Morris Notelovitz

Androgen effects on bone and muscle

Bone health and strength are dependent on the coupling of cone resorption and bone formation. This process is governed by the interaction of osteoclasts and osteoblasts plus the modulating influence of the bone mechanicosensory cells-the osteocytes. Both sex steroids-estrogen (E) and testosterone (T)- have receptors on all bone cells, with androgen dominance on osteoblasts and osteocytes. Specific receptors for the weaker androgens, such as DHEA have also been identified. The activity of the sex steroids, influenced by various enzymes found in bone, is reflective of the hormone ligand before its binding to the bone cells. As a result, T acts both directly and via its aromatization to estradiol. The activity of the androgens also varies with the bone surface; periosteal cells, for example, do not have 5alpha-reductase activity, indicating that T is the active metabolite at this clinically important site. Androgens influence bone cell function via local and systemic growth factors and cytokines. By enhancing osteoblast differentiation, androgens regulate bone matrix production, organization, and mineralization. Androgens also regulate osteoclast recruitment and activity. Endogenous androgens increase bone mineral density (BMD) in both adolescent and adult premenopausal women. Women with excess endogenous androgen-for example, those with hirsutism and polycystic ovary syndrome (PCOS)-have increased BMD compared with normal young women. E and androgen therapy increases BMD to a greater degree than does E therapy alone. This is true for both oral combinations of esterified E and methyltestosterone and for subcutaneous T implants. Androgenic progestins have an additive effect on BMD when combined with E therapy and have the further advantage of being protective to the endometrium in E-treated women. Androgens increase muscle mass and strength. The resulting improvement in physical activity leads to the activation of bone-forming sites and the stimulation of the bone formation-modulating cells, the osteocytes. Mechanical loading, when combined with hormone therapy, results in greater osteogenic response than does either alone.

The effects of postmenopausal hormone therapies on female sexual functioning: a review of double-blind, randomized controlled trials

Double-blind randomized controlled trials of estrogen and/or testosterone on sexual function among natural or surgical menopause in women are reviewed. Power, validity, hormone levels, and methodological issues were examined. Certain types of estrogen therapy were associated with increased frequency of sexual activity, enjoyment, desire, arousal, fantasies, satisfaction, vaginal lubrication, and feeling physically attractive, and reduced dyspareunia, vaginal dryness, and sexual problems. Certain types of testosterone therapy (combined with estrogen) were associated with higher frequency of sexual activity, satisfaction with that frequency of sexual activity, interest, enjoyment, desire, thoughts and fantasies, arousal, responsiveness, and pleasure. Whether specific serum hormone levels are related to sexual functioning and how these group effects apply to individual women are unclear. Other unknowns include long-term safety, optimal types, doses and routes of therapy, which women will be more likely to benefit from (or be put at risk), and the precise interplay between the two sex hormones.

Lp(a) lipoprotein: Relationship to cardiovascular disease risk factors, exercise, and estrogen†

Objective: Lp(a) lipoprotein is a distinct lipoprotein particle that recently has been found to be associated with cardiovascular disease. A study was conducted to assess the influence of cardiovascular disease risk factors on levels of Lp(a) and to evaluate the effects of age, exercise, and estrogen on these levels. Study Design: Two studies, a cross-sectional study of older men ( n = 105) and women ( n = 75) (mean age 76 years) and a prospective study of younger postmenopausal women (mean age 48 years), were carried out. Lp(a) and other lipoproteins were measured in the two studies and differences were sought by statistical analysis. Results: In the cross-sectional study, serum Lp(a) was similar in men and women and was not influenced by age. Lp(a) levels in men and women were higher when there was more than one cardiovascular disease risk factor present ( p p = 0.08). The decrease in Lp(a) with oral estrogen was associated with increases in triglycerides ( p p Conclusion: These data confirm that elevated Lp(a) levels are an independent risk factor for cardiovascular disease. Lp(a) levels are primarily influenced by genetic factors and it appears estrogen may have a minor influence on its hepatic synthesis.

Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of two vaginal doses of estradiol (E2) compared with placebo in the treatment of atrophic vaginitis. METHODS: In a multi-center, randomized, double-blind, parallel-group study, 230 postmenopausal women received treatment with 25 mcg or 10 mcg E2 or placebo for 12 weeks. Efficacy was measured through composite score of three vaginal symptoms and grading of vaginal health. Additional analyses included maturation of vaginal and urethral mucosa. Safety assessments included endometrial biopsy, adverse events, changes in laboratory tests, and physical examinations. After 12 weeks of treatment, all patients were switched to the open-label extension and received treatment with 25 mcg E2 up to week 52. RESULTS: Vaginal tablets with 25 mcg and 10 mcg E2 showed significant (P<.001) improvement in composite score of vaginal health. Other results with 10 mcg E2 were not entirely consistent with those for 25 mcg E2. Over 12 weeks, both active treatments resulted in greater decreases in vaginal pH than placebo. There were no significant differences between the 25 mcg and 10 mcg E2 groups in terms of improvements in maturation value or composite score of three vaginal symptoms. The efficacy was maintained to week 52 with 25 mcg E2. CONCLUSION: Vaginal tablets with 25 mcg and 10 mcg E2 provided relief of vaginal symptoms, improved urogenital atrophy, decreased vaginal pH, and increased maturation of the vaginal and urethral epithelium. Those improvements were greater with 25 mcg than with 10 mcg E2. Both doses were effective in the treatment of atrophic vaginitis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00465192 and NCT00464971 LEVEL OF EVIDENCE: I

Estrogen replacement therapy : indications, contraindications, and agent selection

Three groups of indications exist for postmenopausal estrogen use: relief of symptoms related to estrogen deficiency, osteoporosis prophylaxis and treatment, and cardioprotection. Estrogen replacement therapy enhances a womans sense of well-being and reduces the morbidity, mortality, and health care costs associated with osteoporosis and atherosclerotic heart disease. There are a few absolute contraindications to estrogen replacement therapy. Many estrogen preparations are currently available in the United States. Establishing equivalencies among the different preparations is complicated by the many physiologic and pharmacologic effects of estrogens and the variety of treatment end points used. Most estrogens have the same biologic effect provided equivalent blood levels are achieved. Estrogen replacement therapy has proved beneficial to selected postmenopausal women.

Osteoporosis: screening, prevention, and management *

OBJECTIVE To present clinical recommendations for osteoporosis prevention that include new support for routine bone mass screening of asymptomatic perimenopausal high-risk women. Technological advances make it conceivable that osteoporosis, a metabolic bone disorder rather than a true disease, can be prevented on a wide scale and eventually eliminated. Effective prevention requires that advanced screening procedures be easily accessible and reimbursable as a wise healthcare investment. STUDY SELECTION This article reviews research bearing on clinical management of women potentially at risk for osteopenia and osteoporosis. Background includes the pathogenesis of osteoporosis and known risk factors such as heredity, life-style, gynecological history, eating disorders, endocrinopathies, and scoliosis. Studies of bone mass measurement favor dual-energy roentgenographic absorptiometry as the bone densitometry method of choice for screening women at risk and for use with roentgenograms in evaluating bone health. The balance between bone formation and resorption can be assessed by a number of biochemical markers, which are reviewed. Other factors known to affect bone mass are discussed. CONCLUSIONS Primary care physicians, especially gynecologists, can play a pivotal role by [1] identifying women with higher risks for osteoporosis at earlier ages; [2] stressing the importance of developing maximal bone mass before menopause; and [3] developing individualized patient prescriptions for bone mass determinants under personal control: exercise, nutrition (e.g., calcium and vitamin D), life-style, and hormone replacement therapy.

Estrogen therapy in the management of problems associated with urogenital ageing: A simple diagnostic test and the effect of the route of hormone administration

Estrogen deficient women are prone to problems such as vaginal dryness, dyspareunia and a predilection to recurrent urinary tract infections and urinary incontinence. A preliminary double-blinded study in 67 symptomatic postmenopausal women confirmed: (1) that atrophic vaginitis is associated with an increase in the lateral wall vaginal pH; (2) this is paralleled by similar changes in pH in the urethra; (3) locally applied vaginal conjugated estrogen cream normalizes the pH in the vagina and urethra. Thus, the testing of the vaginal pH serves both as a surrogate for evaluating urethral pH and as a monitor of compliance with treatment.

Distribution of cytoplasmic estrogen and progesterone receptors in human endometrium

Unoccupied estrogen receptors and progesterone receptors were measured in the cytoplasm of five sections along the length of endometrium obtained from noncancerous, premenopausal hysterectomy specimens. The concentrations of the two receptors were measured with tritiated estradiol or R5020 (a synthetic progestin), the latter two having been purified by high-pressure liquid chromatography, and were found to be highest in the fundus and lowest in the cervix. Progesterone receptor levels, ranging from 50 to 3,500 fmoles of R5020 bound per milligram of protein, were generally much higher in each section of the endometrium than estrogen receptor levels, which ranged from 0 to 500 fmoles of estradiol bound per milligram of protein. Near ovulation it seemed that the distribution profiles of both receptors became very steep, with more than a tenfold difference in the receptor levels being found between the fundus and the cervix. Receptor levels measured in endometrial samples obtained by curettage or aspiration should be interpreted with caution.

The effect of low-dose oral contraceptives on cardiorespiratory function, coagulation, and lipids in exercising young women: A preliminary report

A study was undertaken to determine whether low-dose oral contraceptive usage would negate the beneficial effect of exercise on cardiorespiratory fitness, lipid and lipoprotein levels, and coagulation. Twelve exercising women were randomly allocated to groups of either oral contraceptive users or non-oral contraceptive users. When compared with results in the control group, maximal oxygen uptake (ml/kg1 X min1) decreased significantly in the oral contraceptive users during the 6-month period of observation. This was associated with an 8% decrease in both the oxygen uptake (2.34 to 2.17 L/min) and the oxygen pulse (12.1 +/- 3.2 to 11.2 +/- 2.2 ml/beat). The serum cholesterol, triglycerides, high-density lipoprotein/cholesterol, and high-density lipoprotein subfractions 2a and 2b levels were not altered. A significant increase in plasminogen activity was found in the oral contraceptive users: values increased from a coherent time average of 3.8 +/- 0.5 U/ml at baseline to 5.7 +/- 0.7 U/ml at 6 months; values returned to baseline levels 1 month after stopping the oral contraceptives (coherent time average of 3.9 +/- 0.6 U/ml; p less than 0.0001). No other significant changes were noted in the coagulation and anticoagulation factors studied. Low-dose oral contraceptive usage is associated with a decrease in functional aerobic capacity, but it does not impinge on the hemostatic mechanism or lipid-lipoprotein metabolism.

Thiazide diuretics and bone mineral content in postmenopausal women.

This retrospective study of 54 postmenopausal women taking thiazide diuretics found that bone mineral measurements and bone fracture prevalence did not differ significantly from those of matched control subjects. Matching on the variables of type of menopause (surgical/nonsurgical), years postmenopausal, duration of estrogen therapy (if any), daily intake of dietary and supplemental calcium and vitamin D, and Quetelet index was done without knowledge of the bone mineral measurements. Bone mass was recorded as the bone mineral content and bone density of the distal and midshaft radius. Only fractures associated with osteoporosis (hip, rib, vertebrae, and wrist) were recorded. This study suggests that thiazide diuretics do not provide protection against osteoporosis.