients with migraine

The newer antifungal agents are increasingly being used for the treatment of onychomycosis. Tinea unguium is uncommon in children. In young children who are unable or unwilling to swallow capsules, the alternative to itraconazole capsules may be the oral solution. The pharmacokinetics of the itraconazole capsule when it is broken open and the contents sprinkled onto food has not been reported. Two sisters, ages 8 and 11 years, presented with fingernail dystrophy that was confirmed to be onychomycosis due to Trichophyton rubrum and T. soudanense, respectively. The patients were reluctant to swallow capsules and were treated with itraconazole pulse therapy using the oral solution, 3 mg/kg/day. The treatment regimen consisted of two pulses, each 1 week long, with a 3-week period between pulses. Both patients were clinically and mycologically cured with no adverse effects. Itraconazole oral solution (3 mg/kg/day) given as pulse therapy may be a consideration in the treatment of onychomycosis in some children.     

Transdermal delivery of estradiol in postmenopausal women with a novel topical aerosol

The objective of this study was to determine if a novel metered-dose topical aerosol (MDTA) formulation containing the new dermal penetration enhancer, padimate O, could enhance the transdermal delivery of estradiol to an extent that would result in clinically relevant plasma concentrations. The estradiol MDTA (with padimate O) was applied once daily at 0800 h to postmenopausal women for 9 days, and plasma estradiol and estrone was measured daily (24 h postapplication) by radioimmunoassay. The topical dose was administered as three 1 mg doses of estradiol, each applied as a single spray over 10 cm2 which were placed adjacent to each other on the subject's ventral forearm. None of the subjects tested showed any sign of skin irritation at the application site over the entire study period using the Draize irritation score. In four postmenopausal women (age 54-63 years, weight 67-93 kg) the mean estradiol level 24 h postapplication over the 9 day study period was 53 pg/mL. This result was significantly greater (p < 0.001) than the baseline value of 13 pg/mL. The mean estradiol/estrone ratio also rose significantly (p < 0.04) from a baseline value of 0.2 up to 0.8. We conclude that this novel MDTA formulation significantly enhances the transdermal delivery of estradiol to allow a clinically relevant dose of estradiol to be delivered in postmenopausal women with once daily dosing.     

A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.     

Inhibition of prolactin secretion delays extinction of circadian LH surges in ovariectomized rats bearing estradiol implants

Ovariectomized rats bearing Silastic capsules containing estradiol exhibit a daily afternoon surge of luteinizing hormone (LH) which decreases with time until it is undetectable by Day 10 after implantation of estradiol. Increases in basal prolactin levels as well as afternoon surges are also observed. To determine if increased prolactin secretion contributed to the extinction of the circadian LH surges, we examined the patterns of LH and prolactin secretion in rats in which prolactin was suppressed by bromocriptine treatment. In vehicle-treated control rats, the magnitude of the LH surges decreased with time. Large LH surges were observed on Days 2 and 4. A significant decrease in the surge occurred on Day 6, and it disappeared by Day 10. Animals treated with bromocriptine also exhibited large LH surges on Days 2 and 4, and in addition, secreted a greater amount of LH than the control group on Days 6, 8, and 10. In ovariectomized rats bearing estradiol implants, large afternoon surges in prolactin were observed and by Day 6, basal prolactin levels were also elevated. Bromocriptine treatment completely suppressed prolactin secretion through Day 6, but a small afternoon rise was observed on Days 8 and 10. These findings suggest that elevated prolactin secretion may be one factor contributing to the extinction of circadian LH surges in the estrogen-treated rat.     

Tennis elbow. Current concepts of treatment and rehabilitation

OBJECTIVE: Estrogens are known to exhibit antioxidative effects. At present little information exists on the influence of co-administered progestins upon this effect. Therefore we investigated the influence of levonorgestrel, a potent antiestrogenic progestin, on the inhibition of the low-density lipoprotein (LDL) oxidation by 17 beta-estradiol or 17 beta-estradiol valerate in vitro and ex vivo. METHODS: After isolation from blood, the in vitro oxidation of LDL was induced by copper ions and measured continuously by monitoring the formation of conjugated dienes. In 21 female ovariectomized White New Zealand rabbits the antioxidative action of 17 beta-estradiol alone or in combination with levonorgestrel after subcutaneous infusion for 3 days was determined using the copper-induced LDL-oxidation as an endpoint. Eleven postmenopausal women were exposed to sequential estrogen-progestin replacement therapy (day 1-21:2 mg estradiol valerate/day, day 10-21: 0.15 mg levonorgestrel/day). Blood samples were collected at three times: on day 1, on day 10, on day 22 (after the combination phase). The lag time of ex vivo oxidation of LDL, the plasma estradiol and estrone levels were estimated. RESULTS: In the chosen cell-free system, 17 beta-estradiol increased the lag time of the LDL-oxidation in a dose-dependent manner. Levonorgestrel showed neither pro-oxidative nor antioxidative effects when administered alone in different concentrations. Co-administration of different doses of levonorgestrel did not modify the antioxidative action of estrogen either. The two ex-vivo models confirmed these results. In rabbits the co-administered 19-nortestosterone derivative levonorgestrel did not impair or reverse the estradiol-dependent effect. In postmenopausal women the daily oral administration of levonorgestrel in conjunction with 17 beta-estradiol valerate did not diminish the antioxidative action of this estrogen given for the first 9 days. CONCLUSION: The antioxidative potential of estradiol and estradiol valerate is maintained in the presence of levonorgestrel.     

A comparison of fluconazole and itraconazole in the management of denture stomatitis: a pilot study

OBJECTIVES: To compare fluconazole capsules (50 mg daily for 14 days) and itraconazole capsules (100 mg daily for 15 days) in the treatment of denture stomatitis, using objective clinical and mycological outcome measures. METHODS: Twenty complete denture wearers with denture stomatitis were enrolled. At baseline, palatal erythema was measured with an electro-optical instrument, a denture disc specimen was collected from the fitting surface of the denture for culture and an oral rinse and imprint cultures were collected for mycological culture. Ten patients received fluconazole capsules (50 mg daily for 14 days) and 10 received itraconazole capsules (100 mg daily for 15 days). Palatal erythema was reassessed and the microbiological specimens re-collected on day 14. RESULTS: The most common form of denture stomatitis seen in this group of patients was Newton's Type II. All patients responded to advice to leave their dentures out at night but there was a poor overall improvement in denture hygiene. There was an objective reduction in palatal erythema following treatment with both fluconazole and itraconazole. A wide range of yeasts were isolated from the mouths of all the denture stomatitis patients before treatment. C. albicans was the most common isolate. A mycological cure was achieved in only five of the 20 patients, one in the fluconazole group and four in the itraconazole group. A further eight patients in the fluconazole group and three in the itraconazole group had reduced yeast counts by the second visit. CONCLUSION: Fluconazole and itraconazole were of comparable efficacy in the treatment of denture stomatitis, on the basis of reduction in palatal erythema and mycological culture.     

Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally

In a previous study, administration of high doses of estradiol benzoate (100 microgram/kg for 3 days im) to ovariectomized Long-Evans rats counteracted impairments of reinforced T-maze alternation induced by systemic administration of scopolamine, a muscarinic receptor blocker. In the current study, daily administration of lower doses of estradiol benzoate (5 microgram/kg for 3 weeks sc) increased the number of correct reinforced alternations during T-maze acquisition in ovariectomized rats compared to oil-treated controls and prevented impairments of reinforced alternation induced by injection of scopolamine hydrobromide (0.2 mg/kg ip). Furthermore, scopolamine (20 microgram) delivered bilaterally to the dorsal hippocampus reduced reinforced T-maze alternation in ovariectomized rats previously trained to complete this task while daily treatment with estradiol benzoate (5 microgram/kg sc) for 1 week prior to scopolamine infusion counteracted this impairment. In summary, physiological levels of estrogen improved performance during acquisition of reinforced T-maze alternation and prevented impairments induced by scopolamine administered systemically or intrahippocampally.     

Immunoregulatory effects of a nutritional preparation containing bovine lactoferrin taken orally by healthy individuals

The aim of this study was to monitor several immune parameters in 17 healthy volunteers taking orally commercially available capsules containing bovine lactoferrin (BLFT) for 10 days (40 mg of BLFT daily). We determined leukocyte number and content of main blood cell types, spontaneous and phytohemagglutinin A (PHA)-induced proliferation of lymphocytes, plasma levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) as well as spontaneous and lipopolysaccharide (LPS)-induced production of these cytokines in peripheral blood cell cultures. All measurements were performed before, one day and 14 days following cessation of BLFT treatment. We established some, transient drop in the percentage of neutrophils accompanied by an opposite phenomenon with regard to lymphocyte levels. More profound changes were registered in the percentage of other cell types, for example a 100% increase in the level of immature cell forms (bands) was noted. At the same time the percentages of eosinophils and monocytes declined significantly. All these changes were, however, more individual and regulatory, the direction of these changes depended on initial picture of blood cells. Although the proliferative response of lymphocytes showed, on average, a transient decrease, differentiated effects of BLFT treatment were observed depending on initial ability of lymphocytes to proliferate. TNF-alpha serum levels showed a tendency to decrease during the monitoring time, the changes of IL-6 levels were, however, not significant. As in the case of the proliferative response, the treatment with BLFT was regulatory with respect to serum TNF-alpha levels. When we analyzed spontaneous and LPS-induced cytokine production in cell cultures we found that mainly the mean spontaneous response was affected (inhibition). We also observed a typical, regulatory action of BLFT on the level of spontaneously produced IL-6. This kind of regulatory action of BLFT was also found in the case of spontaneously produced TNF-alpha in cell cultures. The influence of other ingredients such as selenium or vitamins, contained in the capsules, cannot be excluded, although our latest data showed that orally taken bovine lactoferrin alone can induce identical changes as BLFT. Taken together, we revealed regulatory effects of oral treatment with commercially available capsules, containing BLFT. The results indicate that oral administration on BLFT-containing capsules may regulate some immune parameters in healthy individuals. In addition, the data suggest that bovine lactoferrin may be applied in clinic to improve the immune status of patients.     

Traumatic arteriovenous fistulas of the meningeal vessels. Remarks on 2 cases (author''s transl)

Serum levels of LSH, LH, estradiol, progesterone, and prolactin were measured daily for 2 months in six women after discontinuation of combination oral contraceptives. The initial LH peak occurred from 21 to 28 days after ingestion of the last tablet. Apart from variable prolongation of the follicular phase in the first postcontraceptive cycle, the patterns and levels of all hormones were indistinguishable from those found in normal ovulatory subjects. These results indicate that after a variable brief interval following discontinuation of oral contraceptive steroids, their suppressive effect on the hypothalamic-pituitary-ovarian axis disappears. This initial recovery results in completely normal endocrine function.     

Estradiol protects against ischemic injury

Clinical studies demonstrate that estrogen replacement therapy in postmenopausal women may enhance cognitive function and reduce neurodegeneration associated with Alzheimer's disease and stroke. This study assesses whether physiologic levels of estradiol prevent brain injury in an in vivo model of permanent focal ischemia. Sprague-Dawley rats were ovariectomized; they then were implanted, immediately or at the onset of ischemia, with capsules that produced physiologically low or physiologically high 17beta-estradiol levels in serum (10 or 60 pg/mL, respectively). One week after ovariectomy, ischemia was induced. Estradiol pretreatment significantly reduced overall infarct volume compared with oil-pretreated controls (mean+/-SD: oil = 241+/-88; low = 139+/-91; high = 132+/-88 mm3); this protective effect was regionally specific to the cortex, since no protection was observed in the striatum. Baseline and ischemic regional CBF did not differ between oil and estradiol pretreated rats, as measured by laser Doppler flowmetry. Acute estradiol treatment did not protect against ischemic injury. Our finding that estradiol pretreatment reduces injury demonstrates that physiologic levels of estradiol can protect against neurodegeneration.     

Treatment of osteopenia and osteoporosis after kidney transplantation

BACKGROUND: Osteopenia and osteoporosis are frequent complications after kidney transplantation. Data for the treatment of low bone mass after kidney transplantation are not available. METHODS: To test the efficacy of antiresorptive treatment, 46 patients with osteopenia or osteoporosis after kidney transplantation (bone mineral density < or =1.5 SD below normal) were randomly assigned to three groups cyclically treated as follows: group 1 with daily oral clodronate (800 mg) and group 2 with daily intranasal calcitonin (200 IU) for 2 weeks every 3 months. These two groups were compared with a control group (group 3). Every patient was supplemented with 500 mg of calcium per day. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at the lumbar spine and femoral neck before and after the 12-month treatment period. RESULTS: BMD at the lumbar spine was increased by 4.6% in the clodronate group (n=15, P=0.005), by 3.2% in the calcitonin group (n=16, P=0.034), and by 1.8% in the control group (n=15, P=0.265). However, the differences in BMD changes among the groups were not statistically significant. During therapy, serum calcium decreased slightly in all groups by 4.6%; however, parathyroid hormone values increased significantly in the treatment groups by 116%. Therapy was well tolerated without impact on graft function. CONCLUSIONS: Cyclical therapy with clodronate or calcitonin appears to induce a gain in BMD at the lumbar spine in patients with low bone mass after kidney transplantation. This treatment had no adverse impact on graft function but may aggravate preexisting secondary hyperparathyroidism.     

Development of an instrument for clinical evaluation after surgery for neuromuscular scoliosis

Surgical treatment for neuromuscular scoliosis is effective for most patients. Although those afflicted constitute a heterogeneous group, the aim of surgical treatment is approximately the same for all patients: a spine balanced in the coronal and sagittal planes over a level pelvis. Surgery results in a more stable and straighter spine, which should in turn improve performance in different activities. Previous evaluations of surgery for neuromuscular scoliosis reported in the literature have focused primarily on Cobb angles; there are very few studies dealing with the ability to perform various activities. A new tool for evaluation was developed in several steps, starting with a telephone interview with patients who had undergone surgery and a literature search. The evaluation instrument was then developed, followed by a pilot study and validation of new parts of the instrument. The instrument focuses on performance components and on activity performance. Eight items are evaluated before and after surgery. These data are complemented by a questionnaire administered to the patient or relatives at follow-up. The new parts of the instrument were developed specifically for patients with neuromuscular scoliosis, and the data obtained have been shown to have a high correlation with established measures of activities of daily living of daily living). They should therefore provide us with useful information concerning functional gains as a result of surgery as well as the effect of surgery on activity performance.     

Induction of progestin receptors by estradiol in the forebrain of estrogen receptor-alpha gene-disrupted mice

Mice, rats, and humans have two types of estrogen receptors, estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta). Estrogen receptor-alpha gene-disrupted (ERalpha-disrupted) mice bear two nonfunctional copies of the ERalpha gene. This mutation blocks the synthesis of full-length ERalpha, renders the animals infertile, and inhibits the induction of female sexual behaviors by estradiol and progesterone. It is likely that many of the processes contributing to the regulation of sexual receptivity by estradiol and progesterone are compromised in ERalpha-disrupted mice. However, given the importance of progesterone in the regulation of sexual receptivity and given the importance of progestin receptors (PRs) in mediating the responses of females to progesterone, we investigated the effects of ERalpha disruption on the induction of PRs by estradiol in the forebrain. We hypothesized that estradiol would induce PRs in wild-type mice but not in ERalpha-disrupted mice. Ovariectomized wild-type and ERalpha-disrupted mice were implanted with either estradiol-filled capsules or empty capsules for 5 d, after which their brains were processed for the immunocytochemical detection of PR. Estradiol increased the number of PR-immunoreactive cells in both wild-type and ERalpha-disrupted mice. The residual responsiveness of ERalpha-disrupted mice to estradiol could be accounted for by an ERbeta-dependent mechanism or another as yet unidentified estrogen receptor; however, because ERalpha-immunoreactivity and PCR product representing the 3' end of ERalpha mRNA were found in at least one PR-containing region of the ERalpha-disrupted mice, an ERalpha splice variant may also mediate the induction of PR-immunoreactivity in ERalpha-disrupted mice.     

Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up

This double-blind, placebo-controlled study was undertaken to determine 1) the efficacy of oral risedronate for prevention of bone loss in healthy, early postmenopausal patients with normal bone mass, 2) the effect on bone mass when treatment was stopped, and 3) the safety and tolerance of risedronate in this population. A group of 111 patients were randomized to oral placebo, risedronate 5 mg daily, or risedronate 5 mg cyclically, for 2 yr followed by 1 yr off treatment. Measurements included percentage change from baseline in lumbar spine bone mineral density (BMD) at 24 months; percentage change from baseline in BMD of the femoral neck, trochanteric region, and Ward's triangle region of the proximal femur; and changes in biochemical markers of bone turnover. After 2 yr, there was a mean increase in BMD of the lumbar spine of 1.4% from baseline and of 5.7% vs. placebo in the risedronate 5 mg daily group. There were decreases from baseline in BMD of 1.6% and 4.3% in the risedronate 5 mg cyclic and placebo groups, respectively. By the end of 24 months, trochanteric bone mass at the hip increased by 5.4% in the risedronate 5 mg daily group and by 3.3% in the risedronate 5 mg cyclic group vs. placebo. Bone mass was maintained at the femoral neck in the 2 active-treatment groups vs. a 2.4% mean loss with placebo. During the treatment-free follow-up, bone turnover increased toward baseline in both risedronate groups. By the end of that year, lumbar spine bone mass in all 3 groups was lower than at baseline. Oral risedronate was well tolerated. We conclude that risedronate (5 mg daily) increases bone mass and risedronate (5 mg cyclic) appears to prevent bone loss in early postmenopausal women with normal BMD.