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Biomedical subjects

B Wiita

Publications and source records attributed to B Wiita.

15 recordsLinked to original sources
PubMed2001

17alpha-methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture.

17alpha-methyl testosterone is a synthetic androgen with affinity for the androgen receptor. 17alpha-methyl testosterone is used widely as a component of hormone replacement therapy. Previous reports have indicated that contrary to testosterone, 17alpha-methyl testosterone is not aromatized. However, 17alpha-methyl testosterone still could affect local estrogen formation by regulating aromatase expression or by inhibiting aromatase action. Both possibilities have important clinical implications. To evaluate the effect of 17alpha-methyl testosterone on the expression and activity of aromatase, we tested the choriocarcinoma Jar cell line, a cell line that express high levels of P450 aromatase, and the macrophage-like THP-1 cells, which express aromatase only after undergoing differentiation. We found that in both cell lines, 17alpha-methyl testosterone inhibits aromatase activity in a dose-related manner. The curve of inhibition parallels that of letrozole and gives complete inhibition at 10(-4) M 17alpha-methyl testosterone, determined by the tritium release assay. 17alpha-methyl testosterone does not have detectable effects on aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells had no aromatase activity and showed no effect of 17alpha-methyl testosterone, but differentiated THP-1 (macrophage-like) cells had a similar inhibition of aromatase activity by 17alpha-methyl testosterone to that seen in Jar cells. The Lineweaver-Burke plot shows 17alpha-methyl testosterone to be a competitive aromatase inhibitor. Our results show for the first time that 17alpha-methyl testosterone acts as an aromatase inhibitor. These findings are relevant for understanding the effects of 17alpha-methyl testosterone as a component of hormone replacement therapy. 17alpha-methyl testosterone may, as a functional androgen and orally active steroidal inhibitor of endogenous estrogen production, also offer special possibilities for the prevention/treatment of hormone-sensitive cancers.

Aromatase↗
PubMed2000

Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey.

A cross-sectional survey was conducted to examine quality of life (QOL) related to physiological, somatic, and vasomotor effects of changing progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women. Eligible women (n = 176) were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1-6 months and had previously received HRT containing MPA. QOL was assessed via telephone interview using the Greene Climacteric Scale and the Women's Health Questionnaire. When compared with the MPA-containing regimen, women using micronized progesterone-containing HRT experienced significant improvement in vasomotor symptoms, somatic complaints, and anxiety and depressive symptoms. Women reported improved perceptions of their patterns of vaginal bleeding and control of menopausal symptoms while on the micronized progesterone-containing regimen. Approximately 80% of women reported overall satisfaction with the micronized progesterone-containing regimen. A micronized progesterone-containing HRT regimen offers the potential for improved QOL as measured by improvement of menopause-associated symptoms.

Administration, Oral↗
PubMed1999

Fluvoxamine treatment of social phobia (social anxiety disorder): a double-blind, placebo-controlled study.

OBJECTIVE: The purpose of this study was to determine the efficacy of fluvoxamine for the treatment of social phobia (social anxiety disorder). METHOD: In a 12-week multicenter, double-blind, randomized, placebo-controlled trial, 92 patients with social phobia were treated with the selective serotonin reuptake inhibitor fluvoxamine; 91.3% of the patients had the generalized subtype of the disorder. The primary criterion for response was a rating of "much improved" or "very much improved" on the Clinical Global Impression of Improvement scale. Secondary response criteria were changes on three specialized rating scales for social phobia symptoms: the Brief Social Phobia Scale, the Social Phobia Inventory, and the Liebowitz Social Anxiety Scale. Psychosocial impairment was assessed in three domains (disruption of work, social life, and home/family life) by using the Sheehan Disability Scale. RESULTS: The mean daily dose of fluvoxamine was 202 mg (SD = 86). At study end or with the last observation carried forward, within the evaluable subjects (N = 86) there was a significantly higher proportion of responders in the fluvoxamine group (42.9%, N = 18) than in the placebo group (22.7%, N = 10). Similarly, fluvoxamine was superior to placebo on all social phobia rating scales at week 8 and beyond. Fluvoxamine also resulted in significantly greater decreases in measures of psychosocial disability than did placebo. Overall, fluvoxamine was well tolerated and safe. CONCLUSIONS: These findings indicate that fluvoxamine is efficacious in the pharmacologic management of serious forms of social phobia.

Adolescent↗
PubMed1999

Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women.

OBJECTIVE: To investigate somatic symptom relief, gonadotropin secretion, and endogenous androgen bioavailability (protein-bound and free) during 3 months of estrogen-androgen therapy or matched estrogen-only replacement therapy. DESIGN: Ninety-three naturally menopausal outpatients with 6 or more months of amenorrhea, who were experiencing mild-to-moderate vasomotor symptoms, were randomized to receive one of five treatments: oral esterified estrogens (0.625 mg or 1.25 mg), oral esterified estrogens combined with methyltestosterone (0.625 mg combined with 1.25 mg methyltestosterone or esterified estrogens 1.25 mg combined with 2.5 mg methyltestosterone), or placebo for 12 weeks. All treatments were preceded by a 4-week placebo lead-in period. RESULTS: Patients receiving the lower dose of estrogen-androgen therapy had fewer somatic menopausal symptoms than patients receiving the lower dose estrogen (0.625 mg), and they experienced somatic symptom relief similar to those patients receiving the higher dose of estrogen (1.25 mg). Significantly greater luteinizing hormone suppression (p < or = 0.03) occurred in estrogen-androgen groups compared to estrogen groups, suggesting that added androgen might mediate a more pronounced negative feedback on the hypothalamic-pituitary axis. Sex hormone-binding globulin increased significantly in both estrogen-treated groups (p < or = 0.01), whereas decreases occurred in both estrogen-androgen groups (p < or = 0.006). The higher dose estrogen-only preparation significantly reduced androstenedione (p < or = 0.01) and dehydroepiandrosterone sulfate (p < or = 0.005). CONCLUSION: The extent of relief with lower dose estrogen-androgen therapy was similar to higher dose estrogen-only treatment. The greater efficacy of combination therapy on somatic symptoms could be mediated by the same mechanism responsible for the suppressive effects of estrogen-androgen therapy on luteinizing hormone secretion. The marked differences in circulating levels of sex hormone building globulin, which were increased by estrogen and decreased by estrogen-androgen, and the resulting impact on bioavailable androgens and estrogens could also explain the differential somatic relief with both treatments. Endogenous adrenal androgens were lower in women treated with esterified estrogens 1.25 mg/day, suggesting that estrogen therapy can produce a significant hypoandrogenic state by inhibiting production or accelerating clearance of adrenal androgens.

Administration, Oral↗
PubMed1999

A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.

OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in surgically menopausal women. STUDY DESIGN: A two-year, parallel-group, double-blind study of 311 women who were randomly assigned to one of four regimens: (1) CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, + methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, + methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone mineral density, side effects and safety. RESULTS: All treatments prevented loss of bone in the spine and hip. The higher E + A dose increased spine and hip BMD more than other treatments (P < .002). All treatments improved menopausal symptoms, with non-significantly greater improvements in well-being and sexual interest in the E + A groups. Similar and significant decreases in low-density lipoprotein were observed in all groups, but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups (P < .05). Hirsutism was uncommon and similar in all groups at two years. Discontinuation rates and reasons for withdrawal from the study were similar in both groups. No clinically significant side effects or laboratory test abnormalities were seen. CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and was well tolerated in surgically menopausal women.

Administration, Oral↗
PubMed1998

Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses.

OBJECTIVE: To investigate the efficacy of esterified estrogens alone and combined with oral androgen on sexual function and menopausal symptoms in postmenopausal women. STUDY DESIGN: Twenty postmenopausal women dissatisfied with their estrogen or estrogen-progestin therapy volunteered to enter a double-blind, randomized trial in which they received either oral esterified estrogens or esterified estrogens + androgen for eight weeks after a single-blind, placebo, lead-in period. Sexual function was assessed with a questionnaire used in the Yale midlife survey, and plasma levels of estradiol, estrone, sex hormone binding globulin (SHBG) and beta-endorphin were measured at two- to four-week intervals. RESULTS: Estrogen-androgen therapy significantly improved sexual sensation and desire after four and eight weeks of double-blind treatment in comparison to previous estrogen therapy and postplacebo baseline assessments. Plasma levels of estradiol and estrone increased significantly in all patients as compared to the postplacebo baseline and decreased in comparison to circulating estrogen concentrations on previous therapy. Relative proportions of free and bound steroid hormone exhibited contrasting shifts during estrogen and estrogen-androgen therapy. SHBG increased in the estrogen group and decreased in the estrogen-androgen group, leading to lower amounts of free androgens during estrogen therapy and increased free androgen levels during estrogen-androgen therapy. Since proportions of free (bioavailable) ovarian steroids would correlate inversely with plasma protein binding capacity, the beneficial effects of oral estrogen-androgen therapy on sexual sensation and desire may be due either to the administered androgen or to the increased availability of endogenous and exogenous androgens, particularly in the central nervous system. CONCLUSION: Sexual desire, satisfaction and frequency in postmenopausal women taking hormonal therapy were improved significantly by combined estrogen-androgen therapy but not by estrogen or estrogen-progestin therapy. Sexual function improved with estrogen-androgen therapy even though circulating estrogen levels were lower than those measured during previous estrogen therapy. This leads to the conclusion that androgens play a pivotal role in sexual function but that estrogens are not a significant factor determining levels of sexual drive and enjoyment.

Double-Blind Method↗
PubMed1997

Vasodilator effects of estrogen are not diminished by androgen in postmenopausal women.

OBJECTIVE: To compare the effects of estrogen with estrogen-androgen treatment on vaginal blood flow velocity and fingertip postocclusive hyperemic blood flow response. DESIGN: Prospective, randomized, parallel, double-blind study. SETTING: Healthy human volunteers in an academic research environment. PATIENT(S): Postmenopausal women receiving estrogen replacement therapy for at least 12 months and treated with placebo before this investigation. INTERVENTION(S): Esterified estrogens or esterified estrogen + methyltestosterone were administered orally; laser Doppler velocimetry was used to determine vaginal and fingertip blood flow responses at baseline and after 4 and 8 weeks of daily drug administration. MAIN OUTCOME MEASURE(S): Fingertip postocclusive area under curve (AUC); vaginal blood flow velocities. RESULT(S): The AUC for postocclusive fingertip blood flow and vaginal blood flow increased to a greater extent in the estrogen-androgen group, but changes were not statistically significant between groups. CONCLUSION(S): Estrogen-androgen treatment does not diminish the vasodilator effects of estrogen treatment in postmenopausal women.

Blood Flow Velocity↗
PubMed1997

A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis.

OBJECTIVES: The aim of this study was to compare the efficacy of mesalamine rectal suspension enema (Rowasa) alone, oral mesalamine tablets (Asacol) alone, and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis. METHODS: Sixty outpatients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm, inclusive, and a total disease activity index (DAI) score between 4 and 10, inclusive, were randomized to either mesalamine rectal enema (n = 18) once nightly, oral mesalamine 2.4 g/day (n = 22), or a combination of both treatments (n = 20). Placebo capsules and enemas were used to maintain a blind procedure. Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6, and wk 1 and 2, respectively. Patients recorded the amount of blood in stools, urgency, straining at stools, and abdominal pain in daily diaries. Physicians and patients rated overall improvement at each visit. RESULTS: At wk 6, combination therapy produced a greater improvement (-5.2) in total DAI scores than did either mesalamine enema (-4.4) or mesalamine tablet (-3.9) therapy alone; similar treatment differences were observed at wk 3. Compared with patients given mesalamine enemas or mesalamine tablets, combination-therapy patients reported an absence of blood in stools significantly sooner and, at all visits, the combination therapy group had the highest percentage of patients who reported no blood in their stools. Physicians' and patients' ratings of improvement indicated that combination therapy significantly improved disease status, compared with mesalamine tablet therapy alone. All treatments were well tolerated. CONCLUSIONS: The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone.

Administration, Oral↗
PubMed1996

Esterified estrogens with and without methyltestosterone decrease arterial LDL metabolism in cynomolgus monkeys.

Although both epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of coronary heart disease, the mechanisms for this beneficial effect are largely unknown. Furthermore, the addition of progestins or androgens to estrogen replacement therapy is of concern. The objective of this study was to examine the effects of esterified estrogens alone or in combination with an androgen on arterial LDL metabolism and early atherogenesis in ovariectomized female cynomolgus monkeys. Arterial LDL metabolism was assessed by using dual-labeled LDL that was injected 24 hours before necropsy. Arterial LDL degradation was reduced by 64% to 84% and cholesteryl ester content was decreased by approximately 50% in the thoracic aorta in both treatment groups compared with controls. In addition, aortic lipid peroxidation products, as assessed by thiobarbituric acid reaction, were significantly lower in animals treated with esterified estrogens, with a similar trend for combined estrogen-androgen treatment. Both treatments also reduced plasma concentrations of apoB-containing lipoproteins, reduced LDL particle size, and increased total-body LDL catabolism. The combination of decreased arterial LDL metabolism, decreased arterial lipid peroxidation, and improved plasma lipoprotein metabolism may explain some of the protective effects of estrogens on coronary heart disease and indicate that beneficial actions extend to a combination of estrogen and androgen.

Animals↗
PubMed1996

Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women.

The present study was undertaken to determine whether the addition of an androgen to estrogen therapy in postmenopausal women would alter the skeletal response as determined by measurements of markers of bone formation and resorption. Postmenopausal women were treated for 9 weeks with either a combination of 1.25 mg esterified estrogen and 2.5 mg methyltestosterone (E+A) or 1.25 mg conjugated equine estrogen (CEE). Both groups showed a similar decrease in urinary excretion of the bone resorption markers, deoxypyridinoline, pyridinoline, and hydroxyproline. Patients treated with CEE showed decreases in the serum markers of bone formation, bone-specific alkaline phosphatase, osteocalcin, and C-terminal procollagen peptide. In contrast, subjects treated with E+A showed increases in these markers of bone formation. CEE increased, and E+A decreased serum levels of sex hormone-binding globulin as well as triglycerides and high density lipoprotein levels. Only CEE significantly reduced low density lipoproteins. Both regimens were effective in reducing postmenopausal somatic symptoms, but only E+A had a significant effect on psychological symptoms. We conclude that short term administration of androgen with estrogen may reverse the inhibitory effects of estrogen on bone formation. Long term studies are needed to determine the relative benefits and risks of the combination of estrogen and androgen and whether this results in greater increases in bone mass and strength.

Aged↗
PubMed1995

Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause.

OBJECTIVE: To compare an oral estrogen-androgen combination with estrogens alone on bone, menopausal symptoms, and lipoprotein profiles in postmenopausal women. METHODS: Surgically menopausal women received oral esterified estrogens (1.25 mg), or esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) daily, for 2 years. Bone mineral density of the lumbar spine and hip, menopausal symptoms, lipoprotein profiles, and biochemical and hematologic indices were evaluated. RESULTS: Sixty-six patients were enrolled in the study. Both treatment regimens prevented bone loss at the spine and hip; combined estrogen-androgen therapy was associated with a significant increase in spinal bone mineral density compared with baseline (n = 24; mean score +/- standard error 3.4 +/- 1.2%, P < .01). In the estrogen group, high-density lipoprotein (HDL) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly. Cholesterol, HDL cholesterol, and triglycerides decreased significantly in the estrogen-androgen group. Menopausal symptoms of somatic origin (hot flashes, vaginal dryness, and insomnia) were improved significantly by both treatments. Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group. CONCLUSION: Oral estrogen-androgen increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms. Safety indices, including lipoprotein levels, indicated that the combination was well tolerated over the 2 years of treatment.

Administration, Oral↗
PubMed1995

Binding of 17-alpha-methyltestosterone in vitro to human sex hormone binding globulin and rat ventral prostate androgen receptors.

We measured the relative binding affinity (RBA) of 17-alpha-methyltestosterone (MET) for the rat prostate androgen receptor and human sex hormone-binding globulin (SHBG) in vitro. The reference compound in both instances was dihydrotestosterone (DHT), the RBA of which was set at 100%. The RBA of methyltestosterone was 44% for the androgen receptor, but 11% for SHBG. The androgen receptor, therefore, would appear to recognize a different part of an androgen compared to the recognition site on SHBG. The difference in RBAs may amplify the biologic action of methyltestosterone.

Animals↗
PubMedDate not supplied

Androgen and estrogen-androgen hormone replacement therapy: a review of the safety literature, 1941 to 1996.

The endocrine physiology of the climacteric supports a rationale for the concomitant replacement of androgen and estrogen following menopause. Clinical and research experience with estrogen-androgen hormone replacement therapy, as well as androgen-only therapy, suggests that the health benefit offered by androgen replacement exceeds the potential risk when treatment is properly managed. In this review, we concentrate on the effects of oral alkylated androgens. The virilizing effects (e.g., hirsutism, acne, voice change, and alopecia) of oral androgens are typically dose and duration dependent; androgen replacement at doses < or = 10 mg once daily administered for prolonged periods (> 6 months) produces masculinization effects that generally abate with dose reduction or discontinuation of treatment. No clinical sequelae or irreversible pathophysiologic effects have been associated with any virilization that may occur. Changes in lipoprotein metabolism associated with oral estrogen-androgen use include reduced total cholesterol levels and reduced high-density lipoprotein cholesterol levels which may reduce the long-term risk of cardiovascular disease. No clinically identifiable risk with respect to other cardiovascular variables, such as blood pressure, has been associated with the longterm administration of low doses of oral androgen. With regard to liver toxicity, reports of jaundice, peliosis hepatis, and hepatocellular carcinoma are extremely rare at the dose levels of androgen used in hormone replacement therapy, although individual sensitivity to the potential hepatotoxic effects of oral alkylated and nonalkylated androgen may vary considerably. Daily dosing with oral alkylated androgen in combination with estrogen is well tolerated. Retrospective and prospective studies involving the use of androgens alone and in combination with estrogens demonstrate that concerns about the adverse effects of androgen use associated with supraphysiologic, self-escalated doses in men do not apply to the much lower doses combined with estrogens for hormone replacement in postmenopausal women.

Androgens↗