Effects of progestin-opposed transdermal estrogen administration on growth hormone and insulin-like growth factor-I in postmenopausal women of different ages.

Prior studies in women have shown a positive correlation of endogenous estrogen levels with spontaneous and stimulated GH secretion and basal insulin-like growth factor-I (IGF-I) levels. In postmenopausal women, estrogen replacement therapy (ERT) by the oral route increases basal and GHRH-stimulated GH secretion but decreases basal IGF-I levels. To assess the corresponding effects of transdermal ERT (tERT) on this axis, we administered four 8-week regimens of transdermal 17 beta-estradiol (Estraderm; 0, 50, 100, or 150 micrograms/day) combined with oral medroxyprogesterone acetate (10 mg each day) during weeks 3-4 and 7-8 of each 8-week regimen (except placebo) to 28 healthy nonobese postmenopausal women, aged 45.3-71.8 yr. Basal levels of estradiol (E2), GH, and IGF-I as well as GH responsivity to bolus iv administration of GH-releasing hormone-(1-44) (1 micrograms/kg), were measured before tERT and at weeks 6 and 8 of each regimen; estrone (E1) levels were measured before tERT and at week 6 of each regimen. Before tERT, age was inversely correlated with both the peak GH response to GHRH (r = -0.43; P less than 0.02) and basal IGF-I levels (r = -0.37; P less than 0.05), but not with basal E2, E1, or GH levels. There were progressive increases in plasma E2 and E1 levels with increasing doses of tERT (P = 0.0001), independent of age (P greater than 0.2) and body mass index (P greater than 0.2). Mean basal GH and IGF-I levels were not altered significantly by tERT or medroxyprogesterone acetate. Peak and integrated GH secretory responses to exogenous GHRH decreased with increasing tERT dose (P less than 0.01) in both younger and older postmenopausal women. Our findings suggest that the known effects of tERT on bone and other tissues are not mediated via increases in circulating levels of immunoreactive GH or IGF-I, but do not preclude the possibility of tERT-induced increases in the biological activity or paracrine action of IGF-I.

Effects of oral versus transdermal estrogen on the growth hormone/insulin-like growth factor I axis in younger and older postmenopausal women: a clinical research center study.

To compare the effects of oral vs. transdermal estrogens on GH secretion and levels of circulating insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in younger vs. older postmenopausal women, we conducted a placebo-controlled, cross-over trial of 6 weeks of oral conjugated estrogen (1.25 mg daily) or transdermal estradiol (100 micrograms/day) administered in random order and separated by an 8-week, treatment-free interval. Sixteen healthy postmenopausal women, ages 49-75 yr, were studied on an NIH-funded General Clinical Research Center grant. Data were analyzed for the combined group as well as in the younger ( 62 yr, n = 8). Spontaneous GH secretion, as assessed by 12-h overnight blood sampling at 20-min intervals; GH responsiveness to i.v. bolus injection of GHRH; and levels of serum IGF-I and IGFBP-3, before and after GHRH stimulation, were measured at enrollment and after 6 weeks of each estrogen treatment. Before estrogen treatment, spontaneous nocturnal GH secretion and morning IGF-I levels tended to be lower, IGFBP-3 levels did not differ, and GHRH-stimulated GH levels were significantly reduced in older vs. younger postmenopausal women. Oral estrogens increased spontaneous GH secretion, decreased serum IGF-I levels, and did not alter IGFBP-3 levels, whereas transdermal estrogens did not alter nocturnal GH secretion or morning IGF-I levels and decreased IGFBP-3 levels only in the older women. GHRH-stimulated GH levels were similar before and after oral or transdermal estrogen treatment. In contrast, after, GHRH administration, IGF-I levels were decreased only with oral estrogens, whereas IGFBP-3 levels were decreased with both oral (younger women only) and transdermal (younger and older women) estrogens. We conclude that, in postmenopausal women, oral and transdermal estrogens exert differing effects on the GH/IGF-I axis, but neither form of estrogen completely reverses the known age-related reductions in spontaneous or GHRH-stimulated GH and IGF-I.

Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men.

Aging is associated with reduced GH, IGF-I, and sex steroid axis activity and with increased abdominal fat. We employed a randomized, double-masked, placebo-controlled, noncross-over design to study the effects of 6 months of administration of GH alone (20 microg/kg BW), sex hormone alone (hormone replacement therapy in women, testosterone enanthate in men), or GH + sex hormone on total abdominal area, abdominal sc fat, and visceral fat in 110 healthy women (n = 46) and men (n = 64), 65-88 yr old (mean, 72 yr). GH administration increased IGF-I levels in women (P = 0.05) and men (P = 0.0001), with the increment in IGF-I levels being higher in men (P = 0.05). Sex steroid administration increased levels of estrogen and testosterone in women and men, respectively (P = 0.05). In women, neither GH, hormone replacement therapy, nor GH + hormone replacement therapy altered total abdominal area, sc fat, or visceral fat significantly. In contrast, in men, administration of GH and GH + testosterone enanthate decreased total abdominal area by 3.9% and 3.8%, respectively, within group and vs. placebo (P = 0.05). Within-group comparisons revealed that sc fat decreased by 10% (P = 0.01) after GH, and by 14% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, sc fat decreased by 14% (P = 0.05) after GH, by 7% (P = 0.05) after testosterone enanthate, and by 16% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, visceral fat did not decrease significantly after administration of GH, testosterone enanthate, or GH + testosterone enanthate. These data suggest that in healthy older individuals, GH and/or sex hormone administration elicits a sexually dimorphic response on sc abdominal fat. The generally proportionate reductions we observed in sc and visceral fat, after 6 months of GH administration in healthy aged men, contrast with the disproportionate reduction of visceral fat reported after a similar period of GH treatment of nonelderly GH deficient men and women. Whether longer term administration of GH or testosterone enanthate, alone or in combination, will reduce abdominal fat distribution-related cardiovascular risk in healthy older men remains to be elucidated.

Air-fluidized bed treatment of nursing home patients with pressure sores.

There are no large studies on long-term treatment of nursing home patients with pressure sores. A 4-year experience of treating 95 nursing home patients on air-fluidized beds was reviewed. Treated patients were elderly (median age 73 years) and neurologically impaired (79% with dementia, cerebral vascular accident, or anoxic encephalopathy). The index pressure sores (deepest truncal sore for each patient) were large (median surface area 35.3 cm2) and commonly located on the sacrum (41%) and trochanters (38%). Only 13 of 95 (14%) index sores healed completely, and only two small sores healed in less than 30 days. No others treated less than 30 days had greater than or equal to 50% reduction in sore surface area. Patients were grouped according to whether or not treatment was less than 30 days, and for those treated greater than or equal to 30 days, according to whether or not greater than or equal to 50% reduction in sore surface area occurred. None of the easily measured patient characteristics examined were associated with longer or more successful treatment. These results indicate that although air-fluidized beds can be used to treat pressure sores successfully, even in severely debilitated nursing home patients, no simple criteria can be used to predict which patients will benefit from this treatment. Because long periods of time are necessary for treatment [median trial length 79 days and 17 of 95 (18%) trials greater than 180 days], substantial patient-care expenditures result.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose tolerance in women: the effects of age, body composition, and sex hormones.

OBJECTIVE: To determine the separate and interactive effects of age, phase of the menstrual cycle, menopausal hormone status, body fat mass, and regional fat distribution on glucose tolerance in healthy women. DESIGN: Retrospective study. SETTING: The Baltimore Longitudinal Study of Aging. PATIENTS: Two hundred sixty healthy women aged 22-89 years. MEASUREMENTS: Plasma levels of estradiol and progesterone, body mass index (BMI), waist-to-hip ratio (WHR), and plasma glucose values in the fasting state (FPG) as well as 120 minutes after 40 gm/m2 of oral glucose (G120) were measured for each participant. RESULTS: We found a progressive decline in oral glucose tolerance of 0.4 mM (6.7 mg/dL)/decade at G120) in women from early to late adult years, with no relationship to phase of the menstrual cycle and no abrupt change associated with the menopause. Multiple regression analysis revealed significant, independent effects of BMI and WHR on FPG and G120. The influence of age (P less than 0.01) on G120 was stronger than that of the BMI or WHR (P less than 0.05). There was no significant relationship between the levels of endogenous sex hormones and glucose tolerance after adjustments for age, BMI, and WHR. However, women taking oral contraceptives, but not those receiving postmenopausal replacement therapy, did exhibit mildly elevated G120 values. CONCLUSIONS: Age per se, and to a lesser extent BMI and WHR, but not levels of endogenous sex steroids, contribute to the physiological decline in glucose tolerance in older women.

Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men.

Age-related reductions in growth hormone (GH) and insulin-like growth factor-I (IGF-I) may contribute to decreased muscle mass and strength in older persons. The relationship of this phenomenon to skeletal muscle bioenergetics has not been reported. We sought to determine whether administration of GH-releasing hormone (GHRH) would sustain increases in GH and IGF-I and improve skeletal muscle function and selected measures of body composition and metabolism. We measured GH secretion, muscle strength, muscle histology, and muscle energy metabolism by phosphorus nuclear magnetic resonance spectroscopy (31P-NMRS), body composition, and endocrine-metabolic functions before and after 6 weeks of treatment. Eleven healthy, ambulatory, non-obese men aged 64 to 76 years with low baseline IGF-I levels were treated at home as outpatients by nightly subcutaneous self-injections of 2 mg GHRH for 6 weeks. We measured GH levels in blood samples obtained every 20 minutes from 8:00 PM to 8:00 AM; AM serum levels of IGF-I, IGF binding protein-3 (IGFBP-3), and GH binding protein (GHBP); muscle strength; muscle histology; the normalized phosphocreatine abundance, PCr/[PCr + Pi], and intracellular pH in forearm muscle by NMRS during both sustained and ramped exercise; body composition by dual-energy x-ray absorptiometry (DEXA); lipid levels; and glucose, insulin, and GH levels during an oral glucose tolerance test (OGTT). GHRH treatment increased mean nocturnal GH release (P < .02), the area under the GH peak ([AUPGH] P < .006), and GH peak amplitude (P < .05), with no change in GH pulse frequency or in levels of IGF-I, IGFBP-3, or GHBP Two of six measures of muscle strength, upright row (P < .02) and shoulder press (P < .04), and a test of muscle endurance, abdominal crunch (P < .03), improved. GHRH treatment did not alter exercise-mediated changes in PCr/[PCr + Pi] or intracellular pH, but decreased or abolished significant relationships between changes in PCr/[PCr + Pi] or pH and indices of muscle strength. GHRH treatment did not change weight, body mass index, waist to hip ratio, DEXA measures of muscle and fat, muscle histology, glucose, insulin, or GH responses to OGTT, or lipids. No significant adverse effects were observed. These data suggest that single nightly doses of GHRH are less effective than multiple daily doses of GHRH in eliciting GH- and/or IGF-I-mediated effects. GHRH treatment may increase muscle strength, and it alters baseline relationships between muscle strength and muscle bioenergetics in a manner consistent with a reduced need for anaerobic metabolism during exercise. Thus, an optimized regimen of GHRH administration might attenuate some of the effects of aging on skeletal muscle function in older persons.

Interrelationships of spontaneous growth hormone axis activity, body fat, and serum lipids in healthy elderly women and men.

Aging is associated with decreased growth hormone (GH) secretion and plasma insulin-like growth factor-I (IGF-I) levels, increased total and abdominal fat, total and low-density lipoprotein (LDL) cholesterol, and triglycerides, and reduced high-density lipoprotein (HDL) cholesterol. Similar changes in lipids and body composition occur in nonelderly GH-deficient adults and are reversed with GH administration. To examine whether GH/IGF-I axis function in the elderly is related to the lipid profile independently of body fat, we evaluated GH secretion, serum IGF-I and IGF binding protein-3 (IGFBP-3) levels, adiposity via the body mass index (BMI), waist to hip ratio (WHR), dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI), and circulating lipids in 101 healthy subjects older than 65 years. Integrated nocturnal GH secretion (log IAUPGH) was inversely related (P < .005) to DEXA total and abdominal fat and MRI visceral fat in both genders. Log IAUPGH was inversely related to visceral fat in women (P < .005) and men (P < .0001), but was not significantly related to total fat in either gender. In women, log IAUPGH was related inversely to total and LDL cholesterol and positively to HDL cholesterol (P < .008). In men, log IAUPGH was inversely related to total cholesterol and triglycerides (P < .005). In women, HDL cholesterol was inversely related to the WHR (P < .005). In men, triglycerides were positively related (P < .001) to the WHR and DEXA abdominal and MRI visceral fat. Multivariate regression revealed log IAUPGH, but not DEXA total body fat, to be an independent determinant of total (P < .001 for women and P = .01 for men) and LDL (P < .007 and P = .05) cholesterol in both sexes and of HDL cholesterol (P < .005) and triglycerides (P < .03) in women. Log IAUPGH, but not DEXA abdominal fat, was related to total (P < .005 and P < .03) and LDL (P < .03 and P = .05) cholesterol in both genders and to HDL in women (P < .05). Log IAUPGH, but not MRI visceral fat, was related to total cholesterol (P < .03 and P = .05) in women and men. Age, IGF-I, and IGFBP-3 were not significantly related to any body fat or lipid measures, except for a positive correlation of IGF-I with triglycerides in men. Thus, endogenous nocturnal GH secretion predicts total, LDL, and HDL cholesterol levels independently of total or abdominal fat, suggesting that it is an independent cardiometabolic risk factor in healthy elderly people.

Osteoporosis: diagnostic screening and its place in current care.

Osteoporosis, or decreased total bone mass, results from a number of factors: accelerated trabecular bone loss in postmenopausal women; age-related loss of trabecular and cortical bone; and multiple chronic diseases and medications. Routine laboratory and radiographic tests are not helpful in assessing bone turnover. However, a ratio of urinary calcium to creatinine exceeding 0.16 on a spot urine sample obtained in the fasted state suggests high bone turnover. Both single and dual photon absorptiometry are useful research tools but are unproved screening tests, especially in light of the more frequent use of preventive measures, such as postmenopausal hormone replacement therapy, calcium supplementation, and weight-bearing exercise.

Osteoporosis prevention and treatment.

Bone fragility resulting from osteoporosis places a significant percentage of elderly women and other patient groups at risk for bone fracture. Risk factors for osteoporosis include hypogonadal states (particularly menopause), smoking, low calcium intake, lack of weight-bearing exercise, family history and use of certain medications. Preventive strategies are based on achieving and maintaining optimal bone mass through diet, exercise, appropriate use of hormone replacement therapy and avoidance of adverse influences, particularly smoking and certain medications. Laboratory investigations are of limited use in the detection and assessment of osteoporosis, but new techniques may help physicians identify patients with accelerated bone metabolism. Currently, the most precise method of radiologically assessing osteoporosis is dual-energy x-ray absorptiometry. Many new agents for the treatment of osteoporosis are being examined. First-line therapies currently include alendronate and calcitonin. The choice of therapy must be individualized and combined with advice about nutrition and exercise, both to optimize bone density and to minimize the risk of trauma.

Transdermal estradiol with oral progestin: biological and clinical effects in younger and older postmenopausal women.

The purpose of this study was to compare the biochemical and clinical effects of transdermal estrogen replacement therapy (tERT) in younger and older postmenopausal women. We treated 15 younger (less than 60 y) and 13 older (greater than or equal to 60 y) healthy postmenopausal women (45-72 y) with four successive 8-week regimens of tERT at doses of 0 to 150 micrograms/day, combined with cyclic oral medroxyprogesterone acetate (MPA). In both age groups, there were similar (p = .0001) dose-responsive increases in plasma estrogen levels and decreases in LH and FSH levels, although LH values were lower in older women both before and after tERT (p less than .02). The addition of MPA further suppressed LH and, to a lesser extent, FSH in both younger and older women. The ratio of estrogenized to nonestrogenized vaginal cells increased with tERT (p less than .007) in both age groups, but significant symptomatic improvement of vaginal irritation was noted only at the highest tERT dose. Adverse effects unrelated to age included short-term nausea in 4/28 women, and skin irritation at the patch sites in 20/28 women. Vaginal bleeding was of shorter duration, but breast tenderness was more common in older women. Further studies of long-term tERT effects in elderly women are indicated.

Cortisol and GH secretory dynamics, and their interrelationships, in healthy aged women and men.

We studied 130 healthy aged women (n = 57) and men (n = 73), age 65-88 yr, with age-related reductions in insulin-like growth factor I and gonadal steroid levels to assess the interrelationships between cortisol and growth hormone (GH) secretion and whether these relationships differ by sex. Blood was sampled every 20 min from 8:00 PM to 8:00 AM; cortisol was measured by RIA and GH by immunoradiometric assay, followed by deconvolution analyses of hormone secretory parameters and assessment of approximate entropy (ApEn) and cross-ApEn. Cortisol mass/burst, cortisol production rate, and mean and integrated serum cortisol concentrations (P < 0.0005), and overnight basal GH secretion (P < 0.05), were elevated in women vs. men. Integrated cortisol concentrations were directly related to most measures of GH secretion in women (P < 0.01) and with mean and integrated GH concentrations in men (P < 0.05). Integrated GH concentrations were directly related to mean and integrated cortisol levels in women (P < 0.005) and men (P < 0.05), with no sex differences. There were no sex differences in cortisol or GH ApEn values; however, the cross-ApEn score was greater in women (P < 0.05), indicating reduced GH-cortisol pattern synchrony in aged women vs. men. There were no significant relationships of integrated cortisol secretion with GH ApEn, or vice versa, in either sex. Thus postmenopausal women appear to maintain elevated cortisol production in patterns that are relatively uncoupled from those of GH, whereas mean hormone outputs remain correlated.